Novel Selective Agents for the Degradation of Androgen Receptor Variants to Treat Castration-Resistant Prostate Cancer

Suriyan Ponnusamy, Christopher C. Coss, Thirumagal Thiyagarajan, Kate Watts, Dong-Jin Hwang, Yali He, Luke A. Selth, Iain J. McEwan, Charles B. Duke, Jayaprakash Pagadala, Geetika Singh, Robert W. Wake, Christopher Ledbetter, Wayne D. Tilley, Tudor Moldoveanu, James T. Dalton, Duane D. Miller, Ramesh Narayanan

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Abstract

Androgen receptor (AR) mediates the growth of prostate cancer (PCa) throughout its course of development, including in abnormal splice variants (AR-SV)-driven advanced stage castration-resistant disease. AR stabilization by androgens makes it distinct from other steroid receptors, which are typically ubiquitinated and degraded by proteasomes after ligand binding. Thus, targeting AR in advanced PCa requires the development of agents that can sustainably degrade variant isoforms for effective therapy. Here we report the discovery and characterization of potent selective AR degraders (SARDs) that markedly reduce the activity of wildtype and splice variant isoforms of AR at sub-micromolar doses. Three SARDs (UT-69, UT-155, and (R)-UT-155) bind the amino-terminal transcriptional activation domain AF-1, which has not been targeted for degradation previously, with two of these SARD (UT-69 and UT-155) also binding the carboxy-terminal ligand binding domain. Despite different mechanisms of action, all three SARDs degraded wild-type AR and inhibited AR function, exhibiting greater inhibitory potency than the approved AR antagonists. Collectively, our results introduce a new candidate class of nextgeneration therapeutics to manage advanced PCa.
Original languageEnglish
Pages (from-to)6282-6298
Number of pages17
JournalCancer Research
Volume77
Issue number22
Early online date4 Oct 2017
DOIs
Publication statusPublished - Nov 2017

Fingerprint

Castration
Androgen Receptors
Prostatic Neoplasms
Protein Isoforms
Androgen Receptor Antagonists
Ligands
Steroid Receptors
Proteasome Endopeptidase Complex
Transcriptional Activation
Androgens
Therapeutics
Growth

Keywords

  • Androgen Receptor (AR)
  • Selective Androgen Receptor Degraders (SARDs)
  • AR Splice Variants (AR-SV)
  • prostate cancer
  • Castration-Resistant Prostate Cancer (CRPC)
  • AR antagonist
  • AF-1-binding AR antagonist
  • AR translocation inhibitor
  • AR pan-antagonist

Cite this

Ponnusamy, S., Coss, C. C., Thiyagarajan, T., Watts, K., Hwang, D-J., He, Y., ... Narayanan, R. (2017). Novel Selective Agents for the Degradation of Androgen Receptor Variants to Treat Castration-Resistant Prostate Cancer. Cancer Research, 77(22), 6282-6298. https://doi.org/10.1158/0008-5472.CAN-17-0976

Novel Selective Agents for the Degradation of Androgen Receptor Variants to Treat Castration-Resistant Prostate Cancer. / Ponnusamy, Suriyan; Coss, Christopher C.; Thiyagarajan, Thirumagal; Watts, Kate; Hwang, Dong-Jin; He, Yali; Selth, Luke A.; McEwan, Iain J.; Duke, Charles B.; Pagadala, Jayaprakash; Singh, Geetika; Wake, Robert W.; Ledbetter, Christopher; Tilley, Wayne D.; Moldoveanu, Tudor; Dalton, James T.; Miller, Duane D.; Narayanan, Ramesh.

In: Cancer Research, Vol. 77, No. 22, 11.2017, p. 6282-6298.

Research output: Contribution to journalArticle

Ponnusamy, S, Coss, CC, Thiyagarajan, T, Watts, K, Hwang, D-J, He, Y, Selth, LA, McEwan, IJ, Duke, CB, Pagadala, J, Singh, G, Wake, RW, Ledbetter, C, Tilley, WD, Moldoveanu, T, Dalton, JT, Miller, DD & Narayanan, R 2017, 'Novel Selective Agents for the Degradation of Androgen Receptor Variants to Treat Castration-Resistant Prostate Cancer', Cancer Research, vol. 77, no. 22, pp. 6282-6298. https://doi.org/10.1158/0008-5472.CAN-17-0976
Ponnusamy, Suriyan ; Coss, Christopher C. ; Thiyagarajan, Thirumagal ; Watts, Kate ; Hwang, Dong-Jin ; He, Yali ; Selth, Luke A. ; McEwan, Iain J. ; Duke, Charles B. ; Pagadala, Jayaprakash ; Singh, Geetika ; Wake, Robert W. ; Ledbetter, Christopher ; Tilley, Wayne D. ; Moldoveanu, Tudor ; Dalton, James T. ; Miller, Duane D. ; Narayanan, Ramesh. / Novel Selective Agents for the Degradation of Androgen Receptor Variants to Treat Castration-Resistant Prostate Cancer. In: Cancer Research. 2017 ; Vol. 77, No. 22. pp. 6282-6298.
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abstract = "Androgen receptor (AR) mediates the growth of prostate cancer (PCa) throughout its course of development, including in abnormal splice variants (AR-SV)-driven advanced stage castration-resistant disease. AR stabilization by androgens makes it distinct from other steroid receptors, which are typically ubiquitinated and degraded by proteasomes after ligand binding. Thus, targeting AR in advanced PCa requires the development of agents that can sustainably degrade variant isoforms for effective therapy. Here we report the discovery and characterization of potent selective AR degraders (SARDs) that markedly reduce the activity of wildtype and splice variant isoforms of AR at sub-micromolar doses. Three SARDs (UT-69, UT-155, and (R)-UT-155) bind the amino-terminal transcriptional activation domain AF-1, which has not been targeted for degradation previously, with two of these SARD (UT-69 and UT-155) also binding the carboxy-terminal ligand binding domain. Despite different mechanisms of action, all three SARDs degraded wild-type AR and inhibited AR function, exhibiting greater inhibitory potency than the approved AR antagonists. Collectively, our results introduce a new candidate class of nextgeneration therapeutics to manage advanced PCa.",
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author = "Suriyan Ponnusamy and Coss, {Christopher C.} and Thirumagal Thiyagarajan and Kate Watts and Dong-Jin Hwang and Yali He and Selth, {Luke A.} and McEwan, {Iain J.} and Duke, {Charles B.} and Jayaprakash Pagadala and Geetika Singh and Wake, {Robert W.} and Christopher Ledbetter and Tilley, {Wayne D.} and Tudor Moldoveanu and Dalton, {James T.} and Miller, {Duane D.} and Ramesh Narayanan",
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AU - Ponnusamy, Suriyan

AU - Coss, Christopher C.

AU - Thiyagarajan, Thirumagal

AU - Watts, Kate

AU - Hwang, Dong-Jin

AU - He, Yali

AU - Selth, Luke A.

AU - McEwan, Iain J.

AU - Duke, Charles B.

AU - Pagadala, Jayaprakash

AU - Singh, Geetika

AU - Wake, Robert W.

AU - Ledbetter, Christopher

AU - Tilley, Wayne D.

AU - Moldoveanu, Tudor

AU - Dalton, James T.

AU - Miller, Duane D.

AU - Narayanan, Ramesh

N1 - Acknowledgements: The authors thank Mr. Maron Lee Barrett and Ms. Mayra Star for their technical help. The authors thank Dr. Dejian Ma for his technical help with the NMR studies. The authors thank the UTHSC and St. Jude NMR core for their help with the NMR studies. The authors thank Drs. Robert Getzenberg and Michael Mohler for providing useful comments on the manuscript. The authors thank Ms. Brandy Grimes for her help with tissue procurement. The authors thank Dr. Daniel Johnson of UT BioCore for microarray data analysis and Mr. Lorne Rose of UT-MRC core for microarray studies. Funding Source: The research presented in this manuscript was supported by a research funding provided by GTx, Inc. Memphis, TN to R. Narayanan and by a research funding provided by West Cancer Center to R. Narayanan.

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N2 - Androgen receptor (AR) mediates the growth of prostate cancer (PCa) throughout its course of development, including in abnormal splice variants (AR-SV)-driven advanced stage castration-resistant disease. AR stabilization by androgens makes it distinct from other steroid receptors, which are typically ubiquitinated and degraded by proteasomes after ligand binding. Thus, targeting AR in advanced PCa requires the development of agents that can sustainably degrade variant isoforms for effective therapy. Here we report the discovery and characterization of potent selective AR degraders (SARDs) that markedly reduce the activity of wildtype and splice variant isoforms of AR at sub-micromolar doses. Three SARDs (UT-69, UT-155, and (R)-UT-155) bind the amino-terminal transcriptional activation domain AF-1, which has not been targeted for degradation previously, with two of these SARD (UT-69 and UT-155) also binding the carboxy-terminal ligand binding domain. Despite different mechanisms of action, all three SARDs degraded wild-type AR and inhibited AR function, exhibiting greater inhibitory potency than the approved AR antagonists. Collectively, our results introduce a new candidate class of nextgeneration therapeutics to manage advanced PCa.

AB - Androgen receptor (AR) mediates the growth of prostate cancer (PCa) throughout its course of development, including in abnormal splice variants (AR-SV)-driven advanced stage castration-resistant disease. AR stabilization by androgens makes it distinct from other steroid receptors, which are typically ubiquitinated and degraded by proteasomes after ligand binding. Thus, targeting AR in advanced PCa requires the development of agents that can sustainably degrade variant isoforms for effective therapy. Here we report the discovery and characterization of potent selective AR degraders (SARDs) that markedly reduce the activity of wildtype and splice variant isoforms of AR at sub-micromolar doses. Three SARDs (UT-69, UT-155, and (R)-UT-155) bind the amino-terminal transcriptional activation domain AF-1, which has not been targeted for degradation previously, with two of these SARD (UT-69 and UT-155) also binding the carboxy-terminal ligand binding domain. Despite different mechanisms of action, all three SARDs degraded wild-type AR and inhibited AR function, exhibiting greater inhibitory potency than the approved AR antagonists. Collectively, our results introduce a new candidate class of nextgeneration therapeutics to manage advanced PCa.

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KW - Selective Androgen Receptor Degraders (SARDs)

KW - AR Splice Variants (AR-SV)

KW - prostate cancer

KW - Castration-Resistant Prostate Cancer (CRPC)

KW - AR antagonist

KW - AF-1-binding AR antagonist

KW - AR translocation inhibitor

KW - AR pan-antagonist

U2 - 10.1158/0008-5472.CAN-17-0976

DO - 10.1158/0008-5472.CAN-17-0976

M3 - Article

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EP - 6298

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JF - Cancer Research

SN - 0008-5472

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