Design and Synthesis of a Highly Selective and In Vivo-Capable Inhibitor of the Second Bromodomain of the Bromodomain and Extra Terminal Domain Family of Proteins

Abstract

Pan-bromodomain and extra terminal domain (BET) inhibitors interact equipotently with the eight bromodomains of the BET family of proteins and have shown profound efficacy in a number of in vitro phenotypic assays and in vivo pre-clinical models in inflammation or oncology. A number of these inhibitors have progressed to the clinic where pharmacology-driven adverse events have been reported. To better understand the contribution of each domain to their efficacy and improve their safety profile, selective inhibitors are required. This article discloses the profile of GSK046, also known as iBET-BD2, a highly selective inhibitor of the second bromodomains of the BET proteins that has undergone extensive pre-clinical in vitro and in vivo characterization.

Targeting Bromodomain and Extraterminal Proteins for Drug Discovery: From Current Progress to Technological Development

“…GSK046 (iBET-BD2, 14 ), although less effective than 8 in the human cancer cell lines examined, exhibits more than 300 times higher selectivity for BD2 over BD1 and appears to ameliorate inflammatory disease in preclinical models . A recent study shows that compound 14 has physicochemical and pharmacokinetic properties suitable for use in vivo , and it retains the ability to effectively inhibit the release of MCP-1 cytokines (pIC 50 = 7.5) in the cellular and whole blood environment . Interestingly, the inhibition of BD1 or BD2 leads to the suppression of MCP-1 despite the fact that these two types of inhibitors have distinct selectivity profiles.…”

Identification of a Series of N-Methylpyridine-2-carboxamides as Potent and Selective Inhibitors of the Second Bromodomain (BD2) of the Bromo and Extra Terminal Domain (BET) Proteins

“…26,38 We have recently reported our own effort toward the identification of drug-like selective BD1 37,44 or BD2 45−47 inhibitors and have characterized their impact on chromatin binding and their efficacy in in vitro and in vivo models of oncology and inflammation. 48 Regarding the discovery of BD2 selective inhibitors, we identified the two hits 1 and 2 by high throughput screening of the GSK compound collection (≈2 M compounds) which led, through a program of optimization, to the identification of potent and selective pan-BD2 selective inhibitors 3 (GSK620), 47 4 (GSK549), 47 and 5 (GSK046), 45 as shown in Figure 2, (BRD4 data used is representative of the other isoforms). Both 3 and 4 were demonstrated to have excellent in vivo pharmacokinetics in rat and dog and developability properties, with the exception of their moderate fasted state simulated intestinal fluid (FaSSIF) solubilities, driven by their highly crystalline nature.…”

GSK973 Is an Inhibitor of the Second Bromodomains (BD2s) of the Bromodomain and Extra-Terminal (BET) Family

“…We (refs − ) like others (refs and ) have recently disclosed the identification of drug-like selective pan-BD2 inhibitors. In particular, we have disclosed the profile of a series of pyridone derivatives with excellent selectivity for BD2s over BD1s (ref ).…”