Discovery of Dihydropyrimido-Pyrimidine-Based Bone Marrow Tyrosine Kinase Gene in Chromosome X Protein Proteolysis-Targeting Chimeras for the Treatment of Prostate Cancer.

Bone marrow tyrosine kinase gene in chromosome X protein (BMX) plays a critical role in the initiation, progression, and development of castration-resistant prostate cancer. While several ATP-competitive BMX inhibitors have been developed as cellular chemical tools to investigate the function of BMX, they are unable to target the nonenzymatic roles of BMX. Proteolysis-targeting chimeras (PROTACs) represent an emerging technology that enables the rapid and complete degradation of target proteins. Here, we describe the design, synthesis, and characterization of BMX PROTACs by conjugating the BMX and cereblon (CRBN) ligands. In LNCaP clone FGC cells, the representative compound 10c (IHMT-BMX-068) induced time- and dose-dependent BMX degradation with nanomolar DC50 values, a process mediated by the CRBN pathway and the proteasome system. It exhibited potent antiproliferative effects on prostate cancer cells. These results indicate that BMX-PROTACs are potential therapeutic candidates for prostate cancer.