Review

Expert Opin. Ther. Patents Downloaded from informahealthcare.com by Dalhousie University on 05/29/14 For personal use only.

Epidermal growth factor receptor inhibitors: a patent review (2010 -- present) 1.

Introduction

2.

Discussion of selected patents and articles

3.

Conclusion

4.

Expert opinion

Si-Ning Li & Huan-Qiu Li† Soochow University, College of Pharmaceutical Science, Suzhou, PR China

Introduction: The signaling pathways downstream of epidermal growth factor receptor (EGFR) are central to the biology of colorectal cancer. EGFR kinase represents an attractive target for the development of novel therapies for the treatment of cancers. A considerable achievement during the past 2 years was the development of targeted therapies against EGFR using small-molecule inhibitors such as quinazoline derivatives, pyrimidine derivatives, thiazole derivatives, acrylamide derivatives and urea derivatives. Some new methods and technologies were also used to discover novel reversible and irreversible EGFR inhibitors. In this review, recent advances in the research of EGFR inhibitors are reviewed. Areas covered: This review summarized new patents and articles published on EGFR inhibitors within 2010 to present. Expert opinion: From 2010 to present, some novel scaffolds have been discovered as first-generation EGFR inhibitors, which are more potent against both EGFR-activating (EGFR WT) and resistance mutations (EGFRDM, T790M/ L858R). ‘Fast-Forwarding Hit to Lead’ and ‘Combi-Molecule’ postulate to represent a novel approach to cancer therapy. The focus on irreversible inhibitors is also of significance for the design of kinase inhibitors. Searching nature for novel scaffolds is a promising way to find new chemical tools with which we can better understand the development of drug resistance to current targeted therapy and study ways to bypass and overcome such drug resistance. Keywords: EGFR inhibitors, irreversible inhibitors, new scaffolds, resistance mutation, reversible inhibitors Expert Opin. Ther. Patents (2014) 24(3):309-321

1.

Introduction

The field of chemotherapy is currently undergoing a paradigm shift from classical cytotoxic chemotherapy toward targeted therapy in order to kill tumor cells more efficiently with fewer side effects on normal tissue. The altered protein expression and activity of receptor tyrosine kinases (TKs) are implicated in the progression of various types of cancers [1]. Receptor TKs act to transmit signals from the outside of a cell to the inside by activating secondary messaging effectors via a phosphorylation event. A variety of cellular processes is promoted by these signals, including proliferation, carbohydrate utilization, protein synthesis, angiogenesis, cell growth and cell survival. Among the growth factor receptor kinases that have been identified as being important in cancer is epidermal growth factor receptor (EGFR) kinase [2]. The EGFR family plays an essential role in normal organ development by mediating morphogenesis and differentiation through effects on cell proliferation, differentiation, apoptosis, invasion and angiogenesis [3,4]. Unlike normal cells that have tight regulatory mechanisms controlling EGFR pathways, tumor cells often have dysregulated EGFR signaling, allowing them to proliferate under adverse conditions, invade surrounding tissues and increase angiogenesis. Normally, EGFR 10.1517/13543776.2014.871527 © 2014 Informa UK, Ltd. ISSN 1354-3776, e-ISSN 1744-7674 All rights reserved: reproduction in whole or in part not permitted

309

S.-N. Li & H.-Q. Li

Article highlights. .

.

.

Expert Opin. Ther. Patents Downloaded from informahealthcare.com by Dalhousie University on 05/29/14 For personal use only.

. .

EGFR kinase represents an attractive target for the development of novel therapies for the treatment of cancers. A comprehensive summary of new developments in the field of EGFR inhibitors through discussion of patent and article literature from 2010 to present is reported. These inhibitors can be categorized into different molecular classes according to their structures such as quinazoline derivatives, pyrimidine derivatives, thiazole derivatives, acrylamide derivatives and urea derivatives. New methods and technologies have also been taken to discover novel EGFR inhibitors in the past 2 years. Novel natural product EGFR inhibitors can serve as lead compounds for derivatization and drug development.

This box summarizes key points contained in the article.

prevents reversible inhibitors from binding at cellular high ATP concentrations, can be overcome by second-generation irreversible EGFR inhibitors able to covalently alkylate a specific cysteine residue (Cys797 in EGFR) [14-16]. Several inhibitors of this class, such as CI-1033 [17], BIBW2992 [18] and HKI-272 [19,20], have progressed to clinical investigation in patients that initially responded to 1 and subsequently relapsed (Figure 1). Therefore, the EGFR kinase represents an attractive target for the development of novel therapies for the treatment of cancers. In this review, about 15 patent publications about EGFR inhibitors on the period of 2010 to present are summarized. Meanwhile, about 30 published articles about EGFR inhibitors have been also reviewed. Readers can get a feel on the organizations, which are categorized according to chemical structures of these compounds. 2.

must be activated by a ligand to initiate downstream signaling, but tumor cells can circumvent this requirement through a number of mechanisms. EGFR is a transmembrane receptor TK that belongs to the human epidermal receptor (HER) family of receptors [5]. Two decades ago, a model for colorectal carcinogenesis was proposed, in which the stepwise histological changes (small adenomatous polyp formation, larger dysplastic polyps, invasive carcinoma) were associated with specific mutations in oncogenes and tumor suppressor genes [6,7]. Genetic alterations in carcinogenesis include disruption of WNT signaling, activation of KRAS, mutation of TP53 and others. In the past years, a number of prognostic and predictive markers have been identified that are helpful for designing individualized treatment strategies aiming to optimize the efficacy of chemotherapy on the tumor and minimize side effects. Among the biomarkers indicative of tumor response to standard chemotherapy (thymidylate synthase, microsatellite instability, ERCC1), molecular markers for EGFR-targeted treatment have been described. To date, the FDA has approved > 15 small-molecule kinase inhibitors for targeted cancer therapy and dozens are currently in clinical trials. Out of these inhibitors, gefitinib (ZD 1839) [8], erlotinib (CP 358774) [9] and lapatinib (GW572016) [10] belong to a class of 4-anilinoquinazolines, which have been designed to selectively inhibit EGF-stimulated signal transduction by reversibly binding at the ATP site of EGFR (Figure 1). Despite the clear clinical benefits of gefitinib and erotinib, their efficacy is eventually diminished because of acquired point mutations in the kinase domain of EGFR as well as the upregulation of bypass signaling pathways [11-13]. Secondary mutation of a single amino acid in the catalytic domain of EGFR, that is, conversion of gatekeeper threonine 790 to methionine (T790M), is the most common mechanism of acquired resistance to reversible tyrosine kinase inhibitors (TKIs). The increased ATP affinity showed by T790M mutants with respect to the L858R mutant of EGFR, which 310

Discussion of selected patents and articles

Quinazoline derivatives Among the EGFR TKIs, the 4-anilinoquinazolines play a key role and has been extensively studied in the past few years; the most representative compounds are gefitinib, erlotinib and lapatinib [17-19]. These TKIs generally designed to selectively inhibit EGF-stimulated signal transduction showed high potency in vitro, inhibiting EGFR at nanomolar concentration. It was concluded that the quinazoline core was the best scaffold for the development of EGFR inhibitors because any alteration of the nitrogen substitution pattern in the bicyclic ring resulted in less active compounds. From 2010 to present, many gefitinib, erlotinib and lapatinib analogs were reported in published patents and articles, and the focal points of the chemical space of these new irreversible and reversible inhibitors were centered on the 4-anilino headgroup moiety, 6, 7-substituents and the bioisosteres of quinazoline ring, which have led to the development and the marketing of new series of antitumor agents [21]. 2.1

Gefitinib analogs as reversible and irreversible inhibitors

2.1.1

In 2010, by incorporating both the 6- and 7-methoxy groups into rings of various size (dioxolane, dioxane and dioxepine rings) on the quinazoline scaffold, Adriana et al. prepared a number of dioxolane, dioxane and dioxepine quinazoline derivatives [22]. The IC50 value of dioxane quinazoline derivative 1 was about 6 times lower than that determined for PD153035 (Figure 2). The molecular docking results showed that compound 1 was able to interact with the ion through the oxygen at the 6 position of the crystal structure of inactive EGFR form (PDB ID: 2GS7). Several patents about 6, 7-substituents quinazoline derivatives of EGFR inhibitors were also published from 2010 to present [23-26]. Scientists from Boehringer Ingelheim International Gmbh developed a novel quinazoline dimaleate derivative, 9-[4-(3-chloro-2-fluoro-phenylamino)-

Expert Opin. Ther. Patents (2014) 24(3)

Epidermal growth factor receptor inhibitors

O

SO2Me HN O O

F

NH

NH O

O

Cl

N

N N O

N

Lapatinib

Erlotinib

F F

Expert Opin. Ther. Patents Downloaded from informahealthcare.com by Dalhousie University on 05/29/14 For personal use only.

O N

Cl

HN HN

HN

O

CN

N O

O

Cl N

N O

BIBW2992

N

Gefitinb

O

F O N

O

O NH

HN HN

Cl

HN N

CN N

O

N

Cl

HN

O

N

O

CI-1033

HKI-272

Figure 1. Chemical structures of reversible and irreversible EGFR tyrosine kinase inhibitors.

7-methoxyquinazoline-6-yloxy]-1,4-diazaspiro[5.5]undecan5-one dimaleate (2), and displayed very potent EGFR-WT inhibitory activity with IC50 value of 4 nM [23]. ICCAS prepared 2-(4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)ethyl)ethane-1,2-diamine (3) with IC50 value of 4.6 nM (Figure 2) [24]. Many second-generation 4-anilinoquinazolines were also developed from 2010 to present [27-33]. These compounds carrying a Michael acceptor group at the 6 position, such as an acrylamide or propargylamide fragment, that irreversibly alkylates a cysteine residue (Cys797) close to the ATP-binding site of EGFR has been shown to overcome resistance [34-37]. Scientists from Chemical Genomics Centre of the Max Planck Society have published a series of 6- and 7-substituted 4-anilinoquinolines as potent irreversible inhibitors of clinically relevant mutant variants of EGFR [27,28]. N-(4-(3-Bromophenylamino) quinoline-6-yl)acrylamide 4 inhibited the enzymatic activities of wild-type and mutated EGFRs, with IC50 values in subnanomolar ranges (EGFR-WT: 1 nM, T790M: 3.2 nM) (Figure 2). From introducing different cysteine-trapping fragments at position+ 6 of a traditional 4-anilinoquinazoline scaffold, Caterina et al. synthesized a new irreversible inhibitor N-(4(3-bromoanilino)quinazolin-6-yl)-3-(piperidin-1-ylmethyl)

oxirane-2-carboxamide (5); this compound inhibited EGFR auto-phosphorylation and downstream signaling pathways, suppressed proliferation and induced apoptosis in gefitinibresistant non-small-cell lung cancer (NSCLC) H1975 cells, harboring the T790M mutation in EGFR [29]. Caterina et al. also synthesized a new series of 3-aminopropanamide-4-anilinoquinazolines as irreversible EGFR inhibitors in 2012, and the 3-aminopropanamide 6 (Figure 2) suppressed proliferation of gefitinib-resistant H1975 cells, harboring the T790M mutation in EGFR, at significantly lower concentrations than did gefitinib [30]. Moreover, 6 did not show covalent binding to cell-free EGFR-TK in a fluorescence assay, while it underwent selective activation in the intracellular environment, releasing an acrylamide derivative which can react with thiol groups of EGFR. Our groups also reported several series of 6-amino-substituted group or 6-acrylamide-substituted group linked to a 4-anilinoquinazoline nucleus as potential EGFR inhibitors. Molecular docking of the most potent inhibitor 7 into ATP-binding site of EGFR kinase was performed. Compound 7 is nicely bound to the region of EGFR with binding interaction energy of -37.83 kJ mol-1. The quinazoline ring of compound 7 is inserted nicely inside the pocket,

Expert Opin. Ther. Patents (2014) 24(3)

311

S.-N. Li & H.-Q. Li

HN O

HN

Br

O

N

(CH2)2 O

O

HN NH

N

N

H3CO

1

Cl F

N

2 F HN HN

Expert Opin. Ther. Patents Downloaded from informahealthcare.com by Dalhousie University on 05/29/14 For personal use only.

H2 N

O

NH

Cl

NH

N

O

N

N

H3CO

Br

4

3

HN HN

O

Br

N

Br

NH

NH

N

O

O

N

N

5

6

HN N Br

NH

S

Cl N

O

N

7

Figure 2. Chemical structures of gefitinib analogues 1 -- 7.

HN

Me

O N O

8

HN NH

N

F

N

O

N

9

N

HN O

O

O

O

N

10

HCl

N

Figure 3. Chemical structures of Erlotinib analogs 8 -- 10.

and the nitrogen atom of amine group of 7 forms hydrogen bond with Cys797, which made the combination ability of 7 acting on EGFR. Their structures are showed in Figure 2 [32,33]. 312

Erlotinib analogs In 2010, Caterina et al. synthesized a series of 6-substituted 4-anilinoquinolineserlotinib analogs (8) as potent type I inhibitors of clinically relevant mutant variants of 2.1.2

Expert Opin. Ther. Patents (2014) 24(3)

Epidermal growth factor receptor inhibitors

enzymatic activity, and compound 13 potently inhibited EGF-stimulated EGFR phosphorylation in Cal27 cells (IC50 < 32 nM). That is a nice example of combining two distinct pharmacologically properties in one molecule.

F O H2NO2S

NH

HN O

Cl N

N

11

F

HO HO

HN

F N

12 Expert Opin. Ther. Patents Downloaded from informahealthcare.com by Dalhousie University on 05/29/14 For personal use only.

Cl N

O

O HO

NH HN O

O

Cl N

13

N HO

NH O O PXD101

S

NH O

Figure 4. Chemical structures of lapatinib analogs 11 -- 13.

EGFR [27], which inhibited both the wild and mutant EGFR kinase (EGFR-WT: 1 nM, T790M: 140 nM) and also showed antiproliferative activity in EGFR-dependent Ba/F3 cells and NSCLC cell lines (Figure 3). Scientists from Hutchison Medipharma Enterprises Ltd. published several patents about quinazoline-1,6-diamine erlotinib analogs as EGFR inhibitors in 2010. 3-(4-(3-ethynylphenylamino)quinazolin-6-yl)-1-(3-fluorobenzyl)-1-methylurea (9) displayed very potent EGFR inhibitory activity with IC50 value of 1 nM [38,39]. Scientists from Zhejiang Beta Pharma, Inc. provided the 4-[(3-ethynylphenyl)amino]-6,7-benzo-12-crown4-quinazoline hydrochloride (10) in 2010 and exhibited the EGFR inhibition of 97% [40]. Lapatinib analogs Scientists from Qilu Pharmaceutical Co., Ltd. synthesized a series of 4-anilinoquinolines lapatinib analogs as novel HER2/EGFR dual kinase inhibitors in 2011, and discovered a representative clinical candidate 11 [41], which showed significant in vivo antitumor efficacy based on HER2/EGFR inhibitory activities (EGFR: 2.7 nM, HER2: 1.5 nM). Another patent in 2013 from Hangzhou Minsheng Pharmaceutical Co., Ltd. discovered HER2/EGFR dual kinase inhibitor 12 [42], and this compound showed excellent inhibitory activity (better than lapatinib) against human A549 lung cancer cells (Figure 4). By combining the structural features of lapatinib with an (E)-3-(aryl)-N-hydroxyacrylamide motif known from some HDAC inhibitors (PXD101), Beckers et al. reported a new series lapatinib hybrid analogs as EGFR, HER2 and HDAC inhibitors [43]. These prototypic analog 13 showed selective and potent inhibition of EGFR/HER2 as well as HDAC 2.1.3

Pyrimidine derivatives Although some new quinazoline derivatives containing a Michael acceptor functional group have been developed as irreversible EGFR inhibitors to overcome the T790M mutation-related resistance, except for a few examples, such as BIBW2992 and PF00299804, these irreversible inhibitors have thus far shown limited clinical efficacy. Inherent weaknesses, including relatively high toxicity and a decreased binding velocity to the mutant kinase, may be responsible for the lack of clinical efficacy [44-46]. Thus, the generation-reversible EGFR inhibitors that can inhibit the drug-resistant T790Mbearing mutants were also developed recently. It is highly desirable to identify EGFR inhibitors with new scaffolds that can inhibit the drug-resistant T790M-bearing mutants and remain potent in other activating mutants. Most recently, Zhou et al. reported a novel series of substituted pyrimidines as irreversible EGFR inhibitors displaying good selectivity against EGFRT790M mutants over the wildtype kinase [47,48]. One of the most active and selective inhibitors, WZ4002 (14), potently inhibited the proliferation of the cancer cells or Ba/F3 cells harboring L858R (IC50 = 5.37 nM), and T790M-mutated EGFR (IC50 = 1.88 nM), which represented a new, promising strategy to overcome the acquired resistance for NSCLC patients (Figure 5). Based on the structural design of WZ4002, Guangzhou Institute of Biomedicine and Health reported a series of 2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidinyl derivatives, and the most active compound 15 [49,50] inhibited the enzymatic activities of wild-type and mutated EGFRs, with IC50 values in subnanomolar ranges (L858R: 0.38 nM, T790M: 0.93 nM). These two series of novel pyrimidines also displayed promising in vivo efficacy in gefitinib-resistant NSCLC models. To develop novel HER2/EGFR dual kinase inhibitors, in 2011, Tomoyasu et al. designed pyrrolo-[3,2-d]pyrimidine derivatives capable of fitting into the receptors’ ATP-binding site of EGFR, and discovered a representative clinical candidate 16 (TAK-285) [51], which showed significant in vivo antitumor efficacy based on HER2/EGFR inhibitory activities (EGFR: 23 nM, HER2: 17 nM). X-ray co-crystal structures of TAK-285 with both HER2 and EGFR confirmed that the pyrrolo[3,2-d]pyrimidine scaffold fits into the ATP pocket and that the N-1 nitrogen interacts with Met801 of HER2 or Met793 of EGFR. Compound 16 (TAK-285) is currently in Phase I clinical trials. Based on the TAK-285 studies, in 2012, Ishikawa developed another pyrrolo-[3,2-d]pyrimidine candidate 17 [52], and compound 4 showed both potent HER2/EGFR inhibitory activities (IC50, 0.98/2.5 nM), as well as breast cancer cell BT-474 GI (GI50, 2.0 nM) activity (Figure 5). 2.2

O

Expert Opin. Ther. Patents (2014) 24(3)

313

S.-N. Li & H.-Q. Li

N

N

N

Cl HN N

HN

O

N

N

Bn

O

O

O NH NH N

N

O

O N

N

15

Expert Opin. Ther. Patents Downloaded from informahealthcare.com by Dalhousie University on 05/29/14 For personal use only.

14 N N

N NH OH

N

HN

F

F

F

N

N

Cl

NH

H2N

O

HN

Cl

O

16 TAK-285

17

O

O

S N

N

N HN

N

N

N

N

NH

NH N H

N

HN

N

N

N

18

19 N

Figure 5. Chemical structures of pyrimidines 14 -- 19.

Using a virtual screening against an in-house focused library containing approximately 650,000 known kinase inhibitors and kinase inhibitor-like compounds containing common kinase inhibitor core scaffolds, Yang et al. found a hit compound, N2-(4-(4-methylpiperazin-1-yl)phenyl)-N8-phenyl-9H-purine-2,8-diamine (18) (Figure 5), which is a reversible kinase inhibitor targeting both EGFR-activating and drug-resistance (T790M) mutations but has poor binding affinity (EGFR L858R: 0.098 µM, EGFR T790M: 0.978 µM) [53]. After the structural optimization of compound 18, they developed a 9-cyclopentyl-N2-(4-(4-methylpiperazin1-yl)phenyl)-N8-phenyl-9H-purine-2,8-diamine (19) that exhibits significant in vitro antitumor potency against the NSCLC cell lines HCC827 and H1975, which harbor EGFR-activating and drug-resistance mutations, respectively (EGFR-WT: 4 nM, L858R/T790M: 16 nM) with good pharmacokinetic properties. 314

Similarly, on the basis of structural biology observations and docking studies of hit compounds 20 and 21 (EGFRWT: 223 nM and 2.6 µM), the researchers in NHRI of Taiwan developed new phenylfuro[2,3-d] pyrimidines 22 and 23 by introduction of acrylamide Michael acceptor group from 20 and 21 (Figure 6), respectively [54,55], which inhibited both the wild and mutant EGFR kinase (EGFR-WT: 7 nM and 8 nM, L858R/T790M: 28 and 100 nM) and also showed antiproliferative activity in HCC827 lung cancer cell line. Starting with a previously reported pyrimidine-based EGFR inhibitor 24, a novel pteridin-7(8H)-one scaffold with a high three-dimensional similarity was found and transformed into irreversible inhibitors of the EGFR T790M mutant by Zhou et al. [56]. The most potent compound 25 exhibited excellent enzyme inhibitory activities, with subnanomolar IC50 values for both the wild-type and T790M/ L858R double-mutant EGFRs, as well as potent cellular

Expert Opin. Ther. Patents (2014) 24(3)

Epidermal growth factor receptor inhibitors

O

OH

OH NH HN HN N N O

N

O

20 EGFR WT = 223 nM

N

22 EGFR WT = 7 nM EGFR DM = 28 nM OH

Expert Opin. Ther. Patents Downloaded from informahealthcare.com by Dalhousie University on 05/29/14 For personal use only.

HN

N

N S

HN

O

N

N

S

21 EGFR WT = 2.6 µM

N

N HN

N

23 EGFR WT = 8 nM EGFR DM = 100 nM N

N

NH

HN

N

N

O O

O

O

24 EGFR WT = 7.7 µM

NH N

25 EGFR WT = 1.21 nM EGFR DM = 0.67 nM

N H

Figure 6. Chemical structures of compounds 20 -- 25.

antiproliferative activities against both gefitinib-sensitive and -resistant cancer cell lines. Thus, library construction, in situ screening and structurebased drug design may provide a tool to identify compounds with the same scaffold but displaying distinct biological target/activities. Thiazole derivatives Thiazole-type compounds have attracted considerable attention to anticancer research [57,58], and several attempts were made for modifying the thiazole nucleus to improve their antitumor activities. Benzothiazoles act via competing with ATP for binding at the catalytic domain of EGFR [59]. Replacing quinazoline ring with benzothiazole since both are isosteric with adenine portion of ATP and can mimic the ATP-competitive binding regions of EGFR TK, Malleshappa et al. presented a new subfamily of compounds containing 2-anilino benzothiazole core as EGFR inhibitors [60]. The most potent compound was 7-chloro-N-(2,6-dichlorophenyl) benzo[d]thiazol-2-amine (26) with GI50 values of 7.18  10-8 M against non-small cell HOP-92 lung cancer cell line (Figure 7). These docking studies 2.3

have revealed that the benzothiazole ring binds to a narrow hydrophobic pocket in the N-terminal domain of EGFR TK where N- of the benzothiazole ring interacts with the backbone NH of Met-793 via a hydrogen bond. The aniline moiety at C-2 of benzothiazole lies in a deep and hydrophobic pocket similar to the 3¢-chloro-4¢-(3-fluorobenzyl)oxy moiety of lapatinib. Lv et al. synthesized two series of thiazolidinone derivatives as dual EGFR and HER-2 kinase inhibitors [61]. Compound 2-(2-(5-bromo-2-hydroxybenzylidene)hydrazinyl)thiazol-4 (5H)-one (27) displayed the most potent inhibitory activity (IC50 = 0.09 µM for EGFR, IC50 = 0.42 µM for HER-2). This compound is nicely bound to the EGFR kinase with its N–H group and owns high antiproliferative activity against MCF-7. Urea derivatives The urea derivatives such as N-nitrosoureas, benzoylureas and thioureas represent one of the generally most useful classes of anticancer agents, with a wide range of activities against various leukemias and solid tumors [62-64]. Due to the vital role 2.4

Expert Opin. Ther. Patents (2014) 24(3)

315

S.-N. Li & H.-Q. Li

Cl O

N

OH N

NH S Cl

N NH

Cl

26

Br

S

27

Expert Opin. Ther. Patents Downloaded from informahealthcare.com by Dalhousie University on 05/29/14 For personal use only.

Figure 7. Chemical structures of thiazole derivatives 26 and 27.

that EGFR signaling plays in tumor angiogenesis, many urea derivatives that have the ability to interrupt EGFR signaling by targeting EGFR or its ligands (VEGFs) have been prepared for the development of anti-angiogenesis--based agents such as thienopyrimidine ureas, 3-aminoindazole ureas and Nhydroxy ureas [65-67]. Our group reported two series of N-benzyl-N-(X-2-hydroxybenzyl)-N¢-phenylureas and thioureas as dual inhibitors of EGFR and HER-2 in 2010, and thiourea 28 (Figure 8) demonstrated potent EGFR and HER-2 inhibitory activity (IC50 = 0.08 µM for EGFR and IC50 = 0.35 µM for HER-2) [68]. Pyrazole derivatives containing thiourea skeleton as EGFR inhibitors were also discovered by Lv et al., and the most potent compound 29 is nicely bound to the EGFR kinase with its N--H group project toward the side-chain carbonyl group of D831 (Asp831), forming a more optimal H-bond  interaction (distance: 1.94 A˚, angle: 127.1 ). Based on the significant EGFR inhibitory activity of pyrazole derivatives containing thiourea skeleton, it can be concluded that this H-bond plays an important effect in the EGFR inhibitory (IC50 = 0.07 µM) [69]. Acrylamide derivatives The acrylamide moiety is a warhead group for covalently binding to a key cysteine residue in the binding domain of at least one mutation of EGFR selectively as compared to EGFR-WT and other protein kinases [70,71]. Thus, arylamide derivatives are supposed to have the same pharmacophore as 4-arylaminoquinazoline, and have been studied as EGFR inhibitors. Scientists from Avila Therapeutics, Inc. developed a novel series of mutant-selective EGFR inhibitors based on the acrylamide moiety, especially compound N-(3-(2-(4-(isopropylamino)-2-methoxyphenylamino)-5-(trifluoromethyl) pyrimidin-4-ylamino)phenyl)acrylamide 30 (Figure 9), and they exhibited significant in vitro antitumor potency against the NSCLC cell lines HCC827 and H1975, which harbor EGFR-activating and drug-resistance mutations, respectively (EGFR-WT: 10 nM, L858R/T790M: 1 nM) [72,73]. The salicylanilide molecule may construct an intramolecular hydrogen bond and form a pseudo six-membered ring. Thus, via selecting the scaffold of N-aryl salicylamide to incorporate the pharmacophore of HDAC inhibitor, Zuo et al. developed a series of N-aryl salicylamides with a hydroxamic acid moiety at 5 position as HDAC--EGFR dual inhibitors. N-(3-Ethynylphenyl)-2-hydroxy-5-(7-hydroxyamino-7-oxoheptyloxy) 2.5

316

benzamide 31 exhibited distinct inhibitory activity against EGFR and HDACs (EGFR: 0.9 µM, HDAC: 1.2 µM) and potent antiproliferative activities in vitro, especially against A431. By combining two distinct pharmacophores into one molecule, HDAC--EGFR dual inhibitors were postulated to represent a novel approach to cancer therapy [74]. Lee et al. used the hit scaffold of 4-(5-aryl-3-(trifluoromethyl)-1H-pyrazol-1-yl)aniline to generate an array of derivatives, identified N-methyl-3-(1-(4-(piperazin-1-yl) phenyl)-5-(40-(trifluoromethyl)-[1,10-biphenyl]-4-yl)-1Hpyrazol-3-yl)propanamide (32) (Figure 9) as a novel EGFR inhibitor, which exhibited high in vitro potency against a panel of prostate and breast cancer cell lines (IC50, 1 -- 2.5 µM), while normal epithelial cells were unaffected. Compound 32 also suppressed the expression of the transcription/translation factor YB-1 and its targets HER2 and EGFR in PC-3 cells [75]. Abou-Seri discovered 2,4¢-(bis-substituted) diphenylamine derivatives as a novel class of EGFR inhibitors, and Compound N-ethyl-5-{2-[4-(5-(ethylamino)-1,3,4-thiadiazol2-yl)-phenylamino]phenyl}-1,3,4-thiadiazol-2-amine 33 was the most active enzyme inhibitor (98% inhibition at 10 µM) and exploited potent antitumor activity with IC50 values of 0.73 µM [76]. Phthalocyanine-peptide conjugates Phthalocyanines (Pcs) are promising cancer diagnostic and treatment agents because of their low dark toxicity, high photostability and ability for preferential accumulation within tumor tissue. Pcs are promising cancer diagnostic and treatment agents. Ongarora et al. designed four Pc-peptide conjugates to target the EGFR. Because of the hydrophobic nature of the Pc macrocycle, a low--molecular-weight PEG linker and a polar or charged peptide ligand are required for adequate aqueous solubility and receptor targeting ability [77]. The studies show that Pc-peptide conjugate 34 (Figure 10) can be used for near-IR fluorescence imaging of cancers overexpressing EGFR, such as CRC. 2.6

3.

Conclusion

In summary, the main patent applications and articles surrounding therapeutic applications of novel small-molecule EGFR inhibitors as antibacterial agents in 2010 -- present have been described in the review. They can be categorized into different molecular classes according to their structures such as quinazoline derivatives, pyrimidine derivatives, thiazole derivatives, acrylamide derivatives and urea derivatives. Some new methods and technologies were also taken to discover novel reversible and irreversible EGFR inhibitors. 4.

Expert opinion

EGFR belongs to the ErbB family of receptor TKs that plays indispensable roles in cell proliferation, survival, adhesion,

Expert Opin. Ther. Patents (2014) 24(3)

Epidermal growth factor receptor inhibitors

OH H

S

Cl

N

H3CO

NH

OCH3

H3CO

28

OH

29

Expert Opin. Ther. Patents Downloaded from informahealthcare.com by Dalhousie University on 05/29/14 For personal use only.

Figure 8. Chemical structures of urea derivatives 28 and 29.

O HN

O HN F 3C

HN

HO

O NH

NH

O

6

N OH NH

N

30

31

O CF3

O NH

O

N

H3CHN

N

N N

32

NH O

N

33 NH

Figure 9. Chemical structures of acrylamide derivatives 30 -- 33.

O

O N N N

N

N

O

NH

O

NH

O

O

Zn N N

LARLLT

O O

N

34

Figure 10. Phthalocyanine-peptide conjugates 34. Expert Opin. Ther. Patents (2014) 24(3)

317

Expert Opin. Ther. Patents Downloaded from informahealthcare.com by Dalhousie University on 05/29/14 For personal use only.

S.-N. Li & H.-Q. Li

migration and differentiation [4]. To date, a number of TKIs have been employed in the treatment of cancer, and several are in various stages of clinical development, demonstrating the importance of TKs as prime targets for novel antitumor agents. The majority of TKIs developed thus far target the ATP-binding site, which is highly conserved across the human protein kinases. ATP-competitive inhibitors typically consist of a heterocyclic ring system that occupies the purine binding site, where it serves as a scaffold for side chains that occupy adjacent hydrophobic regions [78]. The first generation of EGFR-targeting therapeutic agents includes the reversible EGFR inhibitors gefitinib and erlotinib, approved for the treatment of NSCLC, and the dual EGFR/ HER2 reversible inhibitor lapatinib (Tykerb), approved for the treatment of HER2-positive breast cancer [9]. Although these drugs have been extremely effective in patient populations with tumor containing mutated oncogenic forms of TKs (e.g., L858R of EGFR), their usefulness has been diminished by the significant number of nonresponding patients and by the emergence of resistance during treatment [79,80]. Thus, new scaffolds have been discovered as EGFR inhibitors. For example, some new pyrimidine derivatives as Phase I EGFR inhibitors were reported in the past 2 years such as compounds 15 -- 17, and these new inhibitors displayed significant anticancer efficacy in NSCLC cell lines HCC827 and H1975, representing a new, promising lead compound with a different chemical scaffold for further development of EGFR inhibitors to overcome EGFRT790M mutation-induced clinical resistance to gefitinib and erotinib. New methods and technologies have also been taken to discover novel EGFR inhibitors in the past 2 years. For example, ‘Fast-Forwarding Hit to Lead’ is a very useful strategy. Compounds 17, 19, 20 and 29 are nice leading compounds for the strategy. Scientists performed a virtual screening against an in-house focused library containing many known kinase inhibitors and kinase inhibitor-like compounds containing common kinase inhibitor core scaffolds, leading to the identification of some interesting hit compounds. On the basis of structural biology observations and docking studies, we can optimize the structures of hit compounds and derive compounds with higher potency that can inhibit the drug-resistant T790Mbearing mutants while remaining potent in the presence of the activating mutations. On the other hand, many advances have also been reported in the development of irreversible EGFR inhibitors in the past 2 years. The focus on irreversible inhibitors is of significance for the design of kinase inhibitors. Not only could it enhance their affinity toward EGFR, but also extend the role of affecting time. Some research showed superior in vivo activity in animal tumor models in comparison with related reversible inhibitors, particularly by oral dosing regimens [81]. Structure activity and molecular modeling studies have shown that positioning of the acrylamide at the 6 position is optimal for rapid irreversible inhibition (appropriate positioning of the Michael

318

acceptor with respect to the cysteine SH). As shown in this review, compounds 4, 5, 7 19 and 20 shared the similar structure of ‘Michael acceptor’ at the 6 or 7 position on the scaffolds, which is an acrylamide skeleton and capable of undergoing a conjugate addition reaction with thiol groups presenting in cysteine residues, for example, compound 4, based on the 4-anilinoquinazoline core structure, that has a Michael acceptor at the 6 position. These compounds are believed to function in this manner by forming a covalent bond to a Cys residue (Cys 773 in EGFR and Cys 805 in HER-2) located in the ATP-binding pocket of these enzymes. Thus, the irreversible inhibitors with ‘Michael receptor’ skeleton have covered a high proportion of anti-EGFR agents under clinical development. By combining two distinct pharmacological properties in one molecule, we can also postulate to represent a novel approach to cancer therapy. For example, by combining the structural features of lapatinib with an (E)-3-(aryl)-N-hydroxyacrylamide motif known from some HDAC inhibitors (PXD101), a new series lapatinib hybrid analogs as EGFR, HER2 and HDAC inhibitors were discovered; via selecting the scaffold of N-aryl salicylamide to incorporate the pharmacophore of HDAC inhibitor vorinostat, a novel series of N-aryl salicylamides with a hydroxamic acid moiety at 5 position were synthesized efficiently as novel HDAC--EGFR dual inhibitors [43,72-74]. Efforts in the past few years have shown that mutations in the signaling pathways downstream of EGFR frequently occur in colorectal cancer and confer resistance to EGFR-directed therapies. It is possible to target mutated downstream signaling molecules with small-molecule inhibitors, but tumor cells develop resistance to these inhibitors by activating alternative feedback loops and other mechanisms. As pointed out by a survey of the National Cancer Institute, USA, the majority of cancer drugs established in oncology are natural products, derivatives of natural products or drugs mimicking the mode of action of a natural product [82]. Thus, searching for nature for novel scaffolds is a promising way to find new chemical tools, with which we can better understand the development of drug resistance to current targeted therapy and study ways to bypass and overcome such drug resistance. Furthermore, novel natural product EGFR inhibitors can serve as lead compounds for derivatization and drug development.

Declaration of interest The work was supported by PAPD (A Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions), National Natural Science Foundation of China (No: 81102316) and Foundation from State Key Laboratory of Natural Medicines (No: SKLNMKF201319).

Expert Opin. Ther. Patents (2014) 24(3)

Epidermal growth factor receptor inhibitors

Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

Expert Opin. Ther. Patents Downloaded from informahealthcare.com by Dalhousie University on 05/29/14 For personal use only.

2.

Yarden Y, Sliwknowski MX. Untangling the ErbB signaling network. Nat Rev Mol Cell Biol 2001;2:127-37

Fry DW, Kraker AJ, McMichael A, et al. A specific inhibitor of the epidermal growth factor receptor tyrosine kinase. Science 1994;265:1093-5

4.

Ward WHJ, Cook PN, Slater AM, et al. Epidermal growth factor receptor tyrosine kinase. Investigation of catalytic mechanism, structure-based searching and discovery of a potent inhibitor. Biochem Pharmacol 1994;48:659-66 Bridges AJ, Zhou H, Cody DR, et al. Tyrosine kinase inhibitors. 8. An unusually steep structure activity relationship for analogues of 4-(3-bromoanilino)-6,7-dimethoxyquinazoline (PD 153035), a potent inhibitor of the epidermal growth factor receptor. J Med Chem 1996;39:267-76

6.

Vogelstein B, Fearon ER, Hamilton SR, et al. Genetic alterations during colorectal-tumor development. N Engl J Med 1988;319(9):525-32

7.

Vivanco I, Mellinghoff IK. Epidermal growth factor receptor inhibitors in oncology. Curr Opin Oncol 2010;22(6):573-8

8.

Iwata K, Miller PE, Barbacci EG, et al. CP-358, 774: a selective EGFR kinase inhibitor with potent antiproliferative activity against HN5 head and neck tumor cells [abstract 4248]. Proc Am Assoc Cancer Res 1997;38:633-4

9.

10.

12.

Hynes NE, Lane HA. ErbB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 2005;5:341-54

3.

5.

11.

Pao W, Miller VA, Politi KA, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2005;2:1-11

13.

Carmi C, Lodola A, Rivara S. Epidermalgrowth factor receptor irreversible inhibitors: chemical exploration of the cysteine-trap portion. Mini Rev Med Chem 2011;11:1019-30

14.

Zhou W, Ercan D, Chen L, et al. Novel mutant-selective EGFR kinase inhibitors against EGFR T790M. Nature 2009;462:1070-4

15.

Garuti L, Roberti M, Bottegoni G. Irreversible protein kinase inhibitors. Curr Med Chem 2011;18:2981-94

16.

Yun CH, Mengwasser KE, Toms AV, et al. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci USA 2008;105:2070-5

17.

Smaill JB, Rewcastle GW, Loo JA, et al. Tyrosine kinase inhibitors: 17. Irreversible inhibitors of the epidermal growth factor receptor: 4-(phenylamino) quinazoline and 4-(phenylamino)pyrido [3,2-d]pyrimidine-6-acrylamides bearing additional solubilizing functions. J Med Chem 2000;43:1380-97

4-anilinoquinazoline. Curr Med Chem 2012;19:871-92 22.

Adriana C, Maria TC, Giovanni M, et al. Exploring epidermal growth factor receptor (EGFR) inhibitor features: the role of fused dioxygenated rings on the quinazoline scaffold. J Med Chem 2010;53:1862-6

23.

Boehringer Ingelheim International Gmbh. Preparation of 9-[4-(3-chloro-2-fluorophenylamino)-7-methoxyquinazoline-6yloxy]-1,4-diazaspiro[5.5]undecan-5-one dimaleate as EGFR inhibitors. WO104206; 2012

24.

ICCAS. Quinazoline derivatives as EGFR inhibitors and their preparation, pharmaceutical compositions and use in the treatment of cancer. CN102452988; 2012

25.

Boehringer Ingelheim International Gmbh. Proce´de´ de synthe`se ste´re´ose´lective de 9-hydroxy-5-oxo1,4-diaza-spiro [5.5] unde´canes qui sont 1,4-prote´ge´s. WO117568; 2013

26.

Curis, Inc. Quinazoline based EGFR inhibitors. US8349856; 2013

27.

Vijaykumar G, Pawar ML, Sos HB, et al. Synthesis and biological evaluation of 4-anilinoquinolines as potent inhibitors of epidermal growth factor receptor. J Med Chem 2010;53:2892-901

28.

Michalczyk A, Klu¨ter S, Rode HB, et al. Structural insights into how irreversible inhibitors can overcome drug resistance in EGFR. Bioorg Med Chem 2008;16:3482-8

18.

Li D, Ambrogio L, Shimamura T, et al. BIBW2992, an irreversible EGFR/ HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 2008;27:4702-11

29.

Caterina C, Andrea C, Stefano V, et al. Novel irreversible epidermal growth factor receptor inhibitors by chemical modulation of the cysteine-trap portion. J Med Chem 2010;53:2038-50

19.

Tsou HR, Overbeek-Klumpers EG, Hallett WA, et al. Optimization of 6,7disubstituted-4-(arylamino)quinoline-3carbonitriles as orally active, irreversible inhibitors of human epidermal growth factor receptor-2 kinase activity. J Med Chem 2005;48:1107-31

30.

Caterina C, Elena G, Federica V, et al. Irreversible inhibition of epidermal growth factor receptor activity by 3aminopropanamides J Med Chem. 2012;55:2251-64

31.

Bikker JA, Brooijmans N, Wissner A, et al. Kinase domain mutations in cancer: implications for small molecule drug design strategies. J Med Chem 2009;52:1493-509

32.

Li HQ, Li DD, Lu X, et al. Design and synthesis of 4,6-substituted(diaphenylamino)quinazolines as potent EGFR inhibitors with antitumor activity. Bioorg Med Chem 2012;20:317-23

Woodburn JR, Barker AJ, Gibson KH, et al. ZD1839, an epidermal growth factor tyrosine kinase inhibitor selected for clinical development [abstract 4251]. Proc Am Assoc Cancer Res 1997;38:633-4 Wood ER, Truesdale AT, McDonald OB, et al. A unique structure for epidermal growth factor receptor bound to GW572016 (lapatinib): relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells. Cancer Res 2004;64:6652-9

Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 2005;352:786-92

20.

21.

Engelman JA, Zejnullahu F, Gale CM, et al. PF00299804, an irreversible Pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib. Cancer Res 2007;67:11924-92 Li DD, Hou YP, Wang W, et al. Exploration of chemical space based on

Expert Opin. Ther. Patents (2014) 24(3)

319

S.-N. Li & H.-Q. Li

Expert Opin. Ther. Patents Downloaded from informahealthcare.com by Dalhousie University on 05/29/14 For personal use only.

33.

Xu YY, Li SN, Yu GJ, et al. Discovery of novel 4-anilinoquinazoline derivatives as potent inhibitors of epidermal growth factor receptor with antitumor activity. Bioorg Med Chem 2013;21:6084-91

34.

Ban SH, Usui T, Nabeyama W, et al. Discovery of boron-conjugated 4anilinoquinazoline as a prolonged inhibitor of EGFR tyrosine kinase. Org Biomol Chem 2009;7:4415-27

35.

Potashman MH, Duggan ME. Covalent modifiers: an orthogonal approach to drug design. J Med Chem 2009;2:1231-46

36.

37.

38.

39.

40.

41.

42.

43.

320

Yun CH, Mengwasser KE, Toms AV, et al. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci USA 2008;05:2070-5 Blair JA, Rauh D, Kung C, et al. Structure-guided development of affinity probes for tyrosine kinases using chemical genetics. Nat Chem Biol 2007;3:229-38 Hutchison Medipharma Enterprises Ltd. Preparation of quinazoline derivatives as inhibitors of epidermal growth factor receptors for treating tumor. CN101619043; 2010 Hutchison Medipharma Enterprises Ltd. Quinazoline-1,6-diamine derivatives as EGFR inhibitors and their preparation, pharmaceutical compositions and use in the treatment of cancer. WO002845; 2010 Zhejiang Beta Pharma, Inc. Icotinib hydrochloride as EGFR inhibitors and its preparation, crystallographic forms, pharmaceutical compositions and use in the treatment of cancers. WO003313; 2010 Qilu Pharmaceutical Co. Ltd. 4-(substituted anilino)quinazoline derivatives as tyrosine kinase inhibitors. WO030540; 2011 Hangzhou Minsheng Pharmaceutical Co. Ltd. Preparation of quinazoline derivatives as EGFR inhibitors for treating cancer. WO017073; 2013 Siavosh M, Andreas S, Matthias W, et al. Novel chimeric histone deacetylase inhibitors: a series of lapatinib hybrides as potent inhibitors of epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2

.

(HER2), and histone deacetylase activity. J Med Chem 2010;53:8546-55 That is a nice example of combining two distinct pharmacologically properties in one molecule.

44.

Sos ML, Rode HB, Heynck S, et al. Chemogenomic profiling provides insights into the limited activity of irreversible EGFR Inhibitors in tumor cells expressing the T790M EGFR resistance mutation. Cancer Res 2010;70:868-74

45.

Kim Y, Ko J, Cui Z, et al. The EGFR T790M mutation in acquired resistance to an irreversible second-generation EGFR inhibitor. Mol Cancer Ther 2012;11:784-91

46.

Ercan D, Zejnullahu K, Yonesaka K, et al. Amplification of EGFR T790M causes resistance to an irreversible EGFR inhibitor. Oncogene 2010;29:2346-56

47.

Zhou W, Ercan D, Chen L, et al. Novel mutant-selective EGFR kinase inhibitors against EGFR T790M. Nature 2009;462:1070-4

48.

Zhou W, Ercan D, Janne P, et al. Discovery of selective irreversible inhibitors for EGFRT790M. Bioorg Med Chem Lett 2011;21:638-43

49.

50.

..

51.

52.

Chang SH, Zhang LW, Xu SL, et al. Design, synthesis, and biological evaluation of novel conformationally constrained inhibitors targeting epidermal growth factor receptor threonine790 Methionine790 Mutant. J Med Chem 2012;55:2711-23 Guangzhou Institute Of Biomedicine And Health. Pyrimidopyrimidone derivatives as EGFR inhibitors and their preparation, pharmaceutical compositions and use in the treatment of cancers. WO167415; 2012 Novel scaffold have been discovered as first generation EGFR inhibitors which are more potent against both EGFRactivating (EGFR WT) and resistance mutations(EGFRDM, T790M/L858R). Tomoyasu I, Masaki S, Hiroshi B, et al. Design and synthesis of novel human epidermal growth factor receptor 2 (HER2)/epidermal growth factor receptor (EGFR) dual inhibitors bearing a pyrrolo [3,2-d]pyrimidine scaffold. J Med Chem 2011;54:8030-50 Youichi K, Hiroshi B, Tomohiro O, et al. Design and synthesis of pyrrolo [3,2-d]pyrimidine human epidermal growth factor receptor 2 (HER2)/ Expert Opin. Ther. Patents (2014) 24(3)

epidermal growth factor receptor (EGFR) dual inhibitors: exploration of novel back-pocket binders. J Med Chem 2012;55:3975-91 53.

Yang J, Wang LJ, Liu JJ, et al. Structural optimization and structure-activity relationships of N2-(4-(4-Methylpiperazin1-yl)phenyl)-N8-phenyl-9H-purine2,8-diamine derivatives, a new class of reversible kinase inhibitors targeting both EGFR-activating and resistance mutations. J Med Chem 2012;55:10685-99

54.

Coumar MS, Chu CY, Lin CW, et al. Fast-forwarding hit to lead: aurora and epidermal growth factor receptor kinase inhibitor lead identification. J Med Chem 2010;53:4980-8 ‘Fast-Forwarding Hit to Lead’ is a very useful strategy for new EGFR inhibitors discovery.

..

55.

Wu CH, Coumar MS, Chu CY, et al. Design and synthesis of tetrahydropyridothieno[2,3-d]pyrimidine scaffold based epidermal growth factor receptor (EGFR) kinase inhibitors: the role of side chain chirality and michael acceptor group for maximal potency. J Med Chem 2010;53:7316-26

56.

Zhou W, Liu X, Tu Z, et al. Discovery of pteridin-7(8H)-one-based irreversible inhibitors targeting the epidermal growth factor receptor (EGFR) kinase T790M/ L858R mutant. J Med Chem 2013;56:7821-37

57.

Elzahabi HAS. Synthesis, characterization of some benzazoles bearing pyridine moiety: search for novel anticancer agents. Eur J Med Chem 2011;46:4025-34

58.

Hu WP, Chen YK, Liao CC, et al. Synthesis, and biological evaluation of 2(4-aminophenyl)benzothiazole derivatives as photosensitizing agents. Bioorg Med Chem 2012;46:6197-207

59.

Lin RH, Johnson SG, Connolly PJ, et al. Synthesis and evaluation of 2,7-diaminothiazolo[4,5-d] pyrimidine analogues as anti-tumor epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors Bioorg Med Chem Lett. 2009;19:2333

60.

Malleshappa NN, Harun M, Kaur PM, et al. Benzothiazoles: search for anticancer agents. Eur J Med Chem 2012;54:447-62

61.

Lv PC, Wang KR, Yang Y, et al. Synthesis and biological evaluation of novel thiazole derivatives as potent FabH

Epidermal growth factor receptor inhibitors

62.

63.

Expert Opin. Ther. Patents Downloaded from informahealthcare.com by Dalhousie University on 05/29/14 For personal use only.

64.

65.

66.

67.

68.

77.

Ongarora BG, Fontenot KR, Hu K, et al. Phthalocyanine-peptide conjugates for epidermal growth factor receptor targeting. J Med Chem 2012;55:3725-38

78.

Carmi C, Mor M, Petronini PG, et al. Clinical perspectives for irreversible tyrosine kinase inhibitors in cancer. Biochem Pharmacol 2012;84:1388-99

79.

Efferth T. Signal transduction pathways of the epidermal growth factor receptor in colorectal cancer and their inhibition by small molecules. Curr Med Chem 2012;19:5735-44

80.

Vivanco I, Mellinghoff IK. Epidermal growth factor receptor inhibitors in oncology. Curr Opin Oncol 2010;22:573-8

Avila Therapeutics, Inc. Mutant-selective EGFR inhibitors for treatment of Cancer. WO064706; 2012

81.

Tjeerd B, Allard K. Irreversible protein kinase inhibitors: balancing the benefits and risks. J Med Chem 2012;55:6243-62

74.

Zuo M, Zheng YW, Lu SM, et al. Synthesis and biological evaluation of Naryl salicylamides with a hydroxamic acid moiety at 5-position as novel HDAC--EGFR dual inhibitors. Bioorg Med Chem 2012;20:4405-12

82.

Newman DJ, Cragg GM. Natural products as sources of new drugs over the 30 years from 1981 to 2010. J Nat Prod 2012;75:311-35

75.

Lee SL, Hsu EC, Chou CC, et al. Identification and characterization of a novel integrin-linked kinase inhibitor. J Med Chem 2011;54:6364-74

76.

Abou-Seri SM. Synthesis and biological evaluation of novel 2,40-bis substituted diphenylamines as anticancer agents and potential epidermal growth factor receptor tyrosine kinase inhibitors. Eur J Med Chem 2010;45:4113-21

69.

Gnewuch CT, Sosnovsky GA. Critical appraisal of the evolution of Nnitrosoureas as anticancer drugs. Chem Rev 1997;97:829-1013

Lv PC, Li HQ, Sun J, et al. Synthesis and biological evaluation of pyrazole derivatives containing thiourea skeleton asanticancer agents. Bioorg Med Chem 2010;18:4606-14

70.

Okada H, Koyanagi T, Yamada N, et al. Synthesis and antitumor activities of prodrugs of benzoylphenylureas. Chem Pharm Bull 1994;42:57-61

Universita’ Degli Studi Di Parma. Irreversible egfr inhibitor compounds with antiproliferative activity. WO076764; 2010

71.

Pontier SM, Huck L, White DE, et al. Integrin-linked kinase has a critical role in ErbB2 mammary tumor progression: implications for human breast cancer. Oncogene 2010;29:3374-85

72.

Avila Therapeutics, Inc. Heteroaryl compounds and uses thereof. US0249092; 2010

73.

inhibitors. Bioorg Med Chem Lett 2009;19:6750-4

Jiang JD, Denner L, Ling YH, et al. Double blockade of cell cycle at G1-S transition and M phase by 3Iodoacetamido benzoyl ethyl ester, a new type of tubulin ligand. Cancer Res 2002;52:6080-8 Dai Y, Guo Y, Frey RR, et al. Thienopyrimidine ureas as novel and potent multitargeted receptor tyrosine kinase inhibitors. J Med Chem 2005;48:6066-83 Dai Y, Hartandi K, Ji Z, et al. Discovery of N-(4-(3-amino-1H-indazol-4-yl) phenyl)-N’-(2-fluoro-5-methylphenyl) urea (ABT-869), a 3-aminoindazole-based orally active multitargeted receptor tyrosine kinase inhibitor. J Med Chem 2007;50:1584-97 Li HQ, Yan T, Lv PC, et al. Urea derivatives in anticancer agents. Anti Cancer Agents Med Chem 2009;9(4):471-80 Li HQ, Yan T, Yang Y, et al. Synthesis and structure--activity relationships N-benzyl-N-(X-2-hydroxybenzyl)-N¢phenylureas and thioureas as antitumor agents. Bioorg Med Chem 2010;18:305-13

Expert Opin. Ther. Patents (2014) 24(3)

Affiliation

Si-Ning Li1 & Huan-Qiu Li†2 † Author for correspondence 1 Soochow University, College of Pharmaceutical Science, Suzhou 215123, PR China 2 Professor, Soochow University, College of Pharmaceutical Science, Suzhou 215123, PR China Tel: +86 512 65882090; Fax: +86 512 65882090; E-mail: [email protected]

321

Epidermal growth factor receptor inhibitors: a patent review (2010 - present).

The signaling pathways downstream of epidermal growth factor receptor (EGFR) are central to the biology of colorectal cancer. EGFR kinase represents a...
825KB Sizes 0 Downloads 0 Views