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Maximizing ER-α Degradation Maximizes Activity in a Tamoxifen-Resistant Breast Cancer Model: Identification of GDC-0927.
Kahraman, Mehmet; Govek, Steven P; Nagasawa, Johnny Y; Lai, Andiliy; Bonnefous, Celine; Douglas, Karensa; Sensintaffar, John; Liu, Nhin; Lee, KyoungJin; Aparicio, Anna; Kaufman, Josh; Qian, Jing; Shao, Gang; Prudente, Rene; Joseph, James D; Darimont, Beatrice; Brigham, Daniel; Heyman, Richard; Rix, Peter J; Hager, Jeffrey H; Smith, Nicholas D.
Afiliación
  • Kahraman M; Department of Chemistry, Department of Biology, and Department of Drug Safety and Disposition, Seragon Pharmaceuticals, 12780 El Camino Real, Suite 302, San Diego, California 92130, United States.
  • Govek SP; Department of Chemistry, Department of Biology, and Department of Drug Safety and Disposition, Seragon Pharmaceuticals, 12780 El Camino Real, Suite 302, San Diego, California 92130, United States.
  • Nagasawa JY; Department of Chemistry, Department of Biology, and Department of Drug Safety and Disposition, Seragon Pharmaceuticals, 12780 El Camino Real, Suite 302, San Diego, California 92130, United States.
  • Lai A; Department of Chemistry, Department of Biology, and Department of Drug Safety and Disposition, Seragon Pharmaceuticals, 12780 El Camino Real, Suite 302, San Diego, California 92130, United States.
  • Bonnefous C; Department of Chemistry, Department of Biology, and Department of Drug Safety and Disposition, Seragon Pharmaceuticals, 12780 El Camino Real, Suite 302, San Diego, California 92130, United States.
  • Douglas K; Department of Chemistry, Department of Biology, and Department of Drug Safety and Disposition, Seragon Pharmaceuticals, 12780 El Camino Real, Suite 302, San Diego, California 92130, United States.
  • Sensintaffar J; Department of Chemistry, Department of Biology, and Department of Drug Safety and Disposition, Seragon Pharmaceuticals, 12780 El Camino Real, Suite 302, San Diego, California 92130, United States.
  • Liu N; Department of Chemistry, Department of Biology, and Department of Drug Safety and Disposition, Seragon Pharmaceuticals, 12780 El Camino Real, Suite 302, San Diego, California 92130, United States.
  • Lee K; Department of Chemistry, Department of Biology, and Department of Drug Safety and Disposition, Seragon Pharmaceuticals, 12780 El Camino Real, Suite 302, San Diego, California 92130, United States.
  • Aparicio A; Department of Chemistry, Department of Biology, and Department of Drug Safety and Disposition, Seragon Pharmaceuticals, 12780 El Camino Real, Suite 302, San Diego, California 92130, United States.
  • Kaufman J; Department of Chemistry, Department of Biology, and Department of Drug Safety and Disposition, Seragon Pharmaceuticals, 12780 El Camino Real, Suite 302, San Diego, California 92130, United States.
  • Qian J; Department of Chemistry, Department of Biology, and Department of Drug Safety and Disposition, Seragon Pharmaceuticals, 12780 El Camino Real, Suite 302, San Diego, California 92130, United States.
  • Shao G; Department of Chemistry, Department of Biology, and Department of Drug Safety and Disposition, Seragon Pharmaceuticals, 12780 El Camino Real, Suite 302, San Diego, California 92130, United States.
  • Prudente R; Department of Chemistry, Department of Biology, and Department of Drug Safety and Disposition, Seragon Pharmaceuticals, 12780 El Camino Real, Suite 302, San Diego, California 92130, United States.
  • Joseph JD; Department of Chemistry, Department of Biology, and Department of Drug Safety and Disposition, Seragon Pharmaceuticals, 12780 El Camino Real, Suite 302, San Diego, California 92130, United States.
  • Darimont B; Department of Chemistry, Department of Biology, and Department of Drug Safety and Disposition, Seragon Pharmaceuticals, 12780 El Camino Real, Suite 302, San Diego, California 92130, United States.
  • Brigham D; Department of Chemistry, Department of Biology, and Department of Drug Safety and Disposition, Seragon Pharmaceuticals, 12780 El Camino Real, Suite 302, San Diego, California 92130, United States.
  • Heyman R; Department of Chemistry, Department of Biology, and Department of Drug Safety and Disposition, Seragon Pharmaceuticals, 12780 El Camino Real, Suite 302, San Diego, California 92130, United States.
  • Rix PJ; Department of Chemistry, Department of Biology, and Department of Drug Safety and Disposition, Seragon Pharmaceuticals, 12780 El Camino Real, Suite 302, San Diego, California 92130, United States.
  • Hager JH; Department of Chemistry, Department of Biology, and Department of Drug Safety and Disposition, Seragon Pharmaceuticals, 12780 El Camino Real, Suite 302, San Diego, California 92130, United States.
  • Smith ND; Department of Chemistry, Department of Biology, and Department of Drug Safety and Disposition, Seragon Pharmaceuticals, 12780 El Camino Real, Suite 302, San Diego, California 92130, United States.
ACS Med Chem Lett ; 10(1): 50-55, 2019 Jan 10.
Article en En | MEDLINE | ID: mdl-30655946
The further optimization of ER-α degradation efficacy of a series of ER modulators by refining side-chain substitution led to efficacious selective estrogen receptor degraders (SERDs). A fluoromethyl azetidine group was found to be preferred and resulted in the identification of bis-phenol chromene 17ha. In a tamoxifen-resistant breast cancer xenograft model, 17ha (ER-α degradation efficacy = 97%) demonstrated tumor regression, together with robust reduction of intratumoral ER-α levels. However, despite superior oral exposure, 5a (ER-α degradation efficacy = 91%) had inferior activity. This result suggests that optimizing ER-α degradation efficacy leads to compounds with robust effects in a model of tamoxifen-resistant breast cancer. Compound 17ha (GDC-0927) was evaluated in clinical trials in women with metastatic estrogen receptor-positive breast cancer.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Diagnostic_studies Idioma: En Revista: ACS Med Chem Lett Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Diagnostic_studies Idioma: En Revista: ACS Med Chem Lett Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos