Orally -Bioavailable Androgen Receptor Degrader

Potential Next-Generation Therapeutic for Enzalutamide-Resistant Prostate Cancer

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

Research output: Contribution to journalArticle

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. Here, we describe a second-generation AR pan-antagonist (UT-34) that degrades the AR and AR splice variants. 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.
Original languageEnglish
JournalClinical Cancer Research
Early online date3 Sep 2019
DOIs
Publication statusE-pub ahead of print - 3 Sep 2019

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Androgen Receptors
Prostatic Neoplasms
Competitive Binding
Ligands
Pharmaceutical Preparations
Therapeutics
Androgen Receptor Antagonists
G-Protein-Coupled Receptor Kinases
Neoplasms
Castration
Proteasome Endopeptidase Complex
Cytoplasmic and Nuclear Receptors
Ubiquitin
Nuclear Family
Heterografts
MDV 3100
Safety
Growth

Keywords

  • prostate cancer
  • Castration-Resistant Prostate Cancer (CRPC)
  • androgen receptor (AR)
  • AR degrader (SARD)
  • coactivator
  • enzalutamide-resistant prostate cancer

Cite this

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 G.; Fernandez, Elias; Johnson, Daniel; Du, Ziyun; Pfeffer, Lawrence M.; Getzenberg, Robert H.; McEwan, Iain J.; Miller, Duane D.; Narayanan, Ramesh (Corresponding Author).

In: Clinical Cancer Research, 03.09.2019.

Research output: Contribution to journalArticle

Ponnusamy, S, He, Y, Hwang, D-J, Thiyagarajan, T, Houtman, R, Bocharova, V, Sumpter, BG, Fernandez, E, Johnson, D, Du, Z, Pfeffer, LM, Getzenberg, RH, McEwan, IJ, Miller, DD & Narayanan, R 2019, 'Orally -Bioavailable Androgen Receptor Degrader: Potential Next-Generation Therapeutic for Enzalutamide-Resistant Prostate Cancer', Clinical Cancer Research. https://doi.org/10.1158/1078-0432.CCR-19-1458
Ponnusamy, Suriyan ; He, Yali ; Hwang, Dong-Jin ; Thiyagarajan, Thirumagal ; Houtman, Rene ; Bocharova, Vera ; Sumpter, Bobby G. ; Fernandez, Elias ; Johnson, Daniel ; Du, Ziyun ; Pfeffer, Lawrence M. ; Getzenberg, Robert H. ; McEwan, Iain J. ; Miller, Duane D. ; Narayanan, Ramesh. / Orally -Bioavailable Androgen Receptor Degrader : Potential Next-Generation Therapeutic for Enzalutamide-Resistant Prostate Cancer. In: Clinical Cancer Research. 2019.
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title = "Orally -Bioavailable Androgen Receptor Degrader: Potential Next-Generation Therapeutic for Enzalutamide-Resistant Prostate Cancer",
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. Here, we describe a second-generation AR pan-antagonist (UT-34) that degrades the AR and AR splice variants. 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.",
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author = "Suriyan Ponnusamy and Yali He and Dong-Jin Hwang and Thirumagal Thiyagarajan and Rene Houtman and Vera Bocharova and Sumpter, {Bobby G.} and Elias Fernandez and Daniel Johnson and Ziyun Du and Pfeffer, {Lawrence M.} and Getzenberg, {Robert H.} and McEwan, {Iain J.} and Miller, {Duane D.} and Ramesh Narayanan",
note = "Acknowledgement. BGS acknowledges work performed at the Center for Nanophase Materials Sciences, a DOE Office of Science User Facility. VB acknowledges Laboratory Directed Research and Development program of Oak Ridge National Laboratory, managed by UTBattelle, LLC, for the U.S. Department of Energy.",
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T2 - Potential Next-Generation Therapeutic for Enzalutamide-Resistant Prostate Cancer

AU - Ponnusamy, Suriyan

AU - He, Yali

AU - Hwang, Dong-Jin

AU - Thiyagarajan, Thirumagal

AU - Houtman, Rene

AU - Bocharova, Vera

AU - Sumpter, Bobby G.

AU - Fernandez, Elias

AU - Johnson, Daniel

AU - Du, Ziyun

AU - Pfeffer, Lawrence M.

AU - Getzenberg, Robert H.

AU - McEwan, Iain J.

AU - Miller, Duane D.

AU - Narayanan, Ramesh

N1 - Acknowledgement. BGS acknowledges work performed at the Center for Nanophase Materials Sciences, a DOE Office of Science User Facility. VB acknowledges Laboratory Directed Research and Development program of Oak Ridge National Laboratory, managed by UTBattelle, LLC, for the U.S. Department of Energy.

PY - 2019/9/3

Y1 - 2019/9/3

N2 - 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. Here, we describe a second-generation AR pan-antagonist (UT-34) that degrades the AR and AR splice variants. 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.

AB - 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. Here, we describe a second-generation AR pan-antagonist (UT-34) that degrades the AR and AR splice variants. 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.

KW - prostate cancer

KW - Castration-Resistant Prostate Cancer (CRPC)

KW - androgen receptor (AR)

KW - AR degrader (SARD)

KW - coactivator

KW - enzalutamide-resistant prostate cancer

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DO - 10.1158/1078-0432.CCR-19-1458

M3 - Article

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

ER -