MJC13 is a drug candidate with a novel mode of action for the treatment of prostate cancer
MJC13 targets the regulation of androgen receptor (AR) by binding to a recently identified regulatory surface on AR (BF3). MJC13 effectively blocks β-catenin interaction with the AR ligand binding domain and the synergistic up-regulation of AR by FKBP52 and β-catenin. MJC13 was shown to effectively block AR signaling and AR-dependent cancer cell proliferation in a variety of human prostate cancer cell lines, and preclinical studies demonstrate impressive effects on tumor growth in a prostate cancer xenograft model.
FKBP52 is a TPR (tetratricopeptide repeat) domain-containing co-chaperone that plays a critical role in the chaperone dependent folding of steroid hormone receptors (SHRs) into their functionally mature conformations necessary for hormone binding. Given the functional roles of FKBP52 in receptor-specific phenotypes, and its direct participation in the aberrant AR hyperactivity observed in prostate cancer, FKBP52 has emerged as a novel therapeutic target with the potential to treat castration-resistant prostate cancer, thereby filling a major unmet need in treatment. FKBP52 acts as a specific positive regulator of AR, PR, and GR functions through the interaction of the proline-rich loop with the ligand binding domain (LBD) of the SHRs
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Storer Samaniego, C., Suh, J.H., Chattopadhyay, A., Olivares, K., Guy, N., Sivils, J.C., Dey, P., Yumoto, F., Fletterick, R., Strom, A., Gustafsson,J-A., Webb, P., and Cox, M.B. (2015) The FKBP52 cochaperone acts in synergy with β-catenin to potentiate androgen receptor signaling. PLOS ONE. 10(7): e0134015. PMCID: PMC4514735. https://www.ncbi.nlm.nih.gov/pubmed/26207810
Guy, N., Garcia, Y.A., and Cox, M.B. (2015)Therapeutic targeting of the FKBP52 cochaperone in steroid hormone receptor-regulated physiology and disease. Current Molecular Pharmacology. May 19. https://www.ncbi.nlm.nih.gov/pubmed/25986565
Liang, S., Sivils, J., Neckers, L.M., Cox, M.B., and Xie, H. (2014) Solution formulation development and efficacy of MJC13 in a preclinical model of castrate-resistant prostate cancer. Pharmaceutical Development and Technology. 7: 1-6. https://www.ncbi.nlm.nih.gov/pubmed/25380396