Research Papers:

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

Shanchun Guo, Changde Zhang, Melyssa Bratton, Madhusoodanan Mottamal, Jiawang Liu, Peng Ma, Shilong Zheng, Qiu Zhong, Lin Yang, Thomas E. Wiese, Yong Wu, Matthew J. Ellis, Margarite Matossian, Matthew E. Burow, Lucio Miele, Rene Houtman and Guangdi Wang _

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Oncotarget. 2018; 9:6924-6937. https://doi.org/10.18632/oncotarget.24023

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Shanchun Guo1,2, Changde Zhang1,2, Melyssa Bratton2,3, Madhusoodanan Mottamal1,2, Jiawang Liu1,2, Peng Ma2,3, Shilong Zheng1,2, Qiu Zhong1,2, Lin Yang4, Thomas E. Wiese2,3, Yong Wu5, Matthew J. Ellis6, Margarite Matossian7, Matthew E. Burow7, Lucio Miele8, René Houtman9 and Guangdi Wang1,2

1Department of Chemistry, Xavier University of Louisiana, New Orleans, LA 70125, USA

2RCMI Cancer Research Center, Xavier University of Louisiana, New Orleans, LA 70125, USA

3College of Pharmacy, Xavier University of Louisiana, New Orleans, LA 70125, USA

4College of Pharmacy Chongqing Medical and Pharmaceutical College, University Town, Chongqing, 401331, China

5Department of Internal Medicine, Charles Drew University, Los Angeles, CA 90059, USA

6Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA

7Section of Hematology & Medical Oncology, Tulane University School of Medicine, New Orleans, LA 70112, USA

8Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA

9Nuclear Receptor Group, PamGene International, 5211HH Den Bosch, The Netherlands

Correspondence to:

Guangdi Wang, email: [email protected]

Keywords: steroidal oral SERD; breast cancer; estrogen receptor mutant; Y537S; bioavailability

Received: October 12, 2017     Accepted: December 27, 2017     Published: January 08, 2018


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.

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