Effects of MTX-23, a Novel PROTAC of Androgen Receptor Splice Variant-7 and Androgen Receptor, on CRPC Resistant to Second-Line Antiandrogen Therapy
- Mol Cancer Ther. 2021 Mar;20(3):490-499. doi: 10.1158/1535-7163.MCT-20-0417.
- 1. Section of Urologic Oncology, Rutgers Cancer Institute of New Jersey, and Division of Urology, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, New Jersey.
- 2. Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia, Italy.
- 3. Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, Piscataway, New Jersey.
- 4. Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, and Departments of Medicine and Pharmacology, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, New Jersey.
- 5. Department of Urology, Chungbuk National University College of Medicine, Cheongju, Korea.
- 6. Montelino Therapeutics, LLC, Southborough, Massachusetts.
- 7. Section of Urologic Oncology, Rutgers Cancer Institute of New Jersey, and Division of Urology, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, New Jersey. [email protected].
Although second-line antiandrogen therapy (SAT) is the standard of care in men with castration-resistant prostate Cancer (CRPC), resistance inevitably occurs. One major proposed mechanism of resistance to SAT involves the emergence of Androgen Receptor (AR) splice variant-7, AR-V7. Recently, we developed MTX-23 using the principle of proteolysis targeting chimera (PROTAC) to target both AR-V7 and AR-full length (AR-FL). MTX-23 has been designed to simultaneously bind AR's DNA binding domain (DBD) and the Von Hippel-Lindau (VHL) E3 ubiquitin Ligase. Immunoblots demonstrated that MTX-23's degradation concentration 50% (DC50) for AR-V7 and AR-FL was 0.37 and 2 μmol/L, respectively. Further studies revealed that MTX-23 inhibited prostate Cancer cellular proliferation and increased Apoptosis only in androgen-responsive prostate Cancer cells. The antiproliferative effect of MTX-23 was partially reversed when either AR-V7 or AR-FL was overexpressed and was completely abrogated when both were overexpressed. To assess the potential therapeutic value of MTX-23, we next generated 12 human prostate Cancer cell lines that are resistant to the four FDA-approved SAT agents-abiraterone, enzalutamide, apalutamide, and darolutamide. When resistant cells were treated with MTX-23, decreased cellular proliferation and reduced tumor growth were observed both in vitro and in mice. These results collectively suggest that MTX-23 is a novel PROTAC small molecule that may be effective against SAT-resistant CRPC by degrading both AR-V7 and AR-FL.