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Woolford et al., “Fragment-Based Approach to the Development of an Orally Bioavailable Lactam Inhibitor of Lipoprotein-Associated Phospholipase A2 (Lp-PLA2).” J. Med. Chem., 2016, 59 (23), pp 10738–10749

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Abstract

Lp-PLA2 has been explored as a target for a number of inflammation associated diseases, including cardiovascular disease and dementia. This article describes the discovery of a new fragment derived chemotype that interacts with the active site of Lp-PLA2. The starting fragment hit was discovered through an X-ray fragment screen and showed no activity in the bioassay (IC50 > 1 mM). The fragment hit was optimized using a variety of structure-based drug design techniques, including virtual screening, fragment merging, and improvement of shape complementarity. A novel series of Lp-PLA2 inhibitors was generated with low lipophilicity and a promising pharmacokinetic profile.

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Woolford et al. “Fragment-Based Approach to the Development of an Orally Bioavailable Lactam Inhibitor of Lipoprotein-Associated Phospholipase A2 (Lp-PLA2)” J. Med. Chem., 2016, 59 (23), pp 10738–10749, DOI: 10.1021/acs.jmedchem.6b01427

Lebraud et al. “Protein Degradation by In-Cell Self-Assembly of Proteolysis Targeting Chimeras.” ACS Cent. Sci.,2016, 2 (12), pp 927–934

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Summary

Selective degradation of proteins by proteolysis targeting chimeras (PROTACs) offers a promising potential alternative to protein inhibition for therapeutic intervention. Current PROTAC molecules incorporate a ligand for the target protein, a linker, and an E3 ubiquitin ligase recruiting group, which bring together target protein and ubiquitinating machinery. Such hetero-bifunctional molecules require significant linker optimization and possess high molecular weight, which can limit cellular permeation, solubility, and other drug-like properties. We show here that the hetero-bifunctional molecule can be formed intracellularly by bio-orthogonal click combination of two smaller precursors. We designed a tetrazine tagged thalidomide derivative which reacts rapidly with a trans-cyclo-octene tagged ligand of the target protein in cells to form a cereblon E3 ligase recruiting PROTAC molecule. The in-cell click-formed proteolysis targeting chimeras (CLIPTACs) were successfully used to degrade two key oncology targets, BRD4 and ERK1/2. ERK1/2 degradation was achieved using a CLIPTAC based on a covalent inhibitor. We expect this approach to be readily extendable to other inhibitor-protein systems because the tagged E3 ligase recruiter is capable of undergoing the click reaction with a suitably tagged ligand of any protein of interest to elicit its degradation.

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Lebraud et al. “Protein Degradation by In-Cell Self-Assembly of Proteolysis Targeting Chimeras.” ACS Cent. Sci.,2016, 2 (12), pp 927–934 DOI: 10.1021/acscentsci.6b00280

Fang et al.. “: The Novel, Small-Molecule DNA Methylation Inhibitor SGI-110 as an Ovarian Cancer Chemosensitizer.” Clin Cancer Res; 20(24) December 15, 2014

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Summary

PURPOSE: To investigate SGI-110 as a “chemosensitizer” in ovarian cancer and to assess its effects on tumor suppressor genes (TSG) and chemoresponsiveness-associated genes silenced by DNA methylation in ovarian cancer.

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Fang et al.. “: The Novel, Small-Molecule DNA Methylation Inhibitor SGI-110 as an Ovarian Cancer Chemosensitizer.” Clin Cancer Res; 20(24) December 15, 2014

Smyth et al.. “Inhibition of HSP90 by AT13387 Delays the Emergence of Resistance to BRAF Inhibitors and Overcomes Resistance to Dual BRAF and MEK Inhibition in Melanoma Models.” Mol Cancer Ther 2014;13:2793-2804.

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Summary

Emergence of clinical resistance to BRAF inhibitors, alone or in combination with MEK inhibitors, limits clinical responses in melanoma. Inhibiting HSP90 offers an approach to simultaneously interfere with multiple resistance mechanisms. Using the HSP90 inhibitor AT13387, which is currently in clinical trials, we investigated the potential of HSP90 inhibition to overcome or delay the emergence of resistance to these kinase inhibitors in melanoma models. In vitro, treating vemurafenib-sensitive cells (A375 or SK-MEL-28) with a combination of AT13387 and vemurafenib prevented colony growth under conditions in which vemurafenib treatment alone generated resistant colonies. In vivo, when AT13387 was combined with vemurafenib in a SK-MEL-28, vemurafenib-sensitive model, no regrowth of tumors was observed over 5 months, although 2 of 7 tumors in the vemurafenib monotherapy group relapsed in this time. Together, these data suggest that the combination of these agents can delay the emergence of resistance. Cell lines with acquired vemurafenib resistance, derived from these models (A375R and SK-MEL-28R) were also sensitive to HSP90 inhibitor treatment; key clients were depleted, apoptosis was induced, and growth in 3D culture was inhibited. Similar effects were observed in cell lines with acquired resistance to both BRAF and MEK inhibitors (SK-MEL-28RR, WM164RR, and 1205LuRR). These data suggest that treatment with an HSP90 inhibitor, such as AT13387, is a potential approach for combating resistance to BRAF and MEK inhibition in melanoma. Moreover, frontline combination of these agents with an HSP90 inhibitor could delay the emergence of resistance, providing a strong rationale for clinical investigation of such combinations in BRAF-mutated melanoma. Mol Cancer Ther; 13(12); 2793–804. ©2014 AACR.

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Smyth et al.. “Inhibition of HSP90 by AT13387 Delays the Emergence of Resistance to BRAF Inhibitors and Overcomes Resistance to Dual BRAF and MEK Inhibition in Melanoma Models.” Mol Cancer Ther 2014;13:2793-2804.

Chen et al. “A Phase 1 Study of cyclin-dependent kinase inhibitor, AT7519, in patients with advanced cancer: NCIC Clinical Trials Group IND 177.” Br. J. Cancer 2014 Dec 9; 111(12):2262-7

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Summary

BACKGROUND: AT7519 is a small-molecular inhibitor of multiple cyclin-dependent kinases (CDKs). It shows encouraging anti-cancer activity against multiple cell lines and in tumour xenografts. This phase I study was conducted to evaluate the safety and tolerability of AT7519 given as 1-h intravenous infusion on days 1, 4, 8 and 11 every 3 weeks.

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Chen et al. “A Phase 1 Study of cyclin-dependent kinase inhibitor, AT7519, in patients with advanced cancer: NCIC Clinical Trials Group IND 177.” Br. J. Cancer 2014 Dec 9; 111(12):2262-7

Johnson et al. “Structure-Based Design of Type II Inhibitors Applied to Maternal Embryonic Leucine Zipper Kinase.” ACS Medicinal Chemistry Letters, DOI: 10.1021/ml5001273

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Summary

A novel Type II kinase inhibitor chemotype has been identified for maternal embryonic leucine zipper kinase (MELK) using structure-based ligand design. The strategy involved structural characterization of an induced DFG-out pocket by protein–ligand X-ray crystallography and incorporation of a slender linkage capable of bypassing a large gate-keeper residue, thus enabling design of molecules accessing both hinge and induced pocket regions. Optimization of an initial hit led to the identification of a low-nanomolar, cell-penetrant Type II inhibitor suitable for use as a chemical probe for MELK.

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Johnson et al. “Structure-Based Design of Type II Inhibitors Applied to Maternal Embryonic Leucine Zipper Kinase.” ACS Medicinal Chemistry Letters, DOI: 10.1021/ml5001273

Hopkins et al. “The role of ligand efficiency metrics in drug discovery.” Nature Reviews Drug Discovery vol.13 (2014): 105-121. DOI: 10.1038/nrd4163

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Summary

The judicious application of ligand or binding efficiency metrics, which quantify the molecular properties required to obtain binding affinity for a drug target, is gaining traction in the selection and optimization of fragments, hits and leads. Retrospective analysis of recently marketed oral drugs shows that they frequently have highly optimized ligand efficiency values for their targets. Optimizing ligand efficiency metrics based on both molecular mass and lipophilicity, when set in the context of the specific target, has the potential to ameliorate the inflation of these properties that has been observed in current medicinal chemistry practice, and to increase the quality of drug candidates.

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Hopkins et al. “The role of ligand efficiency metrics in drug discovery.” Nature Reviews Drug Discovery vol.13 (2014): 105-121. DOI: 10.1038/nrd4163

Saxty et al. “Identification of orally bioavailable small-molecule inhibitors of hematopoietic prostaglandin D2 synthase using X-ray fragment based drug discovery.” Med. Chem. Commun. vol.5 (2014): 134-141. DOI: 10.1039/c3md00280b

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Summary

Using X-ray crystallographic screening, fragments 4 and 6 were identified as inhibitors of hematopoietic prostaglandin D2 synthase (H-PGDS). Both fragments induced a small protein movement in the X-ray crystal structure relative to the apo structure, where the highly polar nature of the ligand complemented the induced protein conformation. The manuscript describes the fragment optimisation of 4 and 6 followed by fragment growth to lead molecule 10. This showed favourable physicochemical properties and evidence of oral activity in blocking PGD2 generation in vivo.

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Saxty et al. “Identification of orally bioavailable small-molecule inhibitors of hematopoietic prostaglandin D2 synthase using X-ray fragment based drug discovery.” Med. Chem. Commun. vol.5 (2014): 134-141. DOI: 10.1039/c3md00280b

Shapiro et al.. “First-in-Human Phase I Dose Escalation Study of a Second-Generation Non-Ansamycin HSP90 Inhibitor, AT13387, in Patients with Advanced Solid Tumors.” Clinical Cancer Research. 21 October 2014. DOI: 10.1158/1078-0432.CCR-14-0979

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Summary

Purpose: AT13387 is a potent second-generation, fragment-derived HSP90 inhibitor. This phase I study investigated the maximum tolerated dose (MTD)/recommended phase II dose (RP2D) and safety, pharmacokinetic, and pharmacodynamic profiles of two AT13387 regimens in a refractory solid tumor population.

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Shapiro et al.. “First-in-Human Phase I Dose Escalation Study of a Second-Generation Non-Ansamycin HSP90 Inhibitor, AT13387, in Patients with Advanced Solid Tumors.” Clinical Cancer Research. 21 October 2014. DOI: 10.1158/1078-0432.CCR-14-0979

Saalau-Bethell et al.. “Crystal Structure of Human Soluble Adenylate Cyclase Reveals a Distinct, Highly Flexible Allosteric Bicarbonate Binding Pocket.” ChemMedChem, 24 February 2014. DOI: 10.1002/cmdc.201300480

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Summary

Soluble adenylate cyclases catalyse the synthesis of the second messenger cAMP through the cyclisation of ATP and are the only known enzymes to be directly activated by bicarbonate. Here, we report the first crystal structure of the human enzyme that reveals a pseudosymmetrical arrangement of two catalytic domains to produce a single competent active site and a novel discrete bicarbonate binding pocket. Crystal structures of the apo protein, the protein in complex with α,β-methylene adenosine 5′-triphosphate (AMPCPP) and calcium, with the allosteric activator bicarbonate, and also with a number of inhibitors identified using fragment screening, all show a flexible active site that undergoes significant conformational changes on binding of ligands. The resulting nanomolar-potent inhibitors that were developed bind at both the substrate binding pocket and the allosteric site, and can be used as chemical probes to further elucidate the function of this protein.

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Saalau-Bethell et al.. “Crystal Structure of Human Soluble Adenylate Cyclase Reveals a Distinct, Highly Flexible Allosteric Bicarbonate Binding Pocket.” ChemMedChem, 24 February 2014. DOI: 10.1002/cmdc.201300480