A Chinese study team led by Professor LIU Qingsong and Professor LIU Jing at High Magnetic Field Laboratory, Chinese Academy of Sciences (CHMFL) of the Chinese Academy of Sciences discovered a highly potent and selective type II irreversible bone marrow kinase in the X chromosome (BMX) kinase inhibitor.

As a member of TEC family, BMX is a non-receptor tyrosine kinase. Varieties of biological evidence demonstrate that BMX is involved in tumorigenicity, cell motility, adhesion, angiogenesis, proliferation, and differentiation.

BMX is expressed primarily in bone marrow but also wildly found in granulo/monocytic cells, epithelial and endothelial cells, as well as brain, prostate, heart, and lung.

Given the fact that BMX mediated signaling pathway in the physiological and pathological context is still not fully understood yet, selective BMX kinase inhibitors are highly desired for mechanistic investigation and proof-of-concept efficacy validation.

Based on the X-ray structure of BMX kinase, the team designed a highly selective type II irreversible BMX kinase inhibitor CHMFL-BMX-078, through combination of irreversible inhibitor design and type II inhibitor design approaches.

The new inhibitor is bound to the “DFG-out” inactive conformation of BMX kinase, meanwhile took advantage of the cysteine 496 residue to form a covalent bond.

CHMFL-BMX-078 exhibited an IC50 of 11 nM against BMX kinase and exhibited great selectivity over kinases such as BTK, JAK3, EGFR, and MAP2K7 that bore a structurally identical cysteine residue in BMX kinase.

CHMFL-BMX-078 displayed a high selectivity profile (S score(1) = 0.01) against the 468 kinases/mutants in the KINOMEscan evaluation and achieved at least 40-fold selectivity over BTK kinase.

Molecule docking results of CHMFL-BMX-078 and BMX suggested a type II irreversible binding mode, which was proved to be biologically relevant and LC-MS/MS.

CHMFL-BMX-078 potently inhibited BMX total tyrosine phosphorylation but only displayed moderate antiproliferative efficacies against prostate cancer cells, bladder cancer cells, and renal cancer cells that overexpressed BMX kinase, which further suggested that BMX kinase did not play key roles for the growth of these cancer cells.

In addition, CHMFL-BMX-078 displayed a pharmacokinetic profile that was acceptable for iv or ip injection.

The highly selective profile of CHMFL-BMX-078 among all of the known BMX inhibitors made it a useful pharmacological tool to further elucidate the BMX kinase mediated signaling pathways in both the pathological and physiological context.

The results were published in Journal of Medicinal Chemistry.

Novel Type II irreversible BMX kinase inhibitor CHMFL-BMX-078