Patent Review

1.

Introduction

2.

Chemical entities: cyclopropane carboxamide derivatives

3.

F508del-cystic fibrosis transmembrane regulator correctors for treatment of cystic fibrosis: a patent review Hong Yang & Tonghui Ma †

Chemical entities: heterocyclic

School of Life Sciences, Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, Liaoning Normal University, Dalian 116029, P.R.China

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carboxamide derivatives 4.

Chemical entities: aminoheterocyclic derivatives

5.

Chemical entities: coumarin derivatives

6.

Chemical entities: others

7.

Conclusion

8.

Expert opinion

Introduction: Cystic fibrosis (CF) is an autosomal recessive genetic disease caused by malfunction of CF transmembrane regulator (CFTR). The deletion of a phenylalanine at residue 508 (F508del) is the most common mutation that causes cellular processing, chloride channel gating and protein stability defects in CFTR. Pharmacological modulators of F508del-CFTR, aimed at correcting the cellular processing defect (correctors) and the gating defect (potentiators) in CFTR protein, are regarded as promising therapeutic agents for CF disease. Endeavors in searching F508del-CFTR modulators have shown encouraging results, with several small-molecule compounds having entered clinical trials or even represented clinical options. Areas covered: This review covers the discovery of F508del-CFTR correctors described in both patents (2005 -- present) and scientific literatures. Expert opinion: Cyclopropane carboxamide derivatives of CFTR correctors continue to dominate in this area, among which lumacaftor (a NBD1-MSD1/ 2 interface stabilizer) is the most promising compound and is now under the priority review by US FDA. However, the abrogation effect of ivacaftor (potentiator) on lumacaftor suggests the requirement of discovering new correctors and potentiators that can cooperate well. Integration screening for simultaneously identifying combinations of correctors (particularly NBD1 stabilizer) and potentiators should provide an alternative strategy. A recently reported natural product fraction library may be useful for the integration screening. Keywords: cystic fibrosis, cystic fibrosis transmembrane regulator, cystic fibrosis transmembrane regulator corrector, cystic fibrosis transmembrane regulator modulator, cystic fibrosis transmembrane regulator potentiator, ivacaftor, lumacaftor Expert Opin. Ther. Patents [Early Online]

1.

Introduction

Cystic fibrosis (CF) is an incurable inherited lethal disease caused by mutations in CF transmembrane regulator (CFTR) gene [1-3]. CF is the most common monogenic genetic disorder in Caucasian populations with an incidence of 1 in 3700 live birth in the US and 1 in 2500 live birth in the European countries [4,5]. CFTR, a member of ATP-binding cassette transporter family, is ubiquitously expressed in apical membrane of serous epithelial cells in intestines, airways, pancreas, bile ducts, epididymis and conjunctiva [6-9]. CFTR plays a crucial role in transepithelial fluid homeostasis because it is the primary driver of fluid and water secretion [10-13]. Over 1900 different gene mutations in CFTR have been identified that lead to reduced or even lost function of CFTR by impairing its translation, cellular processing, channel gating and/or stabilization [14-16]. The deletion of a code for phenylalanine at position 10.1517/13543776.2015.1045878 © 2015 Informa UK, Ltd. ISSN 1354-3776, e-ISSN 1744-7674 All rights reserved: reproduction in whole or in part not permitted

1

H. Yang & T. Ma

Article highlights .

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.

.

.

Cystic fibrosis transmembrane regulator (CFTR) modulation therapy aimed at restoring the function of CFTR protein is a promising strategy in cystic fibrosis (CF) treatment. F508del-CFTR modulators attracted intense interests in CFTR research community. Orally available small-molecule drugs targeting the impaired CFTR remain the most desired medication. Cyclopropane carboxamide F508del-CFTR correctors continue to dominate in this area; other chemical entities such as heterocyclic carboxamide, aminoheterocyclic and coumarin derivatives are also promising candidates for CFTR repair therapy. Limited efficacy of lumacaftor urges further basic and clinical studies of more candidate drugs. Phase II clinical results using lumacaftor and ivacaftor show encouraging results in homozygous F508del CF patients, but abrogation effect of ivacaftor on lumacaftor mandates further basic research and longterm clinical studies. Integration screening for simultaneously identifying combination of corrector (particularly NBD1 stabilizer) and potentiator should provide an alternative strategy for discovering new correctors and potentiators that can cooperate well. A recently reported natural product fraction library may be useful for the integration screening.

508 (F508del) is by far the most prevalent mutation that is present in ~ 90% of patients with CF [8,17]. F508del is a severe mutation in that it impairs protein folding, chloride channel gating and stability of CFTR [18-21]. Because pulmonary disease is the principal cause of morbidity and mortality in CF, primary medications target airway obstruction, inflammation and infection that relentlessly occur in the lungs of CF patients [22-30]. Although antibiotic, anti-inflammatory and mucus-altering approaches have yielded longer life expectancy in CF patients [31-33], there is still a long way to go before CF patients have a similar quality and quantity of life to those subjects without the disease. Since the identification and cloning of CFTR gene in 1989 [2], the CF research community has been committed to searching new strategies that target the defective genes or the resulting dysfunctional proteins. Gene-based therapy is to introduce healthy CFTR genes into the affected epithelial cells to recover the functional expression of CFTR in CF patients. Although a large number of preclinical and clinical CF gene therapy studies have been performed, progress has been very limited mainly due to the lack of safe and reliable way to deliver healthy genes into the affected cells in the body [34-37]. The observation that the misprocessing defect of F508delCFTR could be corrected by either low temperature (< 30 C) [38] or chemical chaperones (e.g., phenylbutyrate and glycerol) [39-42] led to unyielding efforts to identify chemical modulators that could more selectively and efficiently produce such effects [43-50]. Potential medications in CFTR 2

protein repair therapy include correctors (to improve abnormal CFTR protein folding) and potentiators (to improve channel gating). So far, numerous CFTR potentiators have been identified and verified to be effective in both in vitro and in vivo studies [51-53]. In 2012, the US FDA approved ivacaftor (VX-770, Kalydeco, Vertex Pharmaceuticals), a potentiator that can increase CFTR-mediated chloride transport, for the treatment of CF patients with G551D-CFTR mutation that causes only gating defect. Notably, Kalydeco treatment brings about only mild although significant decrease in sweat chloride concentration as compared with placebo, which does not coincide with the forced expiratory volume in 1 (FEV1) response. Details can be seen in the review article in [54] by Pettit and Fellner. Efficacy of Kalydeco was also confirmed in CF patients with non-G551D gating mutations [55]. Therefore, Kalydeco is now also approved for the treatment of CF patients with eight other gating defect mutations besides G551D [55]. Although G551D mutation represents < 5% of patients with CF, the successful clinical results of Kalydeco has inspired the CF field to develop CFTR modifier medications targeting F508del-CFTR. Kalydeco has also been tested in patients who are homozygous for F508del-CFTR. Kalydeco monotherapy produced little clinical benefit in these patients because only small amount of F508del-CFTR is targeted to the cell plasma membrane. Thereafter, a potentiator/corrector combination therapy was tested in homozygous F508del-CFTR CF patients. Phase II trials conducted on adult patients showed that lumacaftor/ivacaftor combination therapy could significantly improve lung function and decrease sweat chloride concentration, which encourage continued efforts in optimizing the strategy of combination therapy (see review in [54] by Pettit and Fellner). Compared to that of potentiators, the identification and development of CFTR correctors have been proven more challenging because of the complex components involved in the cellular quality control machinery of CFTR processing, although significant progress has been made during the past two decades. Vertex Pharmaceuticals has pioneered the way in clinical development of the cyclopropane carboxamide F508del-CFTR correctors such as VX-809 (lumacaftor), VX-661 and VX-983. Novartis, CF foundation, DiscoveryBiomed, Verkman group, Galietta’s lab, Edelman’s lab and Becq’s lab, among others also made great contribution to the identification of correctors and potentiators for CF therapy. F508del-CFTR correctors such as cyclopropane carboxamide, heterocyclic carboxamide, aminoheterocyclic derivatives and coumarins have been reported and filed in the past decade. Several molecules, including CPX, 4-phenylbutyrate, curcuminoids, VX-661 and VX-809, have been enrolled in clinical trials, although efficacies of these correctors are somewhat disappointing. The present review covers patents filed or issued in the past decade toward F508del-CFTR correctors and their application

Expert Opin. Ther. Patents (2015) ()

F508del-CFTR correctors for treatment of CF

in CF treatment. The patent documents were retrieved from the worldwide database of the European Patent Office.

Chemical entities: cyclopropane carboxamide derivatives

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2.

Vertex Pharmaceuticals has been leading the way in discovery of cycloalkyl (especially cyclopropane) carboxamide F508delCFTR correctors such as VX-809, VX-661 and VX-983 by using voltage-sensitive fluorescent dyes to monitor F508delCFTR-mediated membrane depolarization in response to extracellular Cl- concentration change. Primary high-throughput screening of ~164,000 synthetic drug-like and lead-like compounds first led to the identification of an aminothiazole corrector VRT-768 [51], a carboxamide-containing compound. Further extensive medicinal chemistry and structure activity relationship analyses of carboxamide-containing compounds resulted in the identification of VX-809 (lumacaftor). Lumacaftor could improve F508del-CFTR processing in cultured CF airway epithelial cells to ~ 14% of non-CF human bronchial epithelial cells with a nanomolar (EC50, 81 ± 19 nM) affinity [51,56], and proves the most efficacious and selective corrector identified so far. Although mechanism studies indicated direct action of lumacaftor on F508del-CFTR to promote the proper folding during its endoplasmic reticulum (ER) biogenesis and processing, the molecular basis of correction remains largely elusive [51]. Cyclopropane carboxamide correctors are currently under clinical tests. In a Phase II study, CF patients with homozygous F508del mutation were randomly assigned to receive 25 -- 200 mg/day lumacaftor monotherapy for 4 weeks. It revealed that lumacaftor produced dose-dependent, rapid and sustained reduction in sweat chloride values in CF patients. However, the results were somewhat disappointing, because it showed negative effect on pulmonary exacerbation rate and changes in the FEV1 or CFQ-R score [57]. Further investigations aim to optimize therapeutic strategy and longterm clinical benefit is required. Further clinical trials were performed using combination of lumacaftor and a potentiator ivacaftor in CF patients with F508del mutation. Boyle et al. [58] reported that combination of lumacaftor and ivacaftor could improve the FEV1 values in CF patients with homozygous DF508-CFTR. Two Phase III clinical trials, TRANSPORT (NCT01807949) [59] and TRAFFIC (NCT01807923) [60], have been sponsored by Vertex to evaluate the efficacy and safety of lumacaftor in combination with Kalydeco in March 2013. These trials enrolled a total of 1122 (563 in TRANSPORT and 559 in TRAFFIC) CF patients aged 12 -- 65 years who are homozygous for the F508del mutation. In each study, subjects were randomized to receive Kalydeco (250 mg every 12 h) in combination with 600 mg/day lumacaftor or 400 mg lumacaftor twice-daily or placebo for 24 weeks. Full results of the trials have not been published. The FirstWord Pharma [61] reported that mean absolute improvements in percentage predicted FEV1 (ppFEV1) were 2.6 -- 4% and relative improvements

in ppFEV1 were 4.3 -- 6.7% for patients who received Kalydeco plus lumacaftor, versus placebo. Although the improvement of only ~ 3% in ppFEV1 is somewhat disappointing in CF patients, Bonnie Ramsey (lead principal investigator in the TRANSPORT study) was confident in the combination therapy and suggested that long-term treatment would bring about meaningful difference [61]. In addition, pulmonary exacerbations were significantly reduced among patients who were administered Kalydeco and lumacaftor, which is particularly important for those CF patients who got permanent lung damage [61]. No data about the improvement in chloride concentration in sweat can be acquired. Although studies have fully confirmed that acute ivacaftor/ lumacaftor combination therapy could enhance lumacaftorrescued F508del-CFTR activity, discouraging results should not be neglected. A recent study by Cholon et al. [62] indicated that chronic administration of ivacaftor caused a dosedependent reversal of lumacaftor-mediated CFTR correction in F508del homozygous cultures, which may be due to the destabilization of corrected F508del-CFTR by ivacaftor. Another study by Veit et al. [63] also indicated that some gating potentiators (including ivacaftor) could reduce the correction efficacy of lumacaftor. The abrogation effect of ivacaftor on correction efficacy of lumacaftor suggests the need for further optimization of potentiators to maximize the clinical benefit of corrector--potentiator combination therapy in CF. Moreover, ivacaftor may destabilize the normal version of the CFTR protein in healthy patients, which makes it a less likely candidate for treating other respiratory disorders such as chronic obstructive pulmonary disease [62]. Cyclopropane carboxamide scaffold (1) correctors are currently the major class of lead compounds under development. More than 40 filings from Vertex Pharmaceuticals claimed worldwide rights to develop and commercialize this class of compounds. Vertex has submitted a new drug application to the FDA and is waiting for final decision in July 2015. Vertex Pharma just released the Phase II trial data for VX-661 plus Kalydeco in CF patients with two copies of the F508del mutation. The results were disappointing, because the mean improvement in ppFEV1 for the 100 mg dose of VX-661 was only ~ 4.4 and 3.0% at week 4 and through 12 weeks of treatment, and mean absolute change in ppFEV1 was only 1.0% versus placebo’s -0.4%. Moreover, lung function of the subjects returned to baseline after the treatment [63]. Clinical data for VX-983 is not yet available. The structures of general cyclopropane carboxamide formula (1), VX-809 and VX-661 are illustrated in Figure 1.

Chemical entities: heterocyclic carboxamide derivatives

3.

Heterocyclic carboxamide derivatives here are defined as compounds with the following general formula (2 as shown in Figure 2), wherein ring A is a substituted or unsubstituted pyrimidine, pyridine, quinoline, indole or thiazole ring.

Expert Opin. Ther. Patents (2015) ()

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R1

R1 R1 1 R N R N

A

• Ring A is optionally fused to 5–6 membered carbocyclic or heterocyclic, aromatic or non-aromatic ring. • RN=H or a substituted or unsubstituted alkyl, cycloalkyl. aromatic or heteroaromatic ring • Ar is a substituted or unsubstituted pyrimidine, pyridine, quinoline, indole or thiazole ring • R=H or up to two Cl-C6 alkyl

Ar

O (RXX)X

1

HO F F

O

HO

O

O

F

F F N

OH

O O

N H

N H

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CH3

O N

CO3H

VX-809

VX661

Figure 1. Schematic representations of chemical structures of cyclopropane carboxamide derivatives; summarized from [103-109].

1

R A

2

NHR

O

2

Figure 2. Schematic representation of general structure of heterocyclic carboxamide scaffold.

Novartis identified a series of 3-amino-pyridine-2-carboxamide (picolinamide) DF508-CFTR correctors with similar activity to that of lumacaftor, which makes it a significant competitor in the field. They claimed a series of heterocyclic amide derivatives in five filings to expand on the CFTR correction activities of compounds (see review article in [64]). 4. Chemical entities: aminoheterocyclic derivatives

Pyrimidine derivatives Cystic Fibrosis Foundation claimed a series of aminopyrimidine derivatives as CFTR modulators in three applications. These filings provide general structures (3 and 4 as shown in Figure 3) and pharmaceutical composition and methods of treating CFTR-associated disorders [65-67]. The critical difference between the generic claims of the first two applications (WO2010068863 and WO2010151747) is the position of substituents on the pyrimidine ring. The other difference is the definition of the L and W group. The third (WO2011008931) application utilizes the same basic scaffold with the most critical difference in the definition of the R1 and 4.1

4

R11 substituents. Another substantive difference is that this filing specifically claimed cyclopropane carboxamide derivatives. No biological data were available from the first two applications; therefore, the modulators were contemplated. The third application provides limited short-circuit current Ussing chamber data obtained from transfected Fischer rat thyroid (FRT) epithelial cells. Some claimed aminopyrimidine derivatives showed good potency in in vitro studies and many claimed compounds possess dual corrector-potentiator activities as shown by short-circuit current tests done on transfected FRT cells. It is hard to evaluate the potential of these compounds due to limited biological data available. Aminothiazole derivatives Verkman et al. led the way in identification of thiazolecontaining derivatives by using a cell-based high-throughput screening assay [68]. They screened 150,000 synthetic compounds and discovered several classes of F508del-CFTR correctors. Further optimization of > 1500 compounds yielded several classes of correctors (including aminoarylthiazoles, quinazolinylaminopyrimidinones and bisaminomethylbithiazoles) with micromolar potency, among which Corr-4a has the highest potency and affinity (EC50 < 3 µM). Biochemical studies of these correctors suggested a mechanism of action involving improved F508del-CFTR folding at the ER and stability at the cell surface [69]. Follow-up medicinal chemistry by the same group and in collaboration with Kurth et al. generated a series of aminothiazole-tethered bithiazoles, pyrazolylthiazoles and triazolo-bithiazoles derivatives to improve the hydrophilicity and affinity of these compounds [70-73]. Structure--activity relationship analysis and molecular docking data suggested that efficiencies of these compounds depend on their ability to access CFTR protein. Vertex has also highlighted thiazole ring-containing correctors. Van Goor et al. [51] reported identification of a dual-acting aminothiazole derivative VRT-768 from ~ 164,000 synthetic 4.2

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F508del-CFTR correctors for treatment of CF

(W02010068863) R1 A N R11

W

N

N

3

H

(W02010151747) A R1

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R12

N N

N H

L B

4 (W02011008931)

• A represents a substituted or unsubstituted aromatic or heteroaromatic ring • W represents a substituted alkyl, cycloalkyl. • R1 and R11 are independently OH, -Y-(CRmRn)x-alkyl, -Y-(CRmRn)xcycloalkyl, -Y-(CRmRn)x heterocycloalkyl, -Y-ary, -Y-heteroaryl, -CF3, -CN, -OCF2H, -OCH2F, halogen, -CONR5R6, -NR5R6, -NR5COR6, -NR5S02R7, -SO2R7. Y=bond, O, S, S(O), or S(O)2. Rm and Rn each represent independently for occurrence H, methyl, ethyl or propyl. • A represents a substituted or unsubstituted aromatic or heteroaromatic ring • L= bond, substituted alkyl, cycloalkyl, • B represents a substituted cycloalkyl, heterocycloalkyl or phenyl. • R1 and R12 are independently OH, CN, alkyl, alkoxy, cycloalkyl, clcloalkoxy, -OCF3, OCF2, halogen, -NR7R10, -NR7COR8, -NR7S02R9, or -SO2R9. • A represents a substituted or unsubstituted aromatic or heteroaromatic ring • W represents a substituted alkyl, cycloalkyl. • R1 and R11 are independently OH, -Y-(CRmRn)x- alkyl, -Y-(CRmRn)xcycloalkyl, -Y-(CRmRn)x- heterocycloalkyl, -Y-ary, -Y-heteroaryl, -CF3, -CN, -OCF2H, -OCH2F, halogen, -CONR7R10, -NR7R10, -NR7COR8, -NR7S02R9 • V=bond, O, S, S(O), or S(O)2. • Rm and Rn each represent independently for occurrence H, methyl, ethyl or propyl.

Figure 3. A summary of three patent applications of aminopyrimidine derivatives claimed by Cystic Fibrosis Foundation; summarized from [65-67].

OCH3

4a (EC50 < 3 mM)

5 (EC50 = 300 nM)

VRT-768 (corrector EC50 ª 16mM, potentiator EC50 ª 7.9mM)

OCH3

H3CO

6 (EC50 < 1.0 mM)

7 (EC50 = 1.6 mM)

Figure 4. Schematic representations of examples of aminothiazole-containing correctors; adapted from [51,68,70-72].

drug-like and lead-like compounds. In transfected FRT cells, VRT-768 could increase F508del-CFTR maturation by ~ 2.5-fold (EC50 » 16 µM) and potentiated chloride transport (EC50 » 7.9 µM) compared with controls. Examples of several typical aminothiazole-containing correctors are shown in Figure 4.

Quinoline/quinazoline derivatives Loo et al. [74] reported the first quinazoline F508del-CFTR corrector CFcor-325, a P-gp inhibitor as it inhibited vinblastine-stimulated cellular ATPase activity. Further study indicated that CFcor325 could repair the F508del-type folding defects in P-gp or CFTR, suggesting a mechanism of 4.3

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3a VRT-422

CFpot-532

OCH3

Copo-22

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VRT-325

Figure 5. Schematic representations of examples of quinoline and quinazoline derivatives; adapted from [68,75,76,80].

promoting folding of the transmembrane domains. Although not specific to F508del-CFTR, CFcor-325 (at 1 -- 10 µM) could potently result in maturation and delivery of a functional CFTR to the cell surface in transfected baby hamster kidney cells. In terms of mechanisms, the authors suggested that CFcor-325 rescued CFTR mutants by repairing the folding defects in the transmembrane domains [75]. Later on, the same group identified a pyrazole derivative of CFcor-325 named CFpot-532, which is more specific to F508delCFTR. Notably, CFpot-532 also acts as a potentiator of F508del-CFTR channel activity [75]. In 2006, Van Goor et al. [76] identified a quinazolinone compound, VRT-422, from ~ 164,000 synthetic compounds. VRT-422 and an optimized hit (VRT-325) could potently correct the trafficking of F508del-CFTR to the cell surface at low micromolar affinity. Mechanism studies indicated that these quinazolinone correctors act primarily or initially at the level of the ER to facilitate the folding and export of F508del-CFTR. Verkman et al. [77] also identified a quinoline smallmolecule corrector (3a) of defective F508del-CFTR cellular processing from 150,000 synthetic compounds by highthroughput screening. In collaboration with Kurth et al., they described alternative chemotypes of quinoline derivatives [78,79]. They claim a series of cyanoquinoline compounds with dual corrector and potentiator activities (termed ‘CoPo’) [80]. The scaffold was identified from ~ 110,000 small molecules to find dual-acting compounds with independent F508del-CFTR potentiator and corrector activities. CoPo22 was identified from 180 CoPo analogs, which showed similar maximal corrector activity of Corr-4a (4a) and potentiator activity of genistein. The discovery of dual-acting modulators suggests the possibility of single-drug therapy in CF. Mechanisms underlying the activities remain largely unresolved. Examples of several quinoline/quinazoline correctors are shown in Figure 5. 6

5.

Chemical entities: coumarin derivatives

Two applications expand on the CFTR correction activities of coumarins and trimethylangelicin (TMA) derivatives [81,82]. A patent by DiscoveryBiomed [81] claims coumarin derivatives (generic structure 8 is shown in Figure 6) as correctors for the treatment of CF. Correction of impaired F508del-CFTR processing was evaluated by the 6-methoxy-N-(3-sulfopropyl)quinolinium fluorescence (SPQ) fluorescence assay, epithelial voltohmmeter electrical assay, Ussing chamber measurements and proteomics. The data disclosed in this application indicated that the claimed CFTR correctors possess high potency in in vitro assays: compound DBM 228 showed robust F508del-CFTR correction efficiency with an EC50 of ~ 250 nM and maximum correction at 300 nM; compound DBM 308 (at 300 nM) increased basal Cl- currents to levels greater or equal to lumacaftor (at 3 µM, the optional concentration for lumacaftor’s Ussing chamber effects) in short-circuit current assay. In the biochemical rescue assay, compound DBM 308 is more effective than Corr-4a at the concentration of 2 µM. The application also indicated that the claimed coumarin correctors showed additive effect with lumacaftor in correction of F508del-CFTR and also influenced and upregulated additional Cl- channel populations. Cabrini et al. [82] disclosed TMA and analogs as correctors for the treatment of CF. The claimed compounds could functionally correct defect of F508del-CFTR in primary cultured human bronchial epithelial cells. TMA (at 100 nM) obtained a similar effectiveness to that of 5 mM lumacaftor, manifesting very high affinity of the compound to CFTR protein. Recently, Favia et al. [83] reported that prolonged incubation with TMA (at nanomolar concentrations) could efficiently rescue both F508del-CFTR-dependent chloride secretion and F508del-CFTR cell surface expression in primary or secondary airway cell monolayers homozygous for F508del mutation. Xu et al. [84] and Yang et al. [85] also reported that

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F508del-CFTR correctors for treatment of CF

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8

TMA

002_N8_28(DBM228)

DBM_003_8CI(DBM308)

Figure 6. Schematic representations of examples of coumarin derivatives; adapted from [81,82].

9

10

11

Figure 7. Schematic representations of CFTR correctors from [87-89]. CFTR: Cystic fibrosis transmembrane regulator.

coumarins could potentiate F508del-CFTR chloride channel activities in both transfected FRT cell and rat colonic mucosa. These data suggest that coumarin derivatives could be used as dual-acting compounds with independent F508del-CFTR potentiator and corrector activities. Because coumarins modulate many intracellular pathways [86], the precise molecular mechanisms need to be fully elucidated before application to CF therapy. Examples of several coumarin correctors are shown in Figure 6. 6.

Chemical entities: others

In the recent patent literatures, there are several inventions disclosing CFTR correctors structurally unrelated to the abovementioned chemical entities. DiscoveryBiomed [87,88] disclosed that certain bicyclic and tricyclic derivatives (generic structures 9 and 10 shown Figure 7) can rescue impaired F508del-CFTR processing and claimed use of these compounds for the treatment of CF. Activities of the claimed compounds tested in SPQ fluorescence assay and the shortcircuit current Ussing chamber assay revealed that some compounds showed superior potency that is 10-fold greater than lumacaftor. Prehm [89] disclosed a series of F508del-CFTR correctors which are characterized by the scaffold (11) shown in Figure 7.

Efficacies of the claimed compounds were determined using iodide efflux and transepithelial nasal resistance assays. The results indicated effective correction of the F508del-CFTR trafficking defect. 7.

Conclusion

The excellent results of using Kalydeco in CF patients with G551D mutation have proven conclusively the feasibility of CFTR protein repair therapy in CF treatment. For patients with two copies of F508del, the objective is using CFTR corrector and potentiator to rescue the impaired cellular processing and chloride channel gating, respectively. Identification of new chemical entity CFTR correctors remains a most competitive area in the field. Cyclopropane carboxamide derivatives, the first-generation correctors, continue dominate in this area. Cyclopropane carboxamide corrector (lumacaftor) and potentiator (ivacaftor) combination clinical trials in homozygous F508del CF patients showed limited but significant improvements in lung function and sweat chloride concentration, encouraging further optimization of combination therapy strategy. However, abrogation effect of ivacaftor on correction efficacy of lumacaftor needs to be fully evaluated. Heterocyclic carboxamide, aminoheterocyclic and coumarin derivatives have been introduced and filed as promising

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correctors for CF therapy. Lack of powerful CFTR correctors working efficiently in vivo is still the bottleneck of protein repair therapy in CF.

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8.

Expert opinion

Efforts from both academia and industry to develop new F508del-CFTR correctors have been continuing, and rapid progress has been made in identification of small molecule F508del-CFTR correctors over the past two decades. Unprecedented optimism has been inspired following the approval of Kalydeco in 2013. The FDA has granted Vertex’s request for Priority Review of combination of lumacaftor and ivacaftor in people with CF, and will make the final decision in July 2015 [61,90]. These drugs offer great opportunity for CF therapy by slowing the progress of the disease. However, the limited efficacy of lumacaftor monotherapy and the abrogation effect of ivacaftor on lumacaftor corrector urge the search for new correctors and potentiators to be evaluated in extensive preclinical and clinical studies [62,91]. Moreover, the lack of mechanism information of the available correctors mandates for further basic research. To date, CFTR modulator identification mainly used phenotype assays based on CFTR chloride channel function due to the paucity of crystallographic structural information on full-length CFTR and its mutations. The phenotype assay strategy has been verified as a practicable choice that led to the identification of numerous CFTR modulators including lumacaftor [51-53,74,75,78,83,85]. The molecular basis of available correctors remains largely elusive, only circumstantial evidence indicates that these correctors may stabilize the NBD1--MSD1/2 interface (class I, e.g., lumacaftor), target NBD2 (class II, e.g., corr-4a) or stabilize the DF508-NBD1 (class III) [92]. Recent studies revealed that stabilization of both F508del--NBD1 and NBD1--MSD2 interface is essential for robust plasma membrane expression and function of the mutant CFTR [93]. The limited efficacy of lumacaftor is probably due to its stabilization of only the NBD1--MSD1/2 interface [92,94]. Corrector combination therapy targeting the structural defects, especially the combination of class I and class III correctors, may be essential to achieve a significant clinical improvement in CF patients [92,93,95]. Identification of NBD1 stabilizer is currently a bottleneck in CF pharmacological therapy, because none of the available correctors identified so far from millions of combinatorial small molecules is verified as a NBD1 stabilizer [92]. During the past two decades, the synthetic combinatorial small molecules have been the major source of new chemical entities in CF drug discovery. However, the limited chemical entity of the combinatorial libraries compels generation of compound collections with improved structural diversity. Natural compounds, highly diverse in chemical entities, are important sources of lead compounds in drug discovery [96,97]. However, the difficulty of generating a library with large number of natural compounds hammered the interest of 8

pharmaceutical industry to develop high-throughput screening-based natural product discovery platform. Recently, we generated a fraction library from 500 herbal plants most commonly used in traditional Chinese medicine (TCM). For construction of the TCM fraction library, crude herbal extracts were fractionated into 80 fractions by preparative HPLC. The feasibility of our natural product highthroughput screening method has been validated by identification of 17 new F508del-CFTR correctors for Cystic Fibrosis Foundation (supported by grant MA08XX0: Discovery of Natural compounds F508del-CFTR misprocessing correctors from Chinese medicinal herbs) and several CFTR inhibitors [98-100]; many of them possess new chemical scaffolds that have not been found in combinatorial libraries before. Moreover, the unexpectedly high ‘hit’ rate of the TCM fraction library suggests their usefulness for further exploration in CF therapy, particularly for discovery of NBD1 stabilizers. F508del mutation has both cellular processing and channel gating defects. The rationale behind corrector/potentiator combination therapy is that a corrector can facilitate the trafficking of F508del-CFTR to plasma membrane and a potentiator can stimulate chloride transport of the mutant CFTR protein. Both preclinical and clinical studies indicated that the lumacaftor-induced F508del-CFTR activity could be potentiated significantly with ivacaftor [57,58,101], which verified the proposition well. However, unfavorable results arose from several recent studies that ivacaftor could reduce the correction efficacy of lumacaftor by interfering CFTR stability [62,91]. Dosing optimization alone seems unable to resolve this issue. Rowe and Verkman [102] pointed out that the practical assays for CFTR modulator screening is somewhat artificial because channel gating and cellular processing are interrelated processes that depend on CFTR folding. Compounds with dual potentiator and corrector activity may be a resolution for CF therapy. However, the chance is probably limited because of the multiplicity of defects conferred by the F508del mutation. Integration screening for simultaneously identifying combination of NBD1 stabilizer, NBD1--MSD1/2 interface stabilizer and potentiator should provide an alternative practicable strategy. At this point, our TCM fraction library may be a useful natural product library for the integration screening.

Acknowledgments This work was supported by National Natural Science Foundation of China (Nos. 81473265; 31471099, 81173109; 30973577), Specialized Research Fund for the Doctoral Program of Higher Education (20112136110002).

Declaration of interest The authors state no conflict of interest and have received no payment in preparation of this manuscript. Hong Yang was

Expert Opin. Ther. Patents (2015) ()

F508del-CFTR correctors for treatment of CF

supported by the National Natural Science Foundation of China (Nos. 81473265, 30973577), Specialized Research Fund for the Doctoral Program of Higher Education (20112136110002). Tonghui Ma was supported by the National Natural Science Foundation of China (Nos. Bibliography

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Affiliation

Hong Yang†1 PhD & Tonghui Ma2 MD PhD † Author for correspondece 1 Professor, School of Life Sciences, Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, Liaoning Normal University, Dalian 116029, P.R. China Tel: +86 411 85827085; Fax: +86 411 85827068; E-mail: [email protected] 2 Professor, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, P.R. China

F508del-cystic fibrosis transmembrane regulator correctors for treatment of cystic fibrosis: a patent review.

Cystic fibrosis (CF) is an autosomal recessive genetic disease caused by malfunction of CF transmembrane regulator (CFTR). The deletion of a phenylala...
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