A New Generation of Selective Androgen Receptor Degraders: Our Initial Design, Synthesis, and Biological Evaluation of New Compounds with Enzalutamide-Resistant Prostate Cancer Activity

Dong-Jin Hwang; Yali He; Suriyan Ponnusamy; Michael L. Mohler; Thirumagal Thiyagarajan; Iain J. McEwan; Ramesh Narayanan; Duane D. Miller

doi:10.1021/acs.jmedchem.8b00973

A New Generation of Selective Androgen Receptor Degraders: Our Initial Design, Synthesis, and Biological Evaluation of New Compounds with Enzalutamide-Resistant Prostate Cancer Activity

Dong-Jin Hwang, Yali He, Suriyan Ponnusamy, Michael L. Mohler, Thirumagal Thiyagarajan, Iain J. McEwan, Ramesh Narayanan, Duane D. Miller (Corresponding Author)

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Abstract

In our effort to find small molecule treatments of advanced prostate cancers (PCs), the novel series of indolyl and indolinyl propanamides (series II and III) were discovered as selective androgen receptor degraders (SARDs). Initial studies of androgen receptor (AR) antagonist (1) and agonist (2) propanamides yielded a tertiary aniline (3) with novel SARD activity but poor metabolic stability. Cyclization to II and III produced sub-micromolar AR antagonism and protein degradation selective to AR and AR splice variant (AR SV). II and III maintained potency against enzalutamide-resistant (Enz-R) mutant ARs and PC cells, and were efficacious in Enz-R xenografts, suggesting their potential to treat advanced PCs. Disclosed is the design, synthesis, and biological activity of novel SARDs that could potentially be used for the treatment of a wide spectrum of PCs including castration resistant, Enz-R, and/or AR SV dependent advanced PCs that are often untreatable with known hormone therapies.

Original language	English
Pages (from-to)	491-511
Number of pages	20
Journal	Journal of Medicinal Chemistry
Volume	62
Issue number	2
Early online date	7 Dec 2018
DOIs	https://doi.org/10.1021/acs.jmedchem.8b00973
Publication status	Published - 2019

Keywords

structure-activity relationship
selective androgen receptor degrader
androgen receptor
androgen receptor splice variant
AR-V7
AR escape mutants
Antagonist
prostate cancer
Antiandrogen resistance
Enzalutamide resistance
Castration-resistant prostate cancer
N-terminal domain
Ligand binding domain
Prostate-specific antigen
AR activation function domain-1

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Accepted Manuscript
This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://pubs.acs.org/doi/10.1021/acs.jmedchem.8b00973
Accepted author manuscript, 1.98 MBLicence: Unspecified

Cite this

Hwang, D-J., He, Y., Ponnusamy, S., Mohler, M. L., Thiyagarajan, T., McEwan, I. J., Narayanan, R., & Miller, D. D. (2019). A New Generation of Selective Androgen Receptor Degraders: Our Initial Design, Synthesis, and Biological Evaluation of New Compounds with Enzalutamide-Resistant Prostate Cancer Activity. Journal of Medicinal Chemistry, 62(2), 491-511. https://doi.org/10.1021/acs.jmedchem.8b00973

A New Generation of Selective Androgen Receptor Degraders : Our Initial Design, Synthesis, and Biological Evaluation of New Compounds with Enzalutamide-Resistant Prostate Cancer Activity. / Hwang, Dong-Jin; He, Yali; Ponnusamy, Suriyan et al.

In: Journal of Medicinal Chemistry, Vol. 62, No. 2, 2019, p. 491-511.

Research output: Contribution to journal › Article › peer-review

Hwang, D-J, He, Y, Ponnusamy, S, Mohler, ML, Thiyagarajan, T, McEwan, IJ, Narayanan, R & Miller, DD 2019, 'A New Generation of Selective Androgen Receptor Degraders: Our Initial Design, Synthesis, and Biological Evaluation of New Compounds with Enzalutamide-Resistant Prostate Cancer Activity', Journal of Medicinal Chemistry, vol. 62, no. 2, pp. 491-511. https://doi.org/10.1021/acs.jmedchem.8b00973

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title = "A New Generation of Selective Androgen Receptor Degraders: Our Initial Design, Synthesis, and Biological Evaluation of New Compounds with Enzalutamide-Resistant Prostate Cancer Activity",

abstract = "In our effort to find small molecule treatments of advanced prostate cancers (PCs), the novel series of indolyl and indolinyl propanamides (series II and III) were discovered as selective androgen receptor degraders (SARDs). Initial studies of androgen receptor (AR) antagonist (1) and agonist (2) propanamides yielded a tertiary aniline (3) with novel SARD activity but poor metabolic stability. Cyclization to II and III produced sub-micromolar AR antagonism and protein degradation selective to AR and AR splice variant (AR SV). II and III maintained potency against enzalutamide-resistant (Enz-R) mutant ARs and PC cells, and were efficacious in Enz-R xenografts, suggesting their potential to treat advanced PCs. Disclosed is the design, synthesis, and biological activity of novel SARDs that could potentially be used for the treatment of a wide spectrum of PCs including castration resistant, Enz-R, and/or AR SV dependent advanced PCs that are often untreatable with known hormone therapies.",

keywords = "structure-activity relationship, selective androgen receptor degrader, androgen receptor, androgen receptor splice variant, AR-V7, AR escape mutants, Antagonist, prostate cancer, Antiandrogen resistance, Enzalutamide resistance, Castration-resistant prostate cancer, N-terminal domain, Ligand binding domain, Prostate-specific antigen, AR activation function domain-1",

author = "Dong-Jin Hwang and Yali He and Suriyan Ponnusamy and Mohler, {Michael L.} and Thirumagal Thiyagarajan and McEwan, {Iain J.} and Ramesh Narayanan and Miller, {Duane D.}",

note = "This research was supported by the Van Vleet Endowed Professorship (D.D.M.), and GTx, Inc. grant (R.N. and D.D.M.) We thank GTx, Inc. for supporting this project and Dr. Dejian Ma of UTHSC, College of Pharmacy for assistance with 2D NMR and HRMS experiments.",

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AU - Hwang, Dong-Jin

AU - He, Yali

AU - Ponnusamy, Suriyan

AU - Mohler, Michael L.

AU - Thiyagarajan, Thirumagal

AU - McEwan, Iain J.

AU - Narayanan, Ramesh

AU - Miller, Duane D.

N1 - This research was supported by the Van Vleet Endowed Professorship (D.D.M.), and GTx, Inc. grant (R.N. and D.D.M.) We thank GTx, Inc. for supporting this project and Dr. Dejian Ma of UTHSC, College of Pharmacy for assistance with 2D NMR and HRMS experiments.

PY - 2019

Y1 - 2019

N2 - In our effort to find small molecule treatments of advanced prostate cancers (PCs), the novel series of indolyl and indolinyl propanamides (series II and III) were discovered as selective androgen receptor degraders (SARDs). Initial studies of androgen receptor (AR) antagonist (1) and agonist (2) propanamides yielded a tertiary aniline (3) with novel SARD activity but poor metabolic stability. Cyclization to II and III produced sub-micromolar AR antagonism and protein degradation selective to AR and AR splice variant (AR SV). II and III maintained potency against enzalutamide-resistant (Enz-R) mutant ARs and PC cells, and were efficacious in Enz-R xenografts, suggesting their potential to treat advanced PCs. Disclosed is the design, synthesis, and biological activity of novel SARDs that could potentially be used for the treatment of a wide spectrum of PCs including castration resistant, Enz-R, and/or AR SV dependent advanced PCs that are often untreatable with known hormone therapies.

AB - In our effort to find small molecule treatments of advanced prostate cancers (PCs), the novel series of indolyl and indolinyl propanamides (series II and III) were discovered as selective androgen receptor degraders (SARDs). Initial studies of androgen receptor (AR) antagonist (1) and agonist (2) propanamides yielded a tertiary aniline (3) with novel SARD activity but poor metabolic stability. Cyclization to II and III produced sub-micromolar AR antagonism and protein degradation selective to AR and AR splice variant (AR SV). II and III maintained potency against enzalutamide-resistant (Enz-R) mutant ARs and PC cells, and were efficacious in Enz-R xenografts, suggesting their potential to treat advanced PCs. Disclosed is the design, synthesis, and biological activity of novel SARDs that could potentially be used for the treatment of a wide spectrum of PCs including castration resistant, Enz-R, and/or AR SV dependent advanced PCs that are often untreatable with known hormone therapies.

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KW - selective androgen receptor degrader

KW - androgen receptor

KW - androgen receptor splice variant

KW - AR-V7

KW - AR escape mutants

KW - Antagonist

KW - prostate cancer

KW - Antiandrogen resistance

KW - Enzalutamide resistance

KW - Castration-resistant prostate cancer

KW - N-terminal domain

KW - Ligand binding domain

KW - Prostate-specific antigen

KW - AR activation function domain-1

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M3 - Article

VL - 62

SP - 491

EP - 511

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 2

ER -

A New Generation of Selective Androgen Receptor Degraders: Our Initial Design, Synthesis, and Biological Evaluation of New Compounds with Enzalutamide-Resistant Prostate Cancer Activity

Abstract

Keywords

UN SDGs

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