ZB716, a steroidal selective estrogen receptor degrader (SERD), is orally efficacious in blocking tumor growth in mouse xenograft models

// Shanchun Guo 1, 2 , Changde Zhang 1, 2 , Melyssa Bratton 2, 3 , Madhusoodanan Mottamal 1, 2 , Jiawang Liu 1, 2 , Peng Ma 2, 3 , Shilong Zheng 1, 2 , Qiu Zhong 1, 2 , Lin Yang 4 , Thomas E. Wiese 2, 3 , Yong Wu 5 , Matthew J. Ellis 6 , Margarite Matossian 7 , Matthew E. Burow 7 , Lucio Miele 8 , Rene Houtman 9 and Guangdi Wang 1, 2 1 Department of Chemistry, Xavier University of Louisiana, New Orleans, LA 70125, USA 2 RCMI Cancer Research Center, Xavier University of Louisiana, New Orleans, LA 70125, USA 3 College of Pharmacy, Xavier University of Louisiana, New Orleans, LA 70125, USA 4 College of Pharmacy Chongqing Medical and Pharmaceutical College, University Town, Chongqing, 401331, China 5 Department of Internal Medicine, Charles Drew University, Los Angeles, CA 90059, USA 6 Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA 7 Section of Hematology & Medical Oncology, Tulane University School of Medicine, New Orleans, LA 70112, USA 8 Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA 9 Nuclear Receptor Group, PamGene International, 5211HH Den Bosch, The Netherlands Correspondence to: Guangdi Wang, email: gwang@xula.edu Keywords: steroidal oral SERD; breast cancer; estrogen receptor mutant; Y537S; bioavailability Received: October 12, 2017      Accepted: December 27, 2017      Published: January 08, 2018 ABSTRACT Advances in oral SERDs development so far have been confined to nonsteroidal molecules such as those containing a cinnamic acid moiety, which are in earlystage clinical evaluation. ZB716 was previously reported as an orally bioavailable SERD structurally analogous to fulvestrant. In this study, we examined the binding details of ZB716 to the estrogen receptor alpha (ERα) by computer modeling to reveal its interactions with the ligand binding domain as a steroidal molecule. We also found that ZB716 modulates ERα-coregulator interactions in nearly identical manner to fulvestrant. The ability of ZB716 to inhibit cell growth and downregulate ER expression in endocrine resistant, ERα mutant breast cancer cells was demonstrated. Moreover, in both the MCF-7 xenograft and a patient derived xenograft model, orally administered ZB716 showed superior efficacy in blocking tumor growth when compared to fulvestrant. Importantly, such enhanced efficacy of ZB716 was shown to be attributable to its markedly higher bioavailability, as evidenced in the final plasma and tumor tissue concentrations of ZB716 in mice where drug concentrations were found significantly higher than in the fulvestrant treatment group.