Characterization of a novel p110β-specific inhibitor BL140 that overcomes MDV3100-resistance in castration-resistant prostate cancer cells

BACKGROUND: Our previous studies demonstrated that the class IA PI3K/p110β is critical in castration-resistant progression of prostate cancer (CRPC) and that targeting prostate cancer with nanomicelle-loaded p110β-specific inhibitor TGX221 blocked xenograft tumor growth in nude mice, confirming the feasibility of p110β-targeted therapy for CRPCs. To improve TGX221's aqueous solubility, in this study, we characterized four recently synthesized TGX221 analogs. METHODS: TGX221 analog efficacy were examined in multiple prostate cancer cell lines with the SRB cell growth assay, Western blot assay for AKT phosphorylation and cell cycle protein levels. Target engagement with PI3K isoforms was evaluated with cellular thermal shift assay. PI3K activity was determined with the Kinase-Glo Plus luminescent kinase assay. Cell cycle distribution was evaluated with flow cytometry after propidium iodide staining. RESULTS: protein levels. CONCLUSION: These studies suggested that BL140 is a promising p110β-specific inhibitor with multiple superb properties than GSK2636771 worthy for further clinical development.