Maximizing ER-α Degradation Maximizes Activity in a Tamoxifen-Resistant Breast Cancer Model: Identification of GDC-0927.

Autor:	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.
Jazyk:	angličtina
Zdroj:	ACS medicinal chemistry letters [ACS Med Chem Lett] 2018 Dec 06; Vol. 10 (1), pp. 50-55. Date of Electronic Publication: 2018 Dec 06 (Print Publication: 2019).
DOI:	10.1021/acsmedchemlett.8b00414
Abstrakt:	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. Competing Interests: The authors declare no competing financial interest.
Databáze:	MEDLINE
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