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Editorial: Excellence in Medicinal Chemistry from Australia


discovery that originated at the University of Queensland. In 2016 Cancer Therapeutics CRC (a collaborative partnership of Australian universities, medical research institutes, and CSIRO) licensed a small molecule cancer drug program to Merck U.S. in a AU $730 million deal. In 2017, Canada Pension Plan Investment Board (CPPIB) Credit Europe S.à r.l. acquired partial rights to Australia’s Walter and Eliza Hall Institute of Medical Research (WEHI) anticancer treatment venetoclax. This deal includes payment of U.S. $250 million upfront with potential milestone payments of up to U.S. $75 million. Also in 2017, Protagonist Therapeutics (originating from research at the University of Queensland) and Janssen Biotech agreed on a worldwide license for co-development and commercialization of an oral peptide drug for indications including inflammatory bowel disease in a potentially $940 million deal. In the remainder of this editorial, an overview of content from 15 papers sampled from the Journal of Medicinal Chemistry by corresponding authors based in Australia during the period January 2015 to August 2017 is presented. These papers have been selected to showcase the diversity, sophistication, maturity, and depth of excellence of medicinal chemistry from Australia.

he medicinal chemistry research published in the Journal of Medicinal Chemistry by corresponding authors based in Australia predominantly originated from Australian universities, with academic authors accounting for 49 of the 52 manuscripts published in the period January 2015 to August 2017. The Australian Research Council has responsibility for administering Australia’s national research evaluation framework, known as Excellence in Research for Australia (ERA). ERA evaluates the research conducted within Australia’s higher education research institutions by comparison with international benchmarks including, but not limited to, research outputs, research income, patents, and research commercialization. The ERA evaluation classifies and reports university research performance at the individual discipline level (157 possible disciplines) using a five-point scale, where rating 5 corresponds to outstanding performance “well above world standard” and rating 1 corresponds to performance “well below world standard”. In the most recent ERA round (2015), 12 of Australia’s 40 universities nominated for evaluation against the discipline area of “Medicinal and Biomolecular Chemistry”. Of the 12 universities, two universities were rated as 5 (performance well above world standard), nine universities were rated as 4 (performance above world standard), and one university was rated as 3 (performance at world standard). Notably, 8 of the 12 universities have contributed 46 of the 49 academic corresponding author publications in the Journal of Medicinal Chemistry in the period considered here. More information about ERA can be found at (http://www.arc.gov.au/excellenceresearch-australia). Also apparent from this publication period is that Australia’s current medicinal chemistry research ecosystem exhibits three distinct hotspots, with institutions in the east coast capital cities of Brisbane, Sydney, and Melbourne contributing 45 of the 52 publications. The ecosystem does however extend broadly, including two other capital cities (Perth and Adelaide) and multiple regional institutions. The publication analysis of this period establishes that medicinal chemistry in Australia is highly collaborative, with 82% of papers having multi-institutional coauthorship, while 48% of papers include international coauthors. This collaboration enables engagement of university-based medicinal chemistry researchers with Australia’s medical research institutes, whereby medicinal chemists can contribute the essential drug discovery expertise needed to generate appropriate molecules to alter the activity of a given target from basic biology to preclinical studies. Australia’s public sector research in medicinal chemistry is continually improving in its knowledge and capacity to better engage with the private sector for preclinical and early stage clinical development. Australia has experienced research commercialization success founded on basic medicinal chemistry during the period 2015−2017, a selection of which is summarized here. In 2015, Novartis International acquired Spinefex Pharma for U.S. $200 million upfront and committed up to an additional U.S. $500 million in milestone payments. Spinefex Pharma’s technology targets neuropathic pain, a © XXXX American Chemical Society

NEGLECTED AND INFECTIOUS DISEASE MEDICINAL CHEMISTRY EXCELLENCE Collaboration between the pharmaceutical industry, not-forprofit agencies, and Australian universities is increasingly common in Australia, particularly in the area of infectious disease drug discovery, where Australia has significant interest and breadth of expertise. Sleebs and co-workers utilized results emerging from publically available screening data sets to identify a compound scaffold with activity across multiple lifecycle stages of the malaria parasite.1 After optimization of the selected compound scaffold against asexual stage Plasmodium falciparum, compounds were evaluated against both sexual stage gametocytes and multidrug resistant strains of the parasite. Lead compounds were efficacious and orally active in vivo (mouse model) causing the suppression of parasitemia. The next phase lead optimization will require that medicinal chemistry address metabolic and cardiotoxicity risk of compounds. The starting point for a study reported by Piggott, Baell, and co-workers emerged from a Drug for Neglected Disease initiative (DNDi) sponsored high throughput screen of the WEHI compound collection (∼80 000 compounds).2 Their paper reports a hit-to-lead proof-of-concept study against Trypanosoma cruzi, the causative agent of Chagas disease. Although a metabolic hurdle with the developed compounds remains to be optimized, the compounds reduced the parasite load in T. cruzi infected mice to undetectable levels with compounds showing excellent tolerability. The team provided the Volume 59, Issue 21 cover image of the Journal of Medicinal Chemistry for this work. Together with the study by Sleebs, the


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ships that may inform next steps toward improving the utility of the polymyxin macrocyclic peptide antibiotic class.

collaborative medicinal chemistry projects also demonstrate Australia’s capability in high throughput screening and ADME/ DMPK to accelerate the progress of medicinal chemistry campaigns.


There are several research teams in Australia with demonstrated excellence in the medicinal chemistry of orally bioactive peptides. Swedberg and colleagues developed a rapid and systematic screening strategy to determine the P2′ amino acid residue preference for cyclic peptide protease inhibitors against a panel of diverse serine proteases.7 The library design was based on a broad-range inhibitor scaffold previously engineered by this team. The study design proved extremely effective and was able to reveal unique P2′ residue preferences against 13 proteases. The team then modified several existing known peptide protease inhibitors with the newly identified P2′ residues to yield new variants with improved protease selectivity. Overall their strategy contributes a new approach for synthetic medicinal chemistry-based optimization of potent and selective peptide inhibitors of serine proteases. Glucagon-like peptide-1 (GLP-1) is a hormone that potentiates glucose-dependent insulin release from the pancreas. A truncated GLP-1 (GLP1(7-36)NH2) is currently used as an injectable treatment for type 2 diabetes. Fairlie and colleagues, working with Pfizer, have employed biophysical (NMR) and computational design studies to prepare constrained 11 residue cyclic peptides derivatives of an active downsized GLP-1 linear peptide.8 NMR-derived solution structures, receptor affinity, and agonist potency were determined for the peptides. The optimal cyclization linker matched the turn structure of the acyclic peptide. Furthermore, the structure−potency data subsequently assembled may guide future development of orally available peptidomimetic GLP-1 receptor agonists to treat type 2 diabetes. The insulin-like peptide (relaxin-3) receptor is predominantly expressed in brain and is a potential target for anxiety and depression. Wade, Bathgate, and collaborators employed a “stapled” peptide approach, whereby truncated peptides are covalently cross-linked to stabilize the secondary structure present in the parent protein.9 Their effort successfully downsized the double-chain relaxin-3 to a single-chain α-helical agonist. The team investigated a range of staples, with a hydrocarbon staple being the most effective at mimicking the native structure. Furthermore, the downsized stapled peptide showed in vitro and in vivo efficacy as a relaxin-3 receptor agonist in a well characterized rat feeding model. Daly and Loukas published a study drawing insight from a granulin protein, Ov-GRN-1, secreted from a human parasitic liver fluke.10 In a previous study they demonstrated that picomolar levels of this protein induce angiogenesis and accelerate topical wound repair. The design and synthesis of truncated peptides of Ov-GRN-1, comprising either four or six cysteine residues, enabled the team to identify the basic structural requirements for bioactivity of Ov-GRN-1. Peptide structural analysis was performed using NMR spectroscopy. The team investigated potency in a mouse wound healing model, this showed that the truncated peptides were as effective as full length Ov-GRN-1 as well as Regranex, a clinically used wound healing agent. The structure−activity relationships attained may provide a platform to develop bioactive wound healing peptides without immunogenic liabilities.

ONCOLOGY MEDICINAL CHEMISTRY EXCELLENCE Munoz and Kassiou developed small molecule inhibitors to simultaneously target dual-specificity tyrosine phosphorylationregulated kinases (DYRK1A, DYRK1B, DYRK2) and CDC-like kinases (CLK1).3 Compounds were profiled in patient-derived glioblastoma cell-based models. The study centered on the 7azaindole scaffold and was guided by classic structure−activity relationships. The data generated in this study suggest that DYRK/CLK-targeted therapy may be beneficial in glioblastoma patients, wherein new therapy is urgently sought due to poor outcomes for this cancer. The team has significant expertise in the development of CNS-active compounds and recently finalized a license agreement for molecules targeting glioblastoma with Lin BioScience. Wang and colleagues report a comprehensive medicinal chemistry study to optimize novel and specific cyclin D dependent kinase (CDK4 and CDK6) inhibitors.4 The optimization approach commenced with a critical assessment of the pharmacophore to improve kinase selectivity and avoid the off-target mediated toxicity experienced by current CDK4/ 6 inhibitors. The campaign resulted in the rational development of a compound that showed exceptional selectivity for CDK4/6 with little/no effect on other kinases of the human kinome. The compound had a favorable pharmacokinetic profile and caused striking inhibition of tumor growth in acute myeloid leukemia mouse xenografts without signs of toxicity. The authors propose that the compound has excellent prospects as a clinical development candidate.

ANTIBACTERIAL MEDICINAL CHEMISTRY EXCELLENCE Oakley and colleagues present an elegant study targeting inhibition of the bacterial DNA sliding clamp mechanism of DNA polymerase.5 The paper reports the development of small molecule tetrahydrocarbazole derivatives that inhibit bacterial DNA replication, extending on earlier foundation work from this team. The compounds act by blockade of an essential protein−protein interaction between the DNA sliding clamp and conserved peptide linear motifs found in the sliding clamp partner proteins. The team explored detailed binding of compounds using a combination of isothermal calorimetry and protein X-ray crystallography. The structural analysis demonstrated that the compounds take advantage of both subsites I and II of the linear motif binding site to bind in a binding mechanism that matches that of the native peptide ligands. Blaskovich and Cooper lead the Community for Open Antimicrobial Drug Discovery (CoADD), a global open-access antibiotic screening initiative making strides toward investigating chemical diversity beyond corporate compound screening collections for antibacterial activity.6 In the selected paper, they report the design, synthesis, and bioactivity of 32 analogues of polymyxin lipodecapeptides. All analogues were evaluated against a panel of predominantly Gram-negative bacteria. Although an early phase study, the team’s approach was able to identify structure−activity and structure-toxicity relationB

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METAL-BASED MEDICINAL CHEMISTRY EXCELLENCE Rutledge, Todd, and Triccas recognized a paucity of metal containing ligands had been investigated as potential antituberculosis agents despite the ample antimicrobial success of metal-based drugs.11 They address this issue, reporting a series of cyclam−metal complexes with efficacy against intracellular drug-resistant Mycobacterium tuberculosis. Furthermore, the fluorescent properties of the compounds allowed a study of the uptake and distribution within pathogen host cells. The compounds were without toxicity to human cell lines, and their ease of synthesis, stability, and lack of patent protection flagged them as candidates for open source drug discovery, a distinct approach for new pharmaceutical development that involves the complete sharing of data and ideas as championed by the Todd group. Jansson and Richardson report a study wherein the cellular localization and mechanism of action of anticancer zinc− thiosemicarbazone ligands is characterized.12 The lead ligand employed in this study, di-2-pyridylketone-4-cyclohexyl-4methyl-3-thiosemicarbazone (DpC), has been show to overcome tumor growth, drug resistance, and metastasis and recently commenced a phase I clinical trial (NCT02688101) for a dose-finding and pharmacokinetic study in patients with advanced solid tumors. The team showed the zinc complexes sequester within lysosomes and undergo transmetalation with copper ions present in the lysosomes. The resulting copper species are redox active and induce lysosomal membrane permeability and cytotoxicity.

screening and HTS campaigns. As the promiscuous binding manifested more strongly in the fragment-based study, 2aminothiazoles were subsequently removed from the teams inhouse fragment library. This group was also responsible for Australia’s second dedicated FBDD conference, Fragment Based Drug Discovery Down Under, held in 2016. The second paper in the FBDD area comes from my own research, wherein native state mass spectrometry has been developed for the detection of fragments, complementing more widely used biophysical fragment screening methods.15 The discovery of a new and novel chemotype for an enzyme family that has been dominated for more than 70 years by one compound class of inhibitors was reported. The significance of this is that it firmly establishes that the native state mass spectrometry method is effective beyond proof-of-concept studies, with at least equal potential to other screening methods in common use to accelerate and inform the important initial steps of FBDD. Additionally, native state mass spectrometry was able to generate quantitative data and SAR using a “fragment SAR by MS” approach. Surface plasmon resonance (SPR) was used for validation, with the finding that native state mass spectrometry and SPR provide agreement of both the magnitude and trend of fragment KD values. Lastly, X-ray crystallography was employed to provide a detailed analysis of protein−fragment interactions for validated hits. In closing, the medicinal chemistry publications by Australian-based corresponding authors of the period 2015− 2017 are diverse. Projects employ small molecules, metal complexes, peptides, and peptidomimetics, while utilizing a range of supporting methods and disciplines beyond chemical synthesis and medicinal chemistry. Many of the authors may be considered international leaders in their field of expertise, with excellence being apparent across the varied and intricate study designs that incorporate elements of classic medicinal chemistry alongside refined methodologies to ensure advances within the disease focus result. Extensive collaboration (locally, internationally, within academia, and with not-for-profits and industry) has supported Australia’s medicinal chemists to be at the forefront of highly successful outcomes. “Excellence in Medicinal Chemistry from Australia” virtual issue link: http://pubs.acs.org/page/jmcmar/vi/ medchemaustralia

G-PROTEIN-COUPLED RECEPTOR MEDICINAL CHEMISTRY EXCELLENCE In addition to the above papers by Fairlie,8 Wade and Bathgate9 that report medicinal chemistry associated with G-proteincoupled receptors (GPCRs), Scammells and Lane have recently employed a bitopic ligand approach to selectively target subtypes of the muscarinic, adenosine, and dopamine GPCR families. In the selected manuscript, the team introduces a ligand fragmentation approach to delineate the orthosteric and allosteric pharmacophores of a bitopic ligand for the dopamine D2 receptor (D2R).13 They introduce stepwise structural changes to the allosteric pharmacophore, generating an extensive fragment library to optimize the allosteric pharmacophore with guidance from SAR. The team not only identified fragments with purely allosteric pharmacology, they recombined the optimized allosteric fragment with the orthotopic pharmacophore, producing a novel bitopic ligand with 10-fold increased affinity for D2R over the starting ligand and retention of negative cooperativity.

Sally-Ann Poulsen*

Griffith Institute for Drug Discovery, Griffith University, Nathan, Brisbane, Queensland 4111, Australia


Corresponding Author

*E-mail: [email protected]ffith.edu.au.


FRAGMENT BASED DRUG DISCOVERY MEDICINAL CHEMISTRY EXCELLENCE There are two papers from the period of interest that have been selected for their pioneering work in the field of fragment based drug discovery (FBDD). Scanlon and colleagues demonstrate critical assessment of fragment library collections, applying the concept of pan assay interference compounds (PAINS) to fragment screening.14 The team has built up substantial data from a large number of fragment screens using a rigorously developed in-house fragment library. Despite passing strict compound property filters, promiscuous 2-aminothiazoles (PrATs) were identified as frequent hitters in both fragment

Sally-Ann Poulsen: 0000-0003-4494-3687 Notes

Views expressed in this editorial are those of the author and not necessarily the views of the ACS.


I thank the Editors of the Journal of Medicinal Chemistry for the invitation to guest-edit this virtual issue and for the opportunity to highlight the excellence in medicinal chemistry from Australia. I am grateful to Lorraine Clark, Melanie Thomson, and Jenny Martin for providing data and/or helpful discussions. C

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(13) Mistry, S. N.; Shonberg, J.; Draper-Joyce, C. J.; Klein Herenbrink, C.; Michino, M.; Shi, L.; Christopoulos, A.; Capuano, B.; Scammells, P. J.; Lane, J. R. Discovery of a Novel Class of Negative Allosteric Modulator of the Dopamine D2 Receptor Through Fragmentation of a Bitopic Ligand. J. Med. Chem. 2015, 58, 6819− 6843. (14) Devine, S. M.; Mulcair, M. D.; Debono, C. O.; Leung, E. W. W.; Nissink, J. W. M.; Lim, S. S.; Chandrashekaran, I. R.; Vazirani, M.; Mohanty, B.; Simpson, J. S.; Baell, J. B.; Scammells, P. J.; Norton, R. S.; Scanlon, M. J. Promiscuous 2-Aminothiazoles (PrATs): A Frequent Hitting Scaffold. J. Med. Chem. 2015, 58, 1205−1214. (15) Chrysanthopoulos, P. K.; Mujumdar, P.; Woods, L. A.; Dolezal, O.; Ren, B.; Peat, T. S.; Poulsen, S.-A. Identification of a New Zinc Binding Chemotype by Fragment Screening. J. Med. Chem. 2017, 60, 7333−7349.


(1) Gilson, P. R.; Tan, C.; Jarman, K. E.; Lowes, K. N.; Curtis, J. M.; Nguyen, W.; Di Rago, A. E.; Bullen, H. E.; Prinz, B.; Duffy, S.; Baell, J. B.; Hutton, C. A.; Jousset Subroux, H.; Crabb, B. S.; Avery, V. M.; Cowman, A. F.; Sleebs, B. E. Optimization of 2-Anilino 4-Amino Substituted Quinazolines into Potent Antimalarial Agents with Oral in Vivo Activity. J. Med. Chem. 2017, 60, 1171−1188. (2) Russell, S.; Rahmani, R.; Jones, A. J.; Newson, H. L.; Neilde, K.; Cotillo, I.; Rahmani Khajouei, M.; Ferrins, L.; Qureishi, S.; Nguyen, N.; Martinez-Martinez, M. S.; Weaver, D. F.; Kaiser, M.; Riley, J.; Thomas, J.; De Rycker, M.; Read, K. D.; Flematti, G. R.; Ryan, E.; Tanghe, S.; Rodriguez, A.; Charman, S. A.; Kessler, A.; Avery, V. M.; Baell, J. B.; Piggott, M. J. Hit-to-Lead Optimization of a Novel Class of Potent, Broad-Spectrum Trypanosomacides. J. Med. Chem. 2016, 59, 9686−9720. (3) Zhou, Q.; Phoa, A. F.; Abbassi, R. H.; Hoque, M.; Reekie, T. A.; Font, J. S.; Ryan, R. M.; Stringer, B. W.; Day, B. W.; Johns, T. G.; Munoz, L.; Kassiou, M. Structural Optimization and Pharmacological Evaluation of Inhibitors Targeting Dual-Specificity Tyrosine Phosphorylation-Regulated Kinases (DYRK) and CDC-like kinases (CLK) in Glioblastoma. J. Med. Chem. 2017, 60, 2052−2070. (4) Tadesse, S.; Yu, M.; Mekonnen, L. B.; Lam, F.; Islam, S.; Tomusange, K.; Rahaman, M. H.; Noll, B.; Basnet, S. K. C.; Teo, T.; Albrecht, H.; Milne, R.; Wang, S. Highly Potent, Selective, and Orally Bioavailable 4-Thiazol-N-(pyridin-2-yl)pyrimidin-2-amine Cyclin-Dependent Kinases 4 and 6 Inhibitors as Anticancer Drug Candidates: Design, Synthesis, and Evaluation. J. Med. Chem. 2017, 60, 1892− 1915. (5) Yin, Z.; Whittell, L. R.; Wang, Y.; Jergic, S.; Ma, C.; Lewis, P. J.; Dixon, N. E.; Beck, J. L.; Kelso, M. J.; Oakley, A. J. Bacterial Sliding Clamp Inhibitors that Mimic the Sequential Binding Mechanism of Endogenous Linear Motifs. J. Med. Chem. 2015, 58, 4693−4702. (6) Gallardo-Godoy, A.; Muldoon, C.; Becker, B.; Elliott, A. G.; Lash, L. H.; Huang, J. X.; Butler, M. S.; Pelingon, R.; Kavanagh, A. M.; Ramu, S.; Phetsang, W.; Blaskovich, M. A. T.; Cooper, M. A. Activity and Predicted Nephrotoxicity of Synthetic Antibiotics Based on Polymyxin B. J. Med. Chem. 2016, 59, 1068−1077. (7) de Veer, S. J.; Wang, C. K.; Harris, J. M.; Craik, D. J.; Swedberg, J. E. Improving the Selectivity of Engineered Protease Inhibitors: Optimizing the P2 Prime Residue Using a Versatile Cyclic Peptide Library. J. Med. Chem. 2015, 58, 8257−8268. (8) Hoang, H. N.; Song, K.; Hill, T. A.; Derksen, D. R.; Edmonds, D. J.; Kok, W. M.; Limberakis, C.; Liras, S.; Loria, P. M.; Mascitti, V.; Mathiowetz, A. M.; Mitchell, J. M.; Piotrowski, D. W.; Price, D. A.; Stanton, R. V.; Suen, J. Y.; Withka, J. M.; Griffith, D. A.; Fairlie, D. P. Short Hydrophobic Peptides with Cyclic Constraints Are Potent Glucagon-like Peptide-1 Receptor (GLP-1R) Agonists. J. Med. Chem. 2015, 58, 4080−4085. (9) Hojo, K.; Hossain, M. A.; Tailhades, J.; Shabanpoor, F.; Wong, L. L. L.; Ong-Pålsson, E. E. K.; Kastman, H. E.; Ma, S.; Gundlach, A. L.; Rosengren, K. J.; Wade, J. D.; Bathgate, R. A. D. Development of a Single-Chain Peptide Agonist of the Relaxin-3 Receptor Using Hydrocarbon Stapling. J. Med. Chem. 2016, 59, 7445−7456. (10) Bansal, P. S.; Smout, M. J.; Wilson, D.; Cobos Caceres, C.; Dastpeyman, M.; Sotillo, J.; Seifert, J.; Brindley, P. J.; Loukas, A.; Daly, N. L. Development of a Potent Wound Healing Agent Based on the Liver Fluke Granulin Structural Fold. J. Med. Chem. 2017, 60, 4258− 4266. (11) Yu, M.; Nagalingam, G.; Ellis, S.; Martinez, E.; Sintchenko, V.; Spain, M.; Rutledge, P. J.; Todd, M. H.; Triccas, J. A. Nontoxic Metal− Cyclam Complexes, a New Class of Compounds with Potency against Drug-Resistant Mycobacterium tuberculosis. J. Med. Chem. 2016, 59, 5917−5921. (12) Stacy, A. E.; Palanimuthu, D.; Bernhardt, P. V.; Kalinowski, D. S.; Jansson, P. J.; Richardson, D. R. Zinc(II)−Thiosemicarbazone Complexes Are Localized to the Lysosomal Compartment Where They Transmetallate with Copper Ions to Induce Cytotoxicity. J. Med. Chem. 2016, 59, 4965−4984. D

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Editorial: Excellence in Medicinal Chemistry from Australia.

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