Recent disclosures of clinical candidates. Highlights from the Society of Medicines Research Symposium, held December 4, 2014 - National Heart & Lung Institute, London, UK

Abstract

This symposium featured an international line-up of speakers presenting on the discovery and clinical development of novel therapeutic agents. The program included the Society of Medicines Research (SMR) Award Lecture, given by Dr. Betty Chang from Pharmacyclics on the discovery and development of the marketed drug ibrutinib, as well as talks, several representing first U.K. disclosures, on Toll-like receptor 7 (TLR7) agonists, Na v 1.

Inhibition of Wild-Type p53-Expressing AML by the Novel Small Molecule HDM2 Inhibitor CGM097

“…The synthesis and binding affinity to MDM2 of CGM097 have been described and disclosed (38). Briefly, a screen of 50,000 compounds exploiting a three hotspot 2D/3D pharmacophore led to identification of a series of isoquinolinones, the subsequent optimization of which revealed a novel binding mode with changes in protein organization associated with His 96 interactions (38).…”

“…Briefly, a screen of 50,000 compounds exploiting a three hotspot 2D/3D pharmacophore led to identification of a series of isoquinolinones, the subsequent optimization of which revealed a novel binding mode with changes in protein organization associated with His 96 interactions (38). Additional changes resulted in the clinical candidate CGM097, a substituted 1,2-dihydroisoquinolinone derivative designed to mimic three key hydrophobic interactions made by p53 residues with Phe19, Trp23 and Leu26 in the HDM2 pocket (8, 39).…”

“…Additional changes resulted in the clinical candidate CGM097, a substituted 1,2-dihydroisoquinolinone derivative designed to mimic three key hydrophobic interactions made by p53 residues with Phe19, Trp23 and Leu26 in the HDM2 pocket (8, 39). CGM097 (structure revealed in 38, 40) binds to the p53 pocket of HDM2 with high potency and exceptional selectivity; in biochemical assays, CGM097 displaces the p53 peptide from the surface of HDM2 with an IC 50 of 1.7 nM, compared with an IC 50 of 2,000 nM for HDMX (38, 40). In a cell proliferation assay, CGM097 inhibited the growth of HCT-116 p53 WT cells with a GI 50 of 454 nM and of HCT-116 p53-null cells with a GI 50 of 15,983 nM (38, 40).…”

“…CGM097 (structure revealed in 38, 40) binds to the p53 pocket of HDM2 with high potency and exceptional selectivity; in biochemical assays, CGM097 displaces the p53 peptide from the surface of HDM2 with an IC 50 of 1.7 nM, compared with an IC 50 of 2,000 nM for HDMX (38, 40). In a cell proliferation assay, CGM097 inhibited the growth of HCT-116 p53 WT cells with a GI 50 of 454 nM and of HCT-116 p53-null cells with a GI 50 of 15,983 nM (38, 40). In contrast to HDM2 inhibitors, such as nutlin-3, which have been shown to display limited bioavailability in oral formulations in preclinical models (41), CGM097 is well-absorbed with a moderate to high oral bioavailability ranging from 57 to 81% across multiple animal species tested (mouse, rat, dog and monkey) (38, 42).…”

Benzoxazolinone aryl sulfonamides as potent, selective Na v 1.7 inhibitors with in vivo efficacy in a preclinical pain model

“…In addition, potent and selective acyl sulfonamides have been reported by Amgen (i.e. compound 2) 18 , Pfizer 19 and Merck, 20 with competitive binding studies suggesting a similar binding mode to the aryl sulfonamides.…”