Orally Bioavailable Androgen Receptor Degrader, Potential Next-Generation Therapeutic for Enzalutamide-Resistant Prostate Cancer

Ponnusamy, Suriyan; He, Yali; Hwang, Dong-Jin; Thiyagarajan, Thirumagal; Houtman, Rene; Bocharova, Vera; Sumpter, Bobby; Fernandez, Elias; Johnson, Daniel; Du, Ziyun; Pfeffer, Lawrence M.; Getzenberg, Robert; McEwan, Iain J.; Miller, Duane; Narayanan, Ramesh

doi:10.1158/1078-0432.CCR-19-1458

Title: Orally Bioavailable Androgen Receptor Degrader, Potential Next-Generation Therapeutic for Enzalutamide-Resistant Prostate Cancer

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Abstract

Androgen receptor (AR)-targeting prostate cancer drugs, which are predominantly competitive ligand-binding domain (LBD)-binding antagonists, are inactivated by common resistance mechanisms. It is important to develop next-generation mechanistically distinct drugs to treat castration- and drug-resistant prostate cancers. Second-generation AR pan antagonist UT-34 was selected from a library of compounds and tested in competitive AR binding and transactivation assays. In this study, UT-34 was tested using biophysical methods for binding to the AR activation function-1 (AF-1) domain. Western blot, gene expression, and proliferation assays were performed in various AR-positive enzalutamide-sensitive and -resistant prostate cancer cell lines. Pharmacokinetic and xenograft studies were performed in immunocompromised rats and mice. UT-34 inhibits the wild-type and LBD-mutant ARs comparably and inhibits the in vitro proliferation and in vivo growth of enzalutamide-sensitive and -resistant prostate cancer xenografts. In preclinical models, UT-34 induced the regression of enzalutamide-resistant tumors at doses when the AR is degraded; but, at lower doses, when the AR is just antagonized, it inhibits, without shrinking, the tumors. This indicates that degradation might be a prerequisite for tumor regression. Mechanistically, UT-34 promotes a conformation that is distinct from the LBD-binding competitive antagonist enzalutamide and degrades the AR through the ubiquitin proteasome mechanism. UT-34 has amore »« less

Authors:

Ponnusamy, Suriyan ^[1]; He, Yali ^[1]; Hwang, Dong-Jin ^[1]; Thiyagarajan, Thirumagal ^[1]; Houtman, Rene ^[2];

^[3];

^[3]; Fernandez, Elias ^[4]; Johnson, Daniel ^[1]; Du, Ziyun ^[1]; Pfeffer, Lawrence M. ^[1]; Getzenberg, Robert ^[5]; McEwan, Iain J. ^[6]; Miller, Duane ^[1]; Narayanan, Ramesh ^[7]

Univ. of Tennessee Health Science Center (UTHSC), Memphis, TN (United States)
Pamgene International, Den Bosch (Netherlands)
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Univ. of Tennessee, Knoxville, TN (United States)
GTx, Inc., Memphis, TN (United States)
Univ. of Aberdeen (Scotland)
Univ. of Tennessee Health Science Center (UTHSC), Memphis, TN (United States); West Cancer Center, Memphis, TN (United States)

Publication Date:: Tue Sep 03 00:00:00 EDT 2019

Research Org.:: Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

Sponsoring Org.:: USDOE

OSTI Identifier:: 1607027

Grant/Contract Number:: AC05-00OR22725

Resource Type:: Accepted Manuscript

Journal Name:: Clinical Cancer Research

Additional Journal Information:: Journal Volume: 25; Journal Issue: 22; Journal ID: ISSN 1078-0432

Publisher:: American Association for Cancer Research

Country of Publication:: United States

Language:: English

Subject:: 60 APPLIED LIFE SCIENCES; prostate cancer; castration-resistant prostate cancer (CRPC); androgen receptor (AR); AR degrader (SARD); coactivator; enzalutamide-resistant prostate cancer

Citation Formats


                    Ponnusamy, Suriyan, He, Yali, Hwang, Dong-Jin, Thiyagarajan, Thirumagal, Houtman, Rene, Bocharova, Vera, Sumpter, Bobby, Fernandez, Elias, Johnson, Daniel, Du, Ziyun, Pfeffer, Lawrence M., Getzenberg, Robert, McEwan, Iain J., Miller, Duane, and Narayanan, Ramesh. Orally Bioavailable Androgen Receptor Degrader, Potential Next-Generation Therapeutic for Enzalutamide-Resistant Prostate Cancer.  United States: N. p., 2019. 
Web.  doi:10.1158/1078-0432.CCR-19-1458.

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                    Ponnusamy, Suriyan, He, Yali, Hwang, Dong-Jin, Thiyagarajan, Thirumagal, Houtman, Rene, Bocharova, Vera, Sumpter, Bobby, Fernandez, Elias, Johnson, Daniel, Du, Ziyun, Pfeffer, Lawrence M., Getzenberg, Robert, McEwan, Iain J., Miller, Duane, & Narayanan, Ramesh. Orally Bioavailable Androgen Receptor Degrader, Potential Next-Generation Therapeutic for Enzalutamide-Resistant Prostate Cancer.  United States.  https://doi.org/10.1158/1078-0432.CCR-19-1458

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                    Ponnusamy, Suriyan, He, Yali, Hwang, Dong-Jin, Thiyagarajan, Thirumagal, Houtman, Rene, Bocharova, Vera, Sumpter, Bobby, Fernandez, Elias, Johnson, Daniel, Du, Ziyun, Pfeffer, Lawrence M., Getzenberg, Robert, McEwan, Iain J., Miller, Duane, and Narayanan, Ramesh. Tue .  
"Orally Bioavailable Androgen Receptor Degrader, Potential Next-Generation Therapeutic for Enzalutamide-Resistant Prostate Cancer".  United States.  https://doi.org/10.1158/1078-0432.CCR-19-1458.  https://www.osti.gov/servlets/purl/1607027.

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@article{osti_1607027,

  title        = {Orally Bioavailable Androgen Receptor Degrader, Potential Next-Generation Therapeutic for Enzalutamide-Resistant Prostate Cancer},

  author       = {Ponnusamy, Suriyan and He, Yali and Hwang, Dong-Jin and Thiyagarajan, Thirumagal and Houtman, Rene and Bocharova, Vera and Sumpter, Bobby and Fernandez, Elias and Johnson, Daniel and Du, Ziyun and Pfeffer, Lawrence M. and Getzenberg, Robert and McEwan, Iain J. and Miller, Duane and Narayanan, Ramesh},

  abstractNote = {Androgen receptor (AR)-targeting prostate cancer drugs, which are predominantly competitive ligand-binding domain (LBD)-binding antagonists, are inactivated by common resistance mechanisms. It is important to develop next-generation mechanistically distinct drugs to treat castration- and drug-resistant prostate cancers. Second-generation AR pan antagonist UT-34 was selected from a library of compounds and tested in competitive AR binding and transactivation assays. In this study, UT-34 was tested using biophysical methods for binding to the AR activation function-1 (AF-1) domain. Western blot, gene expression, and proliferation assays were performed in various AR-positive enzalutamide-sensitive and -resistant prostate cancer cell lines. Pharmacokinetic and xenograft studies were performed in immunocompromised rats and mice. UT-34 inhibits the wild-type and LBD-mutant ARs comparably and inhibits the in vitro proliferation and in vivo growth of enzalutamide-sensitive and -resistant prostate cancer xenografts. In preclinical models, UT-34 induced the regression of enzalutamide-resistant tumors at doses when the AR is degraded; but, at lower doses, when the AR is just antagonized, it inhibits, without shrinking, the tumors. This indicates that degradation might be a prerequisite for tumor regression. Mechanistically, UT-34 promotes a conformation that is distinct from the LBD-binding competitive antagonist enzalutamide and degrades the AR through the ubiquitin proteasome mechanism. UT-34 has a broad safety margin and exhibits no cross-reactivity with G-protein–coupled receptor kinase and nuclear receptor family members. Collectively, UT-34 exhibits the properties necessary for a next-generation prostate cancer drug.},

  doi          = {10.1158/1078-0432.CCR-19-1458},

  journal      = {Clinical Cancer Research},

  number       = 22,

  volume       = 25,

  place        = {United States},

  year         = {Tue Sep 03 00:00:00 EDT 2019},

  month        = {Tue Sep 03 00:00:00 EDT 2019}

}

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