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Molecular Pharmacology

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Research ArticleArticle

The Small Molecule Antagonist KCI807 Disrupts Association of the Amino-Terminal Domain of the Androgen Receptor with ELK1 by Modulating the Adjacent DNA Binding Domain

Claire Soave, Charles Ducker, Naeyma Islam, Seongho Kim, Sally Yurgelevic, Nathan I. Nicely, Luke Pardy, Yanfang Huang, Peter E. Shaw, Gregory Auner, Alex Dickson and Manohar Ratnam
Molecular Pharmacology April 2023, 103 (4) 211-220; DOI: https://doi.org/10.1124/molpharm.122.000589
Claire Soave
Department of Oncology (C.S., S.K., Y.H., L.P., M.R.) and Smart Sensors and Integrated Microsystems (SSIM) Program (S.Y., G.A.), Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute, Detroit, Michigan; Department of Biochemistry and Molecular Biology, College of Natural Science, Michigan State University, East Lansing, Michigan (N.I. and A.D.); School of Life Sciences, University of Nottingham, Queens Medical Centre, Nottingham, United Kingdom (C.D. and P.E.S.); and Department of Pharmacology, UNC-Chapel Hill School of Medicine, Chapel Hill, North Carolina (N.N.)
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Charles Ducker
Department of Oncology (C.S., S.K., Y.H., L.P., M.R.) and Smart Sensors and Integrated Microsystems (SSIM) Program (S.Y., G.A.), Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute, Detroit, Michigan; Department of Biochemistry and Molecular Biology, College of Natural Science, Michigan State University, East Lansing, Michigan (N.I. and A.D.); School of Life Sciences, University of Nottingham, Queens Medical Centre, Nottingham, United Kingdom (C.D. and P.E.S.); and Department of Pharmacology, UNC-Chapel Hill School of Medicine, Chapel Hill, North Carolina (N.N.)
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Naeyma Islam
Department of Oncology (C.S., S.K., Y.H., L.P., M.R.) and Smart Sensors and Integrated Microsystems (SSIM) Program (S.Y., G.A.), Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute, Detroit, Michigan; Department of Biochemistry and Molecular Biology, College of Natural Science, Michigan State University, East Lansing, Michigan (N.I. and A.D.); School of Life Sciences, University of Nottingham, Queens Medical Centre, Nottingham, United Kingdom (C.D. and P.E.S.); and Department of Pharmacology, UNC-Chapel Hill School of Medicine, Chapel Hill, North Carolina (N.N.)
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Seongho Kim
Department of Oncology (C.S., S.K., Y.H., L.P., M.R.) and Smart Sensors and Integrated Microsystems (SSIM) Program (S.Y., G.A.), Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute, Detroit, Michigan; Department of Biochemistry and Molecular Biology, College of Natural Science, Michigan State University, East Lansing, Michigan (N.I. and A.D.); School of Life Sciences, University of Nottingham, Queens Medical Centre, Nottingham, United Kingdom (C.D. and P.E.S.); and Department of Pharmacology, UNC-Chapel Hill School of Medicine, Chapel Hill, North Carolina (N.N.)
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Sally Yurgelevic
Department of Oncology (C.S., S.K., Y.H., L.P., M.R.) and Smart Sensors and Integrated Microsystems (SSIM) Program (S.Y., G.A.), Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute, Detroit, Michigan; Department of Biochemistry and Molecular Biology, College of Natural Science, Michigan State University, East Lansing, Michigan (N.I. and A.D.); School of Life Sciences, University of Nottingham, Queens Medical Centre, Nottingham, United Kingdom (C.D. and P.E.S.); and Department of Pharmacology, UNC-Chapel Hill School of Medicine, Chapel Hill, North Carolina (N.N.)
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Nathan I. Nicely
Department of Oncology (C.S., S.K., Y.H., L.P., M.R.) and Smart Sensors and Integrated Microsystems (SSIM) Program (S.Y., G.A.), Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute, Detroit, Michigan; Department of Biochemistry and Molecular Biology, College of Natural Science, Michigan State University, East Lansing, Michigan (N.I. and A.D.); School of Life Sciences, University of Nottingham, Queens Medical Centre, Nottingham, United Kingdom (C.D. and P.E.S.); and Department of Pharmacology, UNC-Chapel Hill School of Medicine, Chapel Hill, North Carolina (N.N.)
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Luke Pardy
Department of Oncology (C.S., S.K., Y.H., L.P., M.R.) and Smart Sensors and Integrated Microsystems (SSIM) Program (S.Y., G.A.), Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute, Detroit, Michigan; Department of Biochemistry and Molecular Biology, College of Natural Science, Michigan State University, East Lansing, Michigan (N.I. and A.D.); School of Life Sciences, University of Nottingham, Queens Medical Centre, Nottingham, United Kingdom (C.D. and P.E.S.); and Department of Pharmacology, UNC-Chapel Hill School of Medicine, Chapel Hill, North Carolina (N.N.)
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Yanfang Huang
Department of Oncology (C.S., S.K., Y.H., L.P., M.R.) and Smart Sensors and Integrated Microsystems (SSIM) Program (S.Y., G.A.), Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute, Detroit, Michigan; Department of Biochemistry and Molecular Biology, College of Natural Science, Michigan State University, East Lansing, Michigan (N.I. and A.D.); School of Life Sciences, University of Nottingham, Queens Medical Centre, Nottingham, United Kingdom (C.D. and P.E.S.); and Department of Pharmacology, UNC-Chapel Hill School of Medicine, Chapel Hill, North Carolina (N.N.)
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Peter E. Shaw
Department of Oncology (C.S., S.K., Y.H., L.P., M.R.) and Smart Sensors and Integrated Microsystems (SSIM) Program (S.Y., G.A.), Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute, Detroit, Michigan; Department of Biochemistry and Molecular Biology, College of Natural Science, Michigan State University, East Lansing, Michigan (N.I. and A.D.); School of Life Sciences, University of Nottingham, Queens Medical Centre, Nottingham, United Kingdom (C.D. and P.E.S.); and Department of Pharmacology, UNC-Chapel Hill School of Medicine, Chapel Hill, North Carolina (N.N.)
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Gregory Auner
Department of Oncology (C.S., S.K., Y.H., L.P., M.R.) and Smart Sensors and Integrated Microsystems (SSIM) Program (S.Y., G.A.), Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute, Detroit, Michigan; Department of Biochemistry and Molecular Biology, College of Natural Science, Michigan State University, East Lansing, Michigan (N.I. and A.D.); School of Life Sciences, University of Nottingham, Queens Medical Centre, Nottingham, United Kingdom (C.D. and P.E.S.); and Department of Pharmacology, UNC-Chapel Hill School of Medicine, Chapel Hill, North Carolina (N.N.)
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Alex Dickson
Department of Oncology (C.S., S.K., Y.H., L.P., M.R.) and Smart Sensors and Integrated Microsystems (SSIM) Program (S.Y., G.A.), Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute, Detroit, Michigan; Department of Biochemistry and Molecular Biology, College of Natural Science, Michigan State University, East Lansing, Michigan (N.I. and A.D.); School of Life Sciences, University of Nottingham, Queens Medical Centre, Nottingham, United Kingdom (C.D. and P.E.S.); and Department of Pharmacology, UNC-Chapel Hill School of Medicine, Chapel Hill, North Carolina (N.N.)
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Manohar Ratnam
Department of Oncology (C.S., S.K., Y.H., L.P., M.R.) and Smart Sensors and Integrated Microsystems (SSIM) Program (S.Y., G.A.), Wayne State University School of Medicine and Barbara Ann Karmanos Cancer Institute, Detroit, Michigan; Department of Biochemistry and Molecular Biology, College of Natural Science, Michigan State University, East Lansing, Michigan (N.I. and A.D.); School of Life Sciences, University of Nottingham, Queens Medical Centre, Nottingham, United Kingdom (C.D. and P.E.S.); and Department of Pharmacology, UNC-Chapel Hill School of Medicine, Chapel Hill, North Carolina (N.N.)
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Abstract

The androgen receptor (AR) is a crucial coactivator of ELK1 for prostate cancer (PCa) growth, associating with ELK1 through two peptide segments (358-457 and 514-557) within the amino-terminal domain (NTD) of AR. The small-molecule antagonist 5-hydroxy-2-(3-hydroxyphenyl)chromen-4-one (KCI807) binds to AR, blocking ELK1 binding and inhibiting PCa growth. We investigated the mode of interaction of KCI807 with AR using systematic mutagenesis coupled with ELK1 coactivation assays, testing polypeptide binding and Raman spectroscopy. In full-length AR, deletion of neither ELK1 binding segment affected sensitivity of residual ELK1 coactivation to KCI807. Although the NTD is sufficient for association of AR with ELK1, interaction of the isolated NTD with ELK1 was insensitive to KCI807. In contrast, coactivation of ELK1 by the AR-V7 splice variant, comprising the NTD and the DNA binding domain (DBD), was sensitive to KCI807. Deletions and point mutations within DBD segment 558-595, adjacent to the NTD, interfered with coactivation of ELK1, and residual ELK1 coactivation by the mutants was insensitive to KCI807. In a glutathione S-transferase pull-down assay, KCI807 inhibited ELK1 binding to an AR polypeptide that included the two ELK1 binding segments and the DBD but did not affect ELK1 binding to a similar AR segment that lacked the sequence downstream of residue 566. Raman spectroscopy detected KCI807-induced conformational change in the DBD. The data point to a putative KCI807 binding pocket within the crystal structure of the DBD and indicate that either mutations or binding of KCI807 at this site will induce conformational changes that disrupt ELK1 binding to the NTD.

SIGNIFICANCE STATEMENT The small-molecule antagonist KCI807 disrupts association of the androgen receptor (AR) with ELK1, serving as a prototype for the development of small molecules for a novel type of therapeutic intervention in drug-resistant prostate cancer. This study provides basic information needed for rational KCI807-based drug design by identifying a putative binding pocket in the DNA binding domain of AR through which KCI807 modulates the amino-terminal domain to inhibit ELK1 binding.

Footnotes

    • Received July 12, 2022.
    • Accepted December 27, 2022.
  • This work was supported by the U.S. Department of Defense [Grant W81XWH-17-1-0242] (to M.R.) and [Grant W81XWH-17-1-0243] (to P.E.S.) and National Institutes of Health National Cancer Institute [Grant 5T32-CA009531-29] (to C.S.).

  • No author has an actual or perceived conflict of interest with the contents of this article.

  • dx.doi.org/10.1124/molpharm.122.000589.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 103 (4)
Molecular Pharmacology
Vol. 103, Issue 4
1 Apr 2023
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Research ArticleArticle

The Binding Site for KCI807 in the Androgen Receptor

Claire Soave, Charles Ducker, Naeyma Islam, Seongho Kim, Sally Yurgelevic, Nathan I. Nicely, Luke Pardy, Yanfang Huang, Peter E. Shaw, Gregory Auner, Alex Dickson and Manohar Ratnam
Molecular Pharmacology April 1, 2023, 103 (4) 211-220; DOI: https://doi.org/10.1124/molpharm.122.000589

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Research ArticleArticle

The Binding Site for KCI807 in the Androgen Receptor

Claire Soave, Charles Ducker, Naeyma Islam, Seongho Kim, Sally Yurgelevic, Nathan I. Nicely, Luke Pardy, Yanfang Huang, Peter E. Shaw, Gregory Auner, Alex Dickson and Manohar Ratnam
Molecular Pharmacology April 1, 2023, 103 (4) 211-220; DOI: https://doi.org/10.1124/molpharm.122.000589
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