Synthesis and Evaluation of Small Molecule Inhibitors of the Androgen Receptor N-Terminal Domain

Martyn C. Henry; Christopher M. Riley; Irene Hunter; Jessica M. L. Elwood; J. Daniel Lopez-Fernandez; Laura Minty; Diane M. Coe; Iain J. McEwan; Craig Jamieson

doi:10.1021/acsmedchemlett.3c00426

Synthesis and Evaluation of Small Molecule Inhibitors of the Androgen Receptor N-Terminal Domain

Martyn C. Henry, Christopher M. Riley, Irene Hunter, Jessica M. L. Elwood, J. Daniel Lopez-Fernandez, Laura Minty, Diane M. Coe, Iain J. McEwan^* (Corresponding Author), Craig Jamieson^* (Corresponding Author)

^*Corresponding author for this work

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

Abstract

The androgen receptor (AR) is central to prostate cancer pathogenesis and has been extensively validated as a drug target. However, small-molecule anti-androgen therapies remain limited due to resistance and will eventually fail to suppress tumor growth, resulting in progression to castration-resistant prostate cancer (CRPC). The intrinsically disordered N-terminal domain (NTD) is crucial for AR transactivation and has been investigated as a suitable target in the presence of ligand binding domain mutations. A screening campaign identified biaryl isoxazole compound 7 as a weak inhibitor of the AR NTD. A library of biaryl analogues were synthesized, and their biological activities were assessed in a VCaP cell-based luciferase reporter gene assay. A structure–activity relationship (SAR) study revealed that indazole analogue 16 exhibited increased potency and favorable physicochemical properties with a benchmarked pharmacokinetic profile, providing a suitable starting point for further optimization of 16 as a CRPC therapeutic in the presence of AR mutations.

Original language	English
Number of pages	7
Journal	ACS Medicinal Chemistry Letters
Early online date	17 Nov 2023
DOIs	https://doi.org/10.1021/acsmedchemlett.3c00426
Publication status	E-pub ahead of print - 17 Nov 2023

Bibliographical note

Acknowledgments
We thank Craig Irving for his assistance with NMR spectroscopy and Pat Keating, Dr. Jessica Bame, and Dr. Graeme Anderson for their assistance with HRMS.
Funding
We thank the Medical Research Council (MR/T02559/X), Prostate Cancer Research (IH), and GlaxoSmithKline for financial support of this work.

Keywords

Prostate cancer
Androgen receptor
Intrinsically disordered protein

UN SDGs

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

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title = "Synthesis and Evaluation of Small Molecule Inhibitors of the Androgen Receptor N-Terminal Domain",

abstract = "The androgen receptor (AR) is central to prostate cancer pathogenesis and has been extensively validated as a drug target. However, small-molecule anti-androgen therapies remain limited due to resistance and will eventually fail to suppress tumor growth, resulting in progression to castration-resistant prostate cancer (CRPC). The intrinsically disordered N-terminal domain (NTD) is crucial for AR transactivation and has been investigated as a suitable target in the presence of ligand binding domain mutations. A screening campaign identified biaryl isoxazole compound 7 as a weak inhibitor of the AR NTD. A library of biaryl analogues were synthesized, and their biological activities were assessed in a VCaP cell-based luciferase reporter gene assay. A structure–activity relationship (SAR) study revealed that indazole analogue 16 exhibited increased potency and favorable physicochemical properties with a benchmarked pharmacokinetic profile, providing a suitable starting point for further optimization of 16 as a CRPC therapeutic in the presence of AR mutations.",

keywords = "Prostate cancer, Androgen receptor, Intrinsically disordered protein",

author = "Henry, {Martyn C.} and Riley, {Christopher M.} and Irene Hunter and Elwood, {Jessica M. L.} and Lopez-Fernandez, {J. Daniel} and Laura Minty and Coe, {Diane M.} and McEwan, {Iain J.} and Craig Jamieson",

note = "Acknowledgments We thank Craig Irving for his assistance with NMR spectroscopy and Pat Keating, Dr. Jessica Bame, and Dr. Graeme Anderson for their assistance with HRMS. Funding We thank the Medical Research Council (MR/T02559/X), Prostate Cancer Research (IH), and GlaxoSmithKline for financial support of this work.",

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doi = "10.1021/acsmedchemlett.3c00426",

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T1 - Synthesis and Evaluation of Small Molecule Inhibitors of the Androgen Receptor N-Terminal Domain

AU - Henry, Martyn C.

AU - Riley, Christopher M.

AU - Hunter, Irene

AU - Elwood, Jessica M. L.

AU - Lopez-Fernandez, J. Daniel

AU - Minty, Laura

AU - Coe, Diane M.

AU - McEwan, Iain J.

AU - Jamieson, Craig

N1 - Acknowledgments We thank Craig Irving for his assistance with NMR spectroscopy and Pat Keating, Dr. Jessica Bame, and Dr. Graeme Anderson for their assistance with HRMS. Funding We thank the Medical Research Council (MR/T02559/X), Prostate Cancer Research (IH), and GlaxoSmithKline for financial support of this work.

PY - 2023/11/17

Y1 - 2023/11/17

N2 - The androgen receptor (AR) is central to prostate cancer pathogenesis and has been extensively validated as a drug target. However, small-molecule anti-androgen therapies remain limited due to resistance and will eventually fail to suppress tumor growth, resulting in progression to castration-resistant prostate cancer (CRPC). The intrinsically disordered N-terminal domain (NTD) is crucial for AR transactivation and has been investigated as a suitable target in the presence of ligand binding domain mutations. A screening campaign identified biaryl isoxazole compound 7 as a weak inhibitor of the AR NTD. A library of biaryl analogues were synthesized, and their biological activities were assessed in a VCaP cell-based luciferase reporter gene assay. A structure–activity relationship (SAR) study revealed that indazole analogue 16 exhibited increased potency and favorable physicochemical properties with a benchmarked pharmacokinetic profile, providing a suitable starting point for further optimization of 16 as a CRPC therapeutic in the presence of AR mutations.

AB - The androgen receptor (AR) is central to prostate cancer pathogenesis and has been extensively validated as a drug target. However, small-molecule anti-androgen therapies remain limited due to resistance and will eventually fail to suppress tumor growth, resulting in progression to castration-resistant prostate cancer (CRPC). The intrinsically disordered N-terminal domain (NTD) is crucial for AR transactivation and has been investigated as a suitable target in the presence of ligand binding domain mutations. A screening campaign identified biaryl isoxazole compound 7 as a weak inhibitor of the AR NTD. A library of biaryl analogues were synthesized, and their biological activities were assessed in a VCaP cell-based luciferase reporter gene assay. A structure–activity relationship (SAR) study revealed that indazole analogue 16 exhibited increased potency and favorable physicochemical properties with a benchmarked pharmacokinetic profile, providing a suitable starting point for further optimization of 16 as a CRPC therapeutic in the presence of AR mutations.

KW - Prostate cancer

KW - Androgen receptor

KW - Intrinsically disordered protein

U2 - 10.1021/acsmedchemlett.3c00426

DO - 10.1021/acsmedchemlett.3c00426

M3 - Article

C2 - 38116409

SN - 1948-5875

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

ER -

Synthesis and Evaluation of Small Molecule Inhibitors of the Androgen Receptor N-Terminal Domain

Abstract

Bibliographical note

Keywords

UN SDGs

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