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Molecular Cancer Therapeutics
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Small Molecule Therapeutics

Effects of MTX-23, a Novel PROTAC of Androgen Receptor Splice Variant-7 and Androgen Receptor, on CRPC Resistant to Second-Line Antiandrogen Therapy

Geun Taek Lee, Naoya Nagaya, Jenny Desantis, Kiran Madura, Hatem E. Sabaawy, Wun-Jae Kim, Roy J. Vaz, Gabriele Cruciani and Isaac Yi Kim
Geun Taek Lee
1Section 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.
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Naoya Nagaya
1Section 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.
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Jenny Desantis
2Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia, Italy.
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Kiran Madura
3Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, Piscataway, New Jersey.
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Hatem E. Sabaawy
3Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, Piscataway, New Jersey.
4Division 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.
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Wun-Jae Kim
5Department of Urology, Chungbuk National University College of Medicine, Cheongju, Korea.
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Roy J. Vaz
6Montelino Therapeutics, LLC, Southborough, Massachusetts.
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Gabriele Cruciani
2Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia, Italy.
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Isaac Yi Kim
1Section 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.
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  • ORCID record for Isaac Yi Kim
  • For correspondence: kimiy@cinj.rutgers.edu
DOI: 10.1158/1535-7163.MCT-20-0417 Published March 2021
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Abstract

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.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Mol Cancer Ther 2021;20:490–9

  • Received May 17, 2020.
  • Revision received August 29, 2020.
  • Accepted November 30, 2020.
  • Published first December 4, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 20 (3)
March 2021
Volume 20, Issue 3
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Effects of MTX-23, a Novel PROTAC of Androgen Receptor Splice Variant-7 and Androgen Receptor, on CRPC Resistant to Second-Line Antiandrogen Therapy
Geun Taek Lee, Naoya Nagaya, Jenny Desantis, Kiran Madura, Hatem E. Sabaawy, Wun-Jae Kim, Roy J. Vaz, Gabriele Cruciani and Isaac Yi Kim
Mol Cancer Ther March 1 2021 (20) (3) 490-499; DOI: 10.1158/1535-7163.MCT-20-0417

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Effects of MTX-23, a Novel PROTAC of Androgen Receptor Splice Variant-7 and Androgen Receptor, on CRPC Resistant to Second-Line Antiandrogen Therapy
Geun Taek Lee, Naoya Nagaya, Jenny Desantis, Kiran Madura, Hatem E. Sabaawy, Wun-Jae Kim, Roy J. Vaz, Gabriele Cruciani and Isaac Yi Kim
Mol Cancer Ther March 1 2021 (20) (3) 490-499; DOI: 10.1158/1535-7163.MCT-20-0417
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Molecular Cancer Therapeutics
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