Discovery of a Bromodomain and Extraterminal Inhibitor with a Low Predicted Human Dose through Synergistic Use of Encoded Library Technology and Fragment Screening

Abstract

The bromodomain and extraterminal (BET) family of bromodomain-containing proteins are important regulators of the epigenome through their ability to recognize N-acetyl lysine (KAc) post-translational modifications on histone tails. These interactions have been implicated in various disease states and, consequently, disruption of BET− KAc binding has emerged as an attractive therapeutic strategy with a number of small molecule inhibitors now under investigation in the clinic. However, until the utility of these advanced candidates is fully assessed by these trials, there remains scope for the discovery of inhibitors from new chemotypes with alternative physicochemical, pharmacokinetic, and pharmacodynamic profiles. Herein, we describe the discovery of a candidate-quality dimethylpyridone benzimidazole compound which originated from the hybridization of a dimethylphenol benzimidazole series, identified using encoded library technology, with an N-methyl pyridone series identified through fragment screening. Optimization via structure-and propertybased design led to I-BET469, which possesses favorable oral pharmacokinetic properties, displays activity in vivo, and is projected to have a low human efficacious dose.

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

“…2-((1H-Indol-4-yl)methyl)-6-(methylcarbamoyl)isonicotinic Acid (51). tert-Butyl 2-(chloromethyl)-6-(methylcarbamoyl)isonicotinate (50, 1 g, 3.51 mmol) was taken up in 1,4-dioxane (20 mL) and water (10 mL).…”

Recent developments in epigenetic cancer therapeutics: clinical advancement and emerging trends

“…Among the bromodomain containing proteins, BET family (BRD2, BRD3, BRD4, and BRDT) has been the most extensively explored and the results of these explorations has ascertained its links with diverse cancers. In light of the aforementioned, the BET family of proteins represents a well-established therapeutic target for oncology and immunoinflammation indications [270][271][272] and numerous small molecule inhibitors capable of abrogating the BET − KAc interactions are currently under clinical investigation (Fig. 7).…”

Trends in Hit-to-Lead Optimization Following DNA-Encoded Library Screens

“…In a separate study, DEL screening identified a structurally novel second generation bromodomain and extraterminal (BET) inhibitor using His-tagged BRD4. 26 The hit-to-lead optimization strategy was derived from an analysis of attrition causes for the first generation BET inhibitors as well as the risk of submaximal target engagement for these compounds due to low systemic concentrations following oral dosing. The strategy therefore emphasized physicochemical properties, solubility, and predicted human daily dose.…”