Abstract 4373: Discovery of ZN-c5, a novel potent and oral selective estrogen receptor degrader
Authors: Ahmed A. Samatar, Jiali Li, Sayee Hegde, Peter Huang, Jianhui Ma, Kevin Bunker, Robert Winkler, Fernando Donate, Masha Sergeeva
Journal: Cancer Research (2020)

Abstract Majority of breast cancers express the estrogen receptor alpha (ERα) and the two major strategies for therapeutic targeting of ER-alpha positive breast cancer are aromatase inhibitors (which deprives estrogen) and inhibition of the estrogen receptor alpha. Although these strategies can be effective, many patients develop resistance which ultimately leads to disease progression which continues to rely on estrogen receptor signaling. One of the resistance mechanisms is the acquisition of activating mutations in the ER gene (ESR1) that allow tumors to proliferate without depending on estrogen. One approach to overcome resistance is to develop high affinity small molecules that degrade the estrogen receptor and effectively shut down ER signaling. Fulvestrant, an ER antagonist and a selective estrogen receptor degrader (SERD) is the only small molecule that is approved for the treatment of ER+/HER2− metastatic breast cancer. However, fulvestrant's limitation include low oral bioavailability and administration via intramuscular injection, which limits its exposure and leads to sub-optimal estrogen receptor degradation. The poor pharmacokinetic properties of fulvestrant has fueled the interest in developing an orally bioavailable small molecule estrogen receptor antagonist and degrader that could potentially benefit breast cancer patients. Here we describe the discovery of Zn-c5 a novel, small molecule with potent antagonism and degradative properties against the estrogen receptor both in vitro and in vivo. ZN-c5 showed a high oral bioavailability across several preclinical species as compared to other SERDs. To test if the high oral bioavailability can be translated to potent efficacy in vivo, we evaluated the anti-tumor activity of ZN-c5 in MCF-7 orthotopic tumor xenograft model. Oral ZN-c5 treatment at 5 mg/kg and 10 mg/kg resulted in 89% and 102% tumor growth inhibition respectively. Combination of ZN-c5 with cell cycle inhibitors such as CDK4/6 inhibitors or PI3K inhibitors results in enhanced antitumor activity. In addition to MCF-7 model, we evaluated the activity of ZN-c5 in ER mutant models including WHIM20, a Y537S ESR1 patient derived xenograft model. Treatment with ZN-c5 at 40 mg/kg induced 64% tumor growth inhibition while fulvestrant at 200 mg/kg (exposures 8-fold higher than that achieved in the clinic) resulted in 13% tumor growth inhibition. These data indicate that ZN-c5 has improved antitumor activity over fulvestrant in human tumor xenograft models. Zn-c5 is currently in clinical trials as a single agent and in combination studies. The PK profile of ZN-c5 in breast cancer patients indicates that Zn-c5 has greater than 5-fold exposure than fulvestrant. We believe that the high exposure of ZN-c5 coupled with its potency and degradative properties could therapeutic benefit estrogen receptor positive breast cancer patients. Citation Format: Ahmed A. Samatar, Jiali Li, Sayee Hegde, Peter Huang, Jianhui Ma, Kevin Bunker, Robert Winkler, Fernando Donate, Masha Sergeeva. Discovery of ZN-c5, a novel potent and oral selective estrogen receptor degrader [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4373.