Investigational MJC13 is a drug candidate with a potentially novel mode of action targeting androgen receptor (AR) inhibition that is important in prostate and breast cancers.

MJC13, and related compound family, has been designed to target the regulation of androgen receptor (AR) by binding to a recently identified regulatory surface on AR (BF3). MJC13 is thought to block β-catenin interaction with the AR ligand binding domain and the synergistic up-regulation of AR by FKBP52 and β-catenin. In preclinical work, 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 demonstrated notable 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 potentially novel therapeutic target with the potential to treat castration-resistant prostate cancer, thereby filling a major unmet need in treatment. FKBP52 is thought to act 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.

MAIA Biotech aims to identify an optimized lead compound for advancement into IND-enabling studies in 2021.



Literature:

De Leon JT, Iwai A, Feau C, Garcia Y, Balsiger HA, Storer CL, et al. Targeting the regulation of androgen receptor signaling by the heat shock protein 90 cochaperone FKBP52 in prostate cancer cells. Proc Natl Acad Sci U S A. 2011; 108(29):11878–83. Epub 2011/07/07. 1105160108 [pii] doi: 10.1073/ pnas.1105160108 PMID: 21730179; PubMed Central PMCID: PMC3141981.  https://www.ncbi.nlm.nih.gov/pubmed/21730179

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