tgx-221 and Prostatic-Neoplasms--Castration-Resistant

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.. 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.. As expected, replacing either one of two major functional groups in TGX221 by more hydrophilic groups dramatically improved the aqueous solubility (about 40-fold) compared to TGX221. In the CETSA assay, all the analogs dramatically shifted the melting curve of p110β protein while none of them largely affected the melting curves of p110α, p110γ, or Akt proteins, indicating target-specific engagement of these analogs with p110β protein. However, functional evaluation showed that only one of the analogs BL140 ubiquitously inhibited AKT phosphorylation in all CRPC cell lines tested with diverse genetic abnormalities including AR, PTEN, and p53 status. BL140 was superior than GSK2636771 (IC. These studies suggested that BL140 is a promising p110β-specific inhibitor with multiple superb properties than GSK2636771 worthy for further clinical development.

Topics: Animals; Antineoplastic Agents; Benzamides; Cell Line, Tumor; Cell Proliferation; Class I Phosphatidylinositol 3-Kinases; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Humans; Male; Mice; Mice, Nude; Morpholines; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Pyrimidinones; Xenograft Model Antitumor Assays