Supplementary Tables and Legends from AZD9496: An Oral Estrogen Receptor Inhibitor That Blocks the Growth of ER-Positive and ESR1-Mutant Breast Tumors in Preclinical Models

Weir, Hazel M.; Bradbury, Robert H.; Lawson, Mandy; Rabow, Alfred A.; Buttar, David; Callis, Rowena J.; Curwen, Jon O.; de Almeida, Camila; Ballard, Peter; Hulse, Michael; Donald, Craig S.; Feron, Lyman J.L.; Karoutchi, Galith; MacFaul, Philip; Moss, Thomas; Norman, Richard A.; Pearson, Stuart E.; Tonge, Michael; Davies, Gareth; Walker, Graeme E.; Wilson, Zena; Rowlinson, Rachel; Powell, Steve; Sadler, Claire; Richmond, Graham; Ladd, Brendon; Pazolli, Ermira; Mazzola, Anne Marie; D'Cruz, Celina; De Savi, Chris

doi:10.1158/0008-5472.22409528.v1

Supplementary Tables and Legends from AZD9496: An Oral Estrogen Receptor Inhibitor That Blocks the Growth of ER-Positive and ESR1-Mutant Breast Tumors in Preclinical Models

journal contribution

posted on 2023-03-30, 23:48 authored by Hazel M. Weir, Robert H. Bradbury, Mandy Lawson, Alfred A. Rabow, David Buttar, Rowena J. Callis, Jon O. Curwen, Camila de Almeida, Peter Ballard, Michael Hulse, Craig S. Donald, Lyman J.L. Feron, Galith Karoutchi, Philip MacFaul, Thomas Moss, Richard A. Norman, Stuart E. Pearson, Michael Tonge, Gareth Davies, Graeme E. Walker, Zena Wilson, Rachel Rowlinson, Steve Powell, Claire Sadler, Graham Richmond, Brendon Ladd, Ermira Pazolli, Anne Marie Mazzola, Celina D'Cruz, Chris De Savi

Supplementary Table 1 contains crystallographic data collection and refinements statistics for AZD9496 binding to the human estrogen receptor α ligand binding domain, Supplementary Table 2 shows the rate constants for association, dissociation and equilibrium dissociation constant for AZD9496 binding to the human estrogen receptor α ligand binding domain, Supplementary Table 3 displays IC50 values for AZD9496 binding to androgen, glucocorticoid, progesterone and estrogen receptor β ligand binding domains, Supplementary Table 4 displays IC50s values for cell growth inhibition of a panel of estrogen receptor positive and negative cell lines using AZD9496.

History

ARTICLE ABSTRACT

Fulvestrant is an estrogen receptor (ER) antagonist administered to breast cancer patients by monthly intramuscular injection. Given its present limitations of dosing and route of administration, a more flexible orally available compound has been sought to pursue the potential benefits of this drug in patients with advanced metastatic disease. Here we report the identification and characterization of AZD9496, a nonsteroidal small-molecule inhibitor of ERα, which is a potent and selective antagonist and downregulator of ERα in vitro and in vivo in ER-positive models of breast cancer. Significant tumor growth inhibition was observed as low as 0.5 mg/kg dose 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 with monotherapy alone. Tumor regressions were also seen in a long-term estrogen-deprived breast model, where significant downregulation of ERα protein was observed. AZD9496 bound and downregulated clinically relevant ESR1 mutants in vitro and inhibited tumor growth in an ESR1-mutant patient-derived xenograft model that included a D538G mutation. Collectively, the pharmacologic evidence showed that AZD9496 is an oral, nonsteroidal, selective estrogen receptor antagonist and downregulator in ER+ breast cells that could provide meaningful benefit to ER+ breast cancer patients. AZD9496 is currently being evaluated in a phase I clinical trial. Cancer Res; 76(11); 3307–18. ©2016 AACR.