Abstract 3650: Discovery of the clinical candidate AZD9496: a potent and orally bioavailable selective estrogen receptor downregulator and antagonist
Authors: De Savi Chris , Bradbury Robert H. , Rabow Alfred A. , Norman Richard A. , Buttar David , Currie Gordon S. , Weir Hazel , Donald Craig , Andrews David , MacFaul Phil , Ballard Peter , Curwen Jon , Wilson Zena , Richmond Graham , D'Cruz Celina , Powell Steve , Walker Graeme , Hulse Michael , Tonge Michael 
Published: August 2015

Abstract
With over 70% of breast cancers expressing the estrogen receptor alpha (ERα), treatment with either anti-hormonal therapies that directly block ER function or therapies that block the production of estrogen itself have proven to be effective treatments of the disease. Following the pioneering discovery of the ERα antagonist tamoxifen in the 1960s, identification of the selective estrogen receptor downregulator (SERD) fulvestrant represented a further step forward in the treatment of advanced ER+ breast cancer especially in the endocrine resistance setting. The pure estrogen downregulator-antagonist fulvestrant offers the advantage of not only antagonising ERα-driven tumor cell growth but also degrading ERα via ubiquitinylation and thus diminishing growth due to reduced ERα content. Given its low level of bioavailability and metabolic profile, fulvestrant has been formulated as an intramuscular monthly injection. We have sought to identify a novel, non-steroidal ERα antagonist and down-regulator that can be administered orally and could yield improved exposure and clinical benefit. This presentation will describe the discovery of AZD9496, a novel, orally bioavailable small molecule that can induce ERα degradation in breast cancer cell lines at picomolar concentrations. Data will be shared for the first time on the medicinal chemistry efforts that led to AZD9496, the good oral pharmacokinetic properties of the compound which led to significant tumor efficacy in both endocrine sensitive model (complete tumor growth inhibition (TGI) in a MCF-7 model at a dose of 10 mpk) and resistant models (tumor regressions in a HCC1428 long term estrogen deprived (LTED) model, with significant down-regulation of ER protein (81%) at 1 mpk QD and tumour growth inhibition in an ESR1 mutant PDX model). These findings strongly supported selection of AZD9496 as a clinical candidate for the treatment of ER+ breast cancer, and on October 2014 the first patient was dosed with AZD9496.
ER alpha human binding IC50 (μM)ER downregulation cell IC50 (μM)MCF7 anti-proliferation EC50 (μM)Aqueous solubility, (pH = 7.4, μM)MCF7 tumor xenograft efficacy (% TGI at 10 mpk PO QD for 22 days)AZD94960.00070.000140.0000411084
Citation Format: Chris De Savi, Robert H. Bradbury, Alfred A. Rabow, Richard A. Norman, David Buttar, Gordon S. Currie, Hazel Weir, Craig Donald, David Andrews, Phil MacFaul, Peter Ballard, Jon Curwen, Zena Wilson, Graham Richmond, Celina D'Cruz, Steve Powell, Graeme Walker, Michael Hulse, Michael Tonge. Discovery of the clinical candidate AZD9496: a potent and orally bioavailable selective estrogen receptor downregulator and antagonist. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3650. doi:10.1158/1538-7445.AM2015-3650