Abstract DDT01-04: Discovery and development of H3B-6545: A novel, oral, selective estrogen receptor covalent antagonist (SERCA) for the treatment of breast cancer
Authors: Smith Peter G. , Puyang Xiaoling , Furman Craig , Zheng Guo Zhu , Banka Deepti , Thomas Michael , Subramanian Vanitha , Irwin Sean , Larsen Nicholas , Caleb Benjamin , Karr Craig , Wu Jeremy , O’Shea Morgan , Yang Joyce , Davis Allison , Kim Amy , Rioux Nathalie , Rimkunas Victoria , Yao Huilan , MacKenzie Crystal , Kumar Pavan , Smith Sherri , Eckley Sean , Hart Andrew , Lai George , Rowbottom Christopher , Fekkes Peter , Buonamici Silvia , Reynolds Dominic , Yu Lihua , Sahmoud Tarek , Warmuth Markus , Mitchell Lorna , Zhu Ping , Korpal Manav 
Published: July 2017

Abstract
Mutations in the estrogen receptor (ER) are detected in up to 30% of patients that initially respond but subsequently relaps to anti-endocrine therapies. ERα mutations, likely through constitutively activating ERα, can functionally confer resistance to existing classes of endocrine therapies. Current endocrine therapies are only partially effective in the ERα mutant setting and a significant proportion of endocrine-therapy resistant breast cancer metastases continue to remain dependent on ERα signaling for growth/survival indicating a critical need to develop the next generation of ERα antagonists that can overcome ERα wild-type and mutant activity. Here we describe a novel series of compounds with a unique mode of inhibition that potently target both wild-type and mutant ERα. These compounds are Selective Estrogen Receptor Covalent Antagonists (SERCAs) that inactivate the estrogen receptor by targeting a cysteine that is not present in other nuclear hormone receptors, leading to a unique biological and activity profile differentiated from Selective Estrogen Receptor Modulators (SERMs) and Selective Estrogen Receptor Degraders (SERDs). Using structure-based drug design approaches we have identified a first-in-class clinical candidate, H3B-6545. H3B-6545 is a highly selective small molecule that potently antagonizes wild-type and mutant ERα in biochemical and cell based assays. In vitro comparisons with standard of care and other experimental agents confirm increased cell potency of H3B-6545 under continuous as well as washout treatment conditions. In vivo, once daily oral dosing of H3B-6545 shows potent activity and superior efficacy to fulvestrant in the MCF-7 xenograft model with maximal antitumor activity at doses &gt;10x below the maximum tolerated dose in mice. In addition, H3B-6545 shows superior antitumor activity to tamoxifen and fulvestrant in patient derived xenograft models of estrogen receptor positive breast cancer including models carrying ERα mutations In non-clinical safety studies in rat and monkeys, H3B-6545 is well tolerated across a broad dose range and at exposures that significantly exceed those required for efficacy in mouse xenograft models. In summary, H3B-6545 is a first-in-class, orally available and potent selective estrogen receptor covalent antagonist with a compelling preclinical efficacy and safety profile that is being developed for the treatment of breast cancer.
Citation Format: Peter G. Smith, Xiaoling Puyang, Craig Furman, Guo Zhu Zheng, Deepti Banka, Michael Thomas, Vanitha Subramanian, Sean Irwin, Nicholas Larsen, Benjamin Caleb, Craig Karr, Jeremy Wu, Morgan O’Shea, Joyce Yang, Allison Davis, Amy Kim, Nathalie Rioux, Victoria Rimkunas, Huilan Yao, Crystal MacKenzie, Pavan Kumar, Sherri Smith, Sean Eckley, Andrew Hart, George Lai, Christopher Rowbottom, Peter Fekkes, Silvia Buonamici, Dominic Reynolds, Lihua Yu, Tarek Sahmoud, Markus Warmuth, Lorna Mitchell, Ping Zhu, Manav Korpal. Discovery and development of H3B-6545: A novel, oral, selective estrogen receptor covalent antagonist (SERCA) for the treatment of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr DDT01-04. doi:10.1158/1538-7445.AM2017-DDT01-04