Design, synthesis, and biological evaluation of novel 4,4‐difluoro‐1‐methyl‐N, 6‐diphenyl‐5, 6‐dihydro‐4H‐pyrimido [4, 5‐b] [1, 2, 4] triazolo [4, 3‐d] [1, 4] diazepin‐8‐amine derivatives as potential BRD4 inhibitors

Abstract

Bromodomain‐containing protein 4 (BRD4) plays an extremely important physiological role in cancer, and the BRD4 inhibitors can effectively inhibit the proliferation of tumor cells. By taking BI‐2536 (PLK1 and BRD4 inhibitor) as the lead compound, sixteen novel BRD4 inhibitors with the 4,4‐difluoro‐1‐methyl‐N,6‐diphenyl‐5,6‐dihydro‐4H‐pyrimido[4,5‐b] [1,2,4] triazolo[4,3‐d] [1,4] diazepine‐8‐amine structure were designed and synthetized. Among the target compounds, compound 15h exhibited outstanding inhibition for BRD4‐BD1 (IC50 value of 0.42 μM) in the BRD4‐BD1 inhibitory activity assay. Additionally, cell growth inhibition assay demonstrated that compound 15h potently suppressed the proliferation of MV4‐11 cells (IC50 value of 0.51 μM). Besides, compound 15h induced apoptosis and G0/G1 cycle arrest in MV4‐11 leukemia cells effectively, and downregulated the expression of c‐Myc in a dose‐dependent manner. In summary, the optimal compound 15h is expected to become the clinical therapeutic drug for further research.

Discovery of potent BET bromodomain 1 stereoselective inhibitors using DNA-encoded chemical library selections

“…Since the report of JQ1 in 2010 ( 8 ), BET bromodomains have emerged as intriguing targets in a variety of diseases, with both tool and clinical compounds reported in the intervening decade. Given the class-wide thrombocytopenia seen with clinical pan-BET inhibitors, recent efforts have focused on BD-specific inhibitors ( 12 – 14 , 20 , 22 – 30 , 35 ). Our findings of BET BD1-specific inhibitors allow us to dissect the role of this bromodomain specifically in spermatogenesis and in cancer ( 21 ).…”

“…Thus, the challenge of overcoming off-target tissue toxicity while maintaining antitumor efficacy remains for all pan-BET small-molecule inhibitors. Recent evidence indicates small-molecule inhibition of the bromodomain 1 (BD1) of BRD4 has similar effects to inhibition of both bromodomains ( 12 – 15 ), while inhibition of BD2 may have more selective effects ( 12 , 16 ). In analogous fashion, it is the first bromodomain of BRDT (BRDT-BD1) that has been shown to be specifically essential for fertility in mice ( 17 – 19 ).…”

“…Comparably, extensive efforts have been directed toward the discovery of BET BD1-specific inhibitors, starting from the early identification of less-potent pan-BD1-biased small molecules ( 13 , 14 , 24 – 30 ). Recently, LT052 was reported to be the first potent inhibitor with 138-fold selectivity for BRD4-BD1 over BRD4-BD2 as confirmed in BROMO scan assays.…”