Abstract P1-10-08: Development of a first-in-class oral selective ERα covalent antagonist (SERCA) for the treatment of ERαWT and ERαMUT breast cancer
Authors: Korpal M , Puyang X , Furman C , Zheng GZ , Banka D , Wu J , Zhang Z , Thomas M , Mackenzie C , Yao H , Rimkunas V , Kumar P , Caleb B , Karr C , Subramanian V , Irwin S , Larsen N , Vaillancourt F , Nguyen T-V , Davis A , Chan B , Hao MH , O'Shea M , Prajapati S , Agoulnik S , Kuznetsov G , Kumar N , Yu Y , Lai G , Hart A , Eckley S , Fekkes P , Bowser T , Joshi JJ , Selvaraj A , Wardell S , Norris J , Smith S , Reynolds D , Mitchell L , Wang J , Yu L , Kim A , Rioux N , Sahmoud T , Warmuth M , Smith PG , Zhu P 
Published: February 2018

Abstract
Mutations in estrogen receptor alpha (ERα) are detected in up to 30% of breast cancer patients who have relapsed during endocrine therapy. ERα mutations functionally confer resistance to existing classes of endocrine therapies, likely through gaining constitutive activity. The fact that current ER-directed therapies are only partially effective in the ERα mutant setting, and that a significant proportion of resistant breast cancer metastases continue to remain dependent on ERα signaling for growth/survival, highlights the critical need to develop the next generation of ERα antagonists that can overcome aberrant ERα activity. Using structure-based drug design approaches we have identified a novel class of ERα antagonist referred to as Selective ERα Covalent Antagonist (SERCA) that inactivate both wild-type and mutant ERα by targeting a unique cysteine residue that is not conserved among other steroid hormone receptors. Biophysical, biochemical and cellular analyses confirm the covalent mechanism of action, specific binding to ER and selective inhibition of ERα-dependent transcription of SERCAs. H3B-6545 is a highly selective SERCA that potently antagonizes wild-type and mutant ERα in biochemical and cell based assays demonstrating increased potency over standard of care and other experimental agents. In vivo, H3B-6545 shows superior efficacy to fulvestrant in the MCF-7 xenograft model with once daily oral dosing, achieving maximal antitumor activity at doses &gt;10x below the maximum tolerated dose in mice. In addition, H3B-6545 shows superior antitumor activity to both tamoxifen and fulvestrant in patient derived xenograft models of breast cancer carrying estrogen receptor mutations. In summary, H3B-6545 is a first-in-class, orally available and selective ER covalent antagonist with a compelling pre-clinical profile that is being developed for the treatment of ERα positive breast cancer.
Citation Format: Korpal M, Puyang X, Furman C, Zheng GZ, Banka D, Wu J, Zhang Z, Thomas M, Mackenzie C, Yao H, Rimkunas V, Kumar P, Caleb B, Karr C, Subramanian V, Irwin S, Larsen N, Vaillancourt F, Nguyen T-V, Davis A, Chan B, Hao MH, O'Shea M, Prajapati S, Agoulnik S, Kuznetsov G, Kumar N, Yu Y, Lai G, Hart A, Eckley S, Fekkes P, Bowser T, Joshi JJ, Selvaraj A, Wardell S, Norris J, Smith S, Reynolds D, Mitchell L, Wang J, Yu L, Kim A, Rioux N, Sahmoud T, Warmuth M, Smith PG, Zhu P. Development of a first-in-class oral selective ERα covalent antagonist (SERCA) for the treatment of ERαWT and ERαMUT breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-10-08.