Discovery of a Selective Irreversible BMX Inhibitor for Prostate Cancer

BMX is a member of the TEC family
of nonreceptor tyrosine kinases.
We have used structure-based drug design in conjunction with kinome
profiling to develop a potent, selective, and irreversible BMX kinase
inhibitor, BMX-IN-1, which covalently modifies Cys496. BMX-IN-1 inhibits
the proliferation of Tel-BMX-transformed Ba/F3 cells at two digit
nanomolar concentrations but requires single digit micromolar concentrations
to inhibit the proliferation of prostate cancer cell lines. Using
a combinatorial kinase inhibitor screening strategy, we discovered
that the allosteric Akt inhibitor, MK2206, is able to potentiate BMX
inhibitor’s antiproliferation efficacy against prostate cancer
cells.