6tq1

Publication Abstract from PubMed

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 property-based 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.

Discovery of a Bromodomain and Extraterminal Inhibitor with a Low Predicted Human Dose through Synergistic Use of Encoded Library Technology and Fragment Screening.,Wellaway CR, Amans D, Bamborough P, Barnett H, Bit RA, Brown JA, Carlson NR, Chung CW, Cooper AWJ, Craggs PD, Davis RP, Dean TW, Evans JP, Gordon L, Harada IL, Hirst DJ, Humphreys PG, Jones KL, Lewis AJ, Lindon MJ, Lugo D, Mahmood M, McCleary S, Medeiros P, Mitchell DJ, O'Sullivan M, Le Gall A, Patel VK, Patten C, Poole DL, Shah RR, Smith JE, Stafford KAJ, Thomas PJ, Vimal M, Wall ID, Watson RJ, Wellaway N, Yao G, Prinjha RK J Med Chem. 2020 Jan 23;63(2):714-746. doi: 10.1021/acs.jmedchem.9b01670. Epub, 2020 Jan 6. PMID:31904959^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.