生物活性

• 描述The estrogen receptor ER-α has been an important target in the pharmaceutical industry for many years, with ER antagonists such as tamoxifen and aromatase inhibitors being key therapeutics in the management of ER-positive breast cancer. GDC-0927 is a novel, potent, orally bioavailable and selective ER-α antagonist with an IC₅₀ value of 0.1 nM and possesses high ER-α degradation efficacy (97%). GDC-0927 displayed an MCF-7 proliferation inhibition with an IC₅₀ value of 0.2 nM. The mouse pharmacokinetic of GDC-0927 is characterized by high clearance (Cl > 60 mL/min/kg) and low bioavailability (%F < 15) and low AUC (po AUC = 0.16 μg•h/mL). GDC-0927 was profiled in a MCF-7 based tamoxifen-resistant xenograft model of breast cancer using subcutaneous estradiol pellets to deliver sufficient levels of estradiol to drive tumor growth. Importantly, GDC-0927 demonstrated high activity with 5 of 8 animals in each cohort showing tumor regressions. Cytochrome P450 inhibition profiling of GDC-0927 indicated it had modest inhibitory effect on CYP2C8 and CYP2C9 (IC₅₀ = 3.0 and 3.2 μM, respectively). When tested for its effect on the hERG channel in a patch clamp assay, GDC-0927 was found to be a moderate inhibitor (IC₅₀ = 4.6 μM)^[1].
• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT02316509	Breast Cancer	Phase 1	Active, not recruiting	November 30, 2019	United States, Massachusetts ... more >> Massachusetts General Hospital. Boston, Massachusetts, United States, 02114 Dana Farber Cancer Institute Boston, Massachusetts, United States, 02215 United States, New York Memorial Sloan Kettering Cancer Center New York, New York, United States, 10065 Stony Brook University Medical Center Stony Brook, New York, United States, 11794 United States, Tennessee Sarah Cannon Cancer Center Germantown, Tennessee, United States, 38138 Vanderbilt Ingram Cancer Ctr Nashville, Tennessee, United States, 37232 Spain ICO I Hospitalet Hospital Duran i Reynals Instituto Catalan de Oncologia de Hospitalet ICO L'Hospitalet de Llobregat, Barcelona, Spain, 08908 Onkologikoa - Kutxaren Institutu Onkologikoa San Sebastian, Guipuzcoa, Spain, 20014 Hospital Univ Vall d'Hebron; Servicio de Oncologia Barcelona, Spain, 08035 MD Anderson Cancer Center Madrid - España; Servicio de Farmacia Madrid, Spain, 28033 Hospital Universitario Ramón y Cajal Madrid, Spain, 28034 Hospital General Universitario Gregorio Maranon Madrid, Spain, 28040 HM Sanchinarro - CIOCC Madrid, Spain, 28050 Hospital Clinico Universitario de Valencia Valencia, Spain, 46010 Collapse <<

• 参考文献

• [1] Kahraman M, Govek SP, Nagasawa JY, et al. Maximizing ER-α Degradation Maximizes Activity in a Tamoxifen-Resistant Breast Cancer Model: Identification of GDC-0927. ACS Med Chem Lett. 2018;10(1):50-55.