BRD4
has recently emerged as a promising drug target. Therefore,
identifying novel inhibitors with distinct properties could enrich
their use in anticancer treatment. Guided by the cocrystal structure
of hit compound 4 harboring a five-membered-ring linker
motif, we quickly identified lead compound 7, which exhibited
good antitumor effects in an MM.1S xenograft model by oral administration.
Encouraged by its high potency and interesting scaffold, we performed
further lead optimization to generate a novel potent series of bromodomain
and extra-terminal (BET) inhibitors with a (1,2,4-triazol-5-yl)-3,4-dihydroquinoxalin-2(1H)-one structure. Among them, compound 19 was
found to have the best balance of activity, stability, and antitumor
efficacy. After confirming its low brain penetration, we conducted
comprehensive preclinical studies, including a multiple-species pharmacokinetics
profile, extensive cellular mechanism studies, hERG assay, and in
vivo antitumor growth effect testing, and we found that compound 19 is a potential BET protein drug candidate for the treatment
of cancer.
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