2. Academic Validation
  3. Inhibiting androgen receptor splice variants with cysteine-selective irreversible covalent inhibitors to treat prostate cancer

Inhibiting androgen receptor splice variants with cysteine-selective irreversible covalent inhibitors to treat prostate cancer

  • Proc Natl Acad Sci U S A. 2023 Jan 3;120(1):e2211832120. doi: 10.1073/pnas.2211832120.
Thirumagal Thiyagarajan 1,  Suriyan Ponnusamy 1,  Dong-Jin Hwang 2,  Yali He 2,  Sarah Asemota 1,  Kirsten L Young 1,  Daniel L Johnson 3,  Vera Bocharova 4,  Weidong Zhou 5,  Abhinav K Jain 6 7,  Emanuel F Petricoin 5,  Zheng Yin 8,  Lawrence M Pfeffer 9 10,  Duane D Miller 2 10,  Ramesh Narayanan 1 10
Affiliations

Affiliations

  • 1 Department of Medicine, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38103.
  • 2 Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163.
  • 3 Molecular Bioinformatics Core, University of Tennessee Health Science Center, Memphis, TN 38103.
  • 4 Oak Ridge National Laboratory, Oak Ridge, TN 37830.
  • 5 Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA 22030.
  • 6 Department of Epigenetics and Molecular Carcinogenesis, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030.
  • 7 Center for Cancer Epigenetics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030.
  • 8 Biomedical and Informatics Services Core, Houston Methodist Research Institute, Houston, TX 77030.
  • 9 Department of Pathology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38103.
  • 10 UTHSC Center for Cancer Research University of Tennessee Health Science Center, Memphis, TN 38163.
PMID: 36577061 DOI: 10.1073/pnas.2211832120
Abstract

Androgen Receptor (AR) and its splice variants (AR-SVs) promote prostate Cancer (PCa) growth by orchestrating transcriptional reprogramming. Mechanisms by which the low complexity and intrinsically disordered primary transactivation domain (AF-1) of AR and AR-SVs regulate transcriptional programming in PCa remains poorly defined. Using omics, live and fixed fluorescent microscopy of cells, and purified AF-1 and AR-V7 recombinant proteins we show here that AF-1 and the AR-V7 splice variant form molecular condensates by liquid-liquid phase separation (LLPS) that exhibit disorder characteristics such as rapid intracellular mobility, coactivator interaction, and euchromatin induction. The LLPS and Other disorder characteristics were reversed by a class of small-molecule-selective AR-irreversible covalent antagonists (SARICA) represented herein by UT-143 that covalently and selectively bind to C406 and C327 in the AF-1 region. Interfering with LLPS formation with UT-143 or mutagenesis resulted in chromatin condensation and dissociation of AR-V7 interactome, all culminating in a transcriptionally incompetent complex. Biochemical studies suggest that C327 and C406 in the AF-1 region are critical for condensate formation, AR-V7 function, and UT-143's irreversible AR inhibition. Therapeutically, UT-143 possesses drug-like pharmacokinetics and metabolism properties and inhibits PCa cell proliferation and tumor growth. Our work provides critical information suggesting that clinically important AR-V7 forms transcriptionally competent molecular condensates and covalently engaging C327 and C406 in AF-1, dissolves the condensates, and inhibits its function. The work also identifies a library of AF-1-binding AR and AR-SV-selective covalent inhibitors for the treatment of PCa.

Keywords

AR splice variants (AR-SVs); Androgen receptor (AR); Selective AR irreversible covalent antagonists (SARICA); castration-resistant prostate cancer (CRPC); liquid–liquid phase separation (LLPS).

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