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Modulating Androgen Receptor-Driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors.
Richters, André; Doyle, Shelby K; Freeman, David B; Lee, Christina; Leifer, Becky S; Jagannathan, Sajjeev; Kabinger, Florian; Koren, Jost Vrabic; Struntz, Nicholas B; Urgiles, Julie; Stagg, Ryan A; Curtin, Brice H; Chatterjee, Deep; Mathea, Sebastian; Mikochik, Peter J; Hopkins, Tamara D; Gao, Hua; Branch, Jonathan R; Xin, Hong; Westover, Lori; Bignan, Gilles C; Rupnow, Brent A; Karlin, Kristen L; Olson, Calla M; Westbrook, Thomas F; Vacca, Joseph; Wilfong, Chris M; Trotter, B Wesley; Saffran, Douglas C; Bischofberger, Norbert; Knapp, Stefan; Russo, Joshua W; Hickson, Ian; Bischoff, James R; Gottardis, Marco M; Balk, Steven P; Lin, Charles Y; Pop, Marius S; Koehler, Angela N.
Afiliação
  • Richters A; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; MIT Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Doyle SK; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; MIT Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Departmen
  • Freeman DB; Kronos Bio, Inc., Cambridge, MA 02139, USA.
  • Lee C; Kronos Bio, Inc., Cambridge, MA 02139, USA.
  • Leifer BS; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; MIT Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Jagannathan S; Therapeutic Innovation Center, Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
  • Kabinger F; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; MIT Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Koren JV; Therapeutic Innovation Center, Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
  • Struntz NB; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; MIT Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Urgiles J; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Harvard-MIT Health Sciences and Technology, Boston, MA 02115, USA.
  • Stagg RA; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Biology, Boston University, Boston, MA 02215, USA.
  • Curtin BH; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; MIT Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Chatterjee D; Goethe-Universität Frankfurt, 60438 Frankfurt am Main, Germany.
  • Mathea S; Goethe-Universität Frankfurt, 60438 Frankfurt am Main, Germany.
  • Mikochik PJ; Kronos Bio, Inc., Cambridge, MA 02139, USA.
  • Hopkins TD; Kronos Bio, Inc., Cambridge, MA 02139, USA.
  • Gao H; Kronos Bio, Inc., Cambridge, MA 02139, USA.
  • Branch JR; Janssen Research & Development, LLC, Spring House, PA, USA.
  • Xin H; Janssen Research & Development, LLC, Spring House, PA, USA.
  • Westover L; Janssen Research & Development, LLC, Spring House, PA, USA.
  • Bignan GC; Janssen Research & Development, LLC, Spring House, PA, USA.
  • Rupnow BA; Janssen Research & Development, LLC, Spring House, PA, USA.
  • Karlin KL; Therapeutic Innovation Center, Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
  • Olson CM; Therapeutic Innovation Center, Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
  • Westbrook TF; Therapeutic Innovation Center, Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
  • Vacca J; Kronos Bio, Inc., Cambridge, MA 02139, USA.
  • Wilfong CM; Kronos Bio, Inc., Cambridge, MA 02139, USA.
  • Trotter BW; Kronos Bio, Inc., Cambridge, MA 02139, USA.
  • Saffran DC; Kronos Bio, Inc., Cambridge, MA 02139, USA.
  • Bischofberger N; Kronos Bio, Inc., Cambridge, MA 02139, USA.
  • Knapp S; Goethe-Universität Frankfurt, 60438 Frankfurt am Main, Germany.
  • Russo JW; Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
  • Hickson I; Janssen Research & Development, LLC, Spring House, PA, USA; Cancer Research UK Newcastle Drug Discovery Unit, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
  • Bischoff JR; Janssen Research & Development, LLC, Spring House, PA, USA.
  • Gottardis MM; Janssen Research & Development, LLC, Spring House, PA, USA.
  • Balk SP; Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
  • Lin CY; Kronos Bio, Inc., Cambridge, MA 02139, USA; Therapeutic Innovation Center, Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
  • Pop MS; Kronos Bio, Inc., Cambridge, MA 02139, USA.
  • Koehler AN; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; MIT Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Departmen
Cell Chem Biol ; 28(2): 134-147.e14, 2021 02 18.
Article em En | MEDLINE | ID: mdl-33086052
ABSTRACT
Castration-resistant prostate cancers (CRPCs) lose sensitivity to androgen-deprivation therapies but frequently remain dependent on oncogenic transcription driven by the androgen receptor (AR) and its splice variants. To discover modulators of AR-variant activity, we used a lysate-based small-molecule microarray assay and identified KI-ARv-03 as an AR-variant complex binder that reduces AR-driven transcription and proliferation in prostate cancer cells. We deduced KI-ARv-03 to be a potent, selective inhibitor of CDK9, an important cofactor for AR, MYC, and other oncogenic transcription factors. Further optimization resulted in KB-0742, an orally bioavailable, selective CDK9 inhibitor with potent anti-tumor activity in CRPC models. In 22Rv1 cells, KB-0742 rapidly downregulates nascent transcription, preferentially depleting short half-life transcripts and AR-driven oncogenic programs. In vivo, oral administration of KB-0742 significantly reduced tumor growth in CRPC, supporting CDK9 inhibition as a promising therapeutic strategy to target AR dependence in CRPC.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Transcrição Gênica / Receptores Androgênicos / Quinase 9 Dependente de Ciclina / Inibidores de Proteínas Quinases / Antagonistas de Receptores de Andrógenos / Neoplasias de Próstata Resistentes à Castração Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: Cell Chem Biol Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Transcrição Gênica / Receptores Androgênicos / Quinase 9 Dependente de Ciclina / Inibidores de Proteínas Quinases / Antagonistas de Receptores de Andrógenos / Neoplasias de Próstata Resistentes à Castração Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: Cell Chem Biol Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos