生物活性

• 描述AZD9496 is a potent and selective non-steroidal ERα inhibitor and down-regulator of ERα in ER-positive models of breast cancer, with IC50 values of 0.82nM, 0.14nM, 0.28nM and 0.04nM for ERα binding, ERα downregulation, ERα antagonism and MCF-7 cell growth inhibition. AZD9496 could antagonize and downregulate mutant ER in vitro. It exhibited IC50 values of 0.2nM, 0.5nM and 0.6nM for binding to ERα wt, ERα D538G mutant and ERα Y537S mutant, respectively. Significant tumour growth inhibition was observed at doses ranging in 0.5-50mg/kg (p.o., q.d.) in the estrogen-dependent MCF-7 xenograft model, where this effect was accompanied by a dose-dependent decrease in PR protein levels demonstrating potent antagonist activity. Combining AZD9496 with PI3K pathway and CDK4/6 inhibitors led to further growth inhibitory effects compared to monotherapy alone. AZD9496 bound and down-regulated clinically relevant ESR1 mutants in vitro and inhibited tumour growth in an ESR1-mutant patient derived xenograft model that included a D538G mutation.
• 作用机制AZD9496 occupies a "lipophilic hole" in the ER protein.^[1]

• 动物研究
  剂量	Rat[1] (p.o.): 5 mg/kg - 50 mg/kg
  给药途径	p.o.
  动物药代数据	Animal Mice[2] Rats[2] Dogs[2] Dose 2.3 μmol/kg (i.v.) 5.6 μmol/kg (p.o.) 2.2 μmol/kg (i.v.) 4.5 μmol/kg (p.o.) 2.5 μmol/kg (i.v.) 5 μmol/kg (p.o.) Administration i.v. p.o. i.v. p.o. i.v. p.o. F 1.28 0.63 0.79 Vdss 2.2 L/kg 0.43 L/kg 0.4 L/kg CL 43 ml/min/kg 1.0 ml/min/kg 0.28 ml/min/kg

• 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
  NCT02780713	Breast Cancer	Phase 1	Completed	-	United States, Maryland ... more >> Research Site Baltimore, Maryland, United States Collapse <<
  NCT02248090	ER+ HER2- Advanced Breast Canc... more >>er Collapse <<	Phase 1	Active, not recruiting	December 31, 2018	United States, Florida ... more >> Florida Cancer Specialists Sarasota, Florida, United States, 34232 United States, New York Research Site New York, New York, United States, 10065 United States, Tennessee Sarah Cannon Nashville, Tennessee, United States, 37203 Korea, Republic of Seoul National Univ. Hospital Seoul, Korea, Republic of, 110-744 United Kingdom Research Site Cambridge, United Kingdom, CB2 0QQ Christie Manchester, United Kingdom, M20 4BX Collapse <<
  NCT03236974	Postmenopausal Women With ER+ ... more >>HER2- Primary Breast Cancer Collapse <<	Phase 1	Recruiting	February 15, 2019	Germany ... more >> Research Site Recruiting Berlin, Germany, 10117 Research Site Recruiting Erlangen, Germany, 91054 Research Site Recruiting Kiel, Germany, 24105 Research Site Recruiting Köln, Germany, 50935 Research Site Recruiting Minden, Germany, 32429 Research Site Withdrawn Mönchengladbach, Germany, 41061 Research Site Recruiting München, Germany, 81377 Research Site Recruiting Schwerin, Germany, 19049 United Kingdom Research Site Withdrawn Birmingham, United Kingdom, B15 2TG Research Site Withdrawn Bournemouth, United Kingdom, BH7 7DW Research Site Recruiting Derby, United Kingdom, DE22 3DT Research Site Recruiting Edinburgh, United Kingdom, EH4 2XU Research Site Recruiting London, United Kingdom, EC1M 6BQ Research Site Recruiting London, United Kingdom, SE1 9RT Research Site Recruiting London, United Kingdom, W12 0NN Research Site Recruiting Manchester, United Kingdom, M23 9LT Research Site Recruiting Poole, United Kingdom, BH15 2JB Research Site Recruiting Sutton In Ashfield, United Kingdom, NG17 4JL Collapse <<

• 参考文献

• [1] Weir HM, Bradbury RH, et al. AZD9496: An Oral Estrogen Receptor Inhibitor That Blocks the Growth of ER-Positive and ESR1-Mutant Breast Tumors in Preclinical Models. Cancer Res. 2016 Jun 1;76(11):3307-18.

  [2] De Savi C, Bradbury RH, et al. Optimization of a Novel Binding Motif to (E)-3-(3,5-Difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic Acid (AZD9496), a Potent and Orally Bioavailable Selective Estrogen Receptor Downregulator and Antagonist. J Med Chem. 2015 Oct 22;58(20):8128-40.