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

Abstract

Pan-BET inhibitors have shown profound efficacy in a number of in vivo preclinical models and have entered the clinic in oncology trials where adverse events have been reported. These inhibitors interact equipotently with the eight bromodomains of the BET family of proteins. To better understand the contribution of each domain to their efficacy and to improve from their safety profile, selective inhibitors are required. This Letter discloses the profile of GSK973, a highly selective inhibitor of the second bromodomains of the BET proteins that has undergone extensive preclinical in vitro and in vivo characterization.

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

“…1 H NMR (400 MHz, MeOH-d 4 ): δ ppm 8.46 (d, 1H, J = 1.5 Hz), 8.12 (d, 1H, J = 1.5 Hz), 2.96 (s, 3H), 1.62 (s, 9H); LCMS (formic): R t = 1.15 min, [M + H] + 315/317, 76% purity. 2-Bromo-6-(methylcarbamoyl)isonicotinic Acid (46). tert-Butyl 2bromo-6-(methylcarbamoyl)isonicotinate (45, 667 mg, 2.12 mmol) was dissolved in DCM (12 mL) and TFA (3 mL, 38.9 mmol) was added, and the reaction stirred at room temperature for 5 h. The solution was concentrated to afford the title compound 46 (648 mg, 80 wt %, 2.13 mmol, 100% yield) and was used crude in further synthesis.…”

“…These inhibitors showed high levels of potency and selectivity (similar to 5) but again exhibited nonideal solubility. 46 Herein, we describe the development of a series of BD2 selective ligands with similar potency, selectivity, and in vivo pharmacokinetics to compounds 3 and 4 but with an improved developability profile, in particular increased solubility in biorelevant media, for example, FaSSIF.…”

“…We have recently reported our own effort toward the identification of drug-like selective BD1 , or BD2 − inhibitors and have characterized their impact on chromatin binding and their efficacy in in vitro and in vivo models of oncology and inflammation …”

Fragment-based Scaffold Hopping: Identification of Potent, Selective, and Highly Soluble Bromo and Extra Terminal Domain (BET) Second Bromodomain (BD2) Inhibitors

“…In particular, for oral molecules, it is accepted that suitable intestinal solubility to deliver the predicted efficacious dose correlates with improved probability of success in development. In Figure , the previous GSK BD2 inhibitors ( 1–4 ) − alongside ABBV-744 ( 5 ) are shown, with their potency, selectivity, and developability properties in Table . All of these molecules are pan-BD2 inhibitors, with similar published data for the four isoforms.…”

Design, synthesis, biological evaluation, and molecular docking of 1,7-dibenzyl-substituted theophylline derivatives as novel BRD4-BD1-selective inhibitors

“…Furthermore, although drug-like properties of BRD4 inhibitors have been verified preliminarily in clinical trials for the treatment of cancers and cardiovascular diseases [18][19][20][21][22][23][24][25][26][27], only a few inhibitors fulfill the selectivity between two tandem bromodomains of BRD4 (Fig. 1A) [28][29][30][31][32][33] and mechanism-based toxicity appeared in clinical trials of some pan-BRD4 inhibitors, such as thrombocytopenia and gastrointestinal toxicity [24,34], impeding more extensive clinical application. Hence the acquisition of novel BRD4 inhibitors with excellent selectivity is imperative.…”