Design, Synthesis, and Mechanism Study of Novel BMX Inhibitors Based on the Core of 1,3,5-Triazin-2-Amine for the Treatment of Gastric Carcinoma

BMX, a member of the Tec family of kinases, plays a pivotal
role
in the occurrence and progression of cancers and multiple chronic
inflammations. However, there are rarely BMX inhibitors reported,
and the signaling pathways mediated by BMX are still poorly understood.
In this study, a series of novel BMX inhibitors bearing the core of
1,3,5-triazin-2-amine were designed and synthesized by structural
modifications from the lead compound B1c. Among them,
compound B6a irreversibly and selectively inhibited BMX
(IC50 = 12 nM) and displayed good antiproliferative activities
in various cancer cell lines. A mechanism study in gastric carcinoma
HGC-27 and MGC-803 cells revealed that B6a promoted cell
cycle arrest and apoptosis, triggered protective autophagy, and suppressed
the BMX/AKT/mTOR pathway. Notably, although B6a’s
bioavailability was extremely low, it still exhibited excellent antitumor
potency in the HGC-27 xenograft model with high safety, demonstrating
that B6a was a promising BMX inhibitor and worth further
exploration.