Discovery and optimization of novel 4-morpholinothieno[3,2-d]pyrimidine derivatives as potent BET inhibitors for cancer therapy.

The identification of structurally novel and potently active BET inhibitors represents a significant advancement in the field of anticancer therapeutics. In the present investigation, leveraging the outcomes of previous screening endeavors, we successfully optimized and synthesized a novel series of bromodomain and extra-terminal (BET) inhibitors with a 4-morpholinothieno[3,2-d]pyrimidine structure. Among the synthesized compounds, compound 6c emerged as a promising candidate, exhibiting exceptional inhibitory activities against various BET isoform proteins, with IC values ranging from 3.3 to 42.0 nM. In cellular assays, compound 6c demonstrated robust antiproliferative effects in SU-DHL-4 cells, achieving an IC value of 8.6 ± 3.3 nM. Further mechanistic studies revealed that compound 6c effectively decreased the expression of c-Myc, a critical oncogenic driver regulated by the BET protein, and induced cell cycle arrest at the G1 phase, as well as cell apoptosis, in a dose-dependent manner. Moreover, in-silico prediction of the physiochemical and pharmacokinetic properties clarified that compound 6c has acceptable drug-like profiles. Taken these findings together, compound 6c represents a novel and potent BET inhibitor, thus positioning it as a promising candidate for subsequent pre-clinical evaluations in the realm of cancer therapy.