Abstract 424: Development of HJC0152-based proteolysis-targeting chimera degraders for breast cancer therapy

Abstract

Abstract Signal transducer and activator of transcription 3 (STAT3), a member of the STAT family, is constitutively activated in various human cancers, and has been recognized as an attractive therapeutic target in cancer. STAT3 protein dimerizes and translocates to the nucleus to eventually transactivate downstream target genes. Despite some progress has been made in the past two decades, to date there is still lack of FDA-approved STAT3 inhibitors available for clinical use. Recently, proteolysis-targeting chimera (PROTAC) technology has dramatically advanced the development of therapeutics by introducing targeted protein degradation. Previously, our team has developed HJC0152, a promising STAT3 inhibitor, via structure- and fragment-based drug design strategies and in silico molecular modeling and docking. HJC0152 has demonstrated an attractive cancer therapeutic and preventive efficacy by targeting the non- estrogen receptor (ER)-based STAT3 signaling pathway. To achieve better potency and inhibition of STAT3 signaling, we therefore developed a series of HJC0152-based PROTAC protein degraders. These potential anticancer agents have been initially evaluated and several showed favorable potency in inhibiting the proliferation in a panel of breast cancer cell lines. We found that compounds JMX1122, JMX1123, and JMX1124 significantly inhibited proliferation and colony formation of a highly aggressive triple-negative breast cancer (TNBC) cell line, MDA-MB-231, and the ER-positive breast cancer cell lines. Different from the lead compound HJC0152, which showed an early inhibition on the phosphorylation of STAT3 at the Tyr705 and Ser727 residues, the newly developed HJC0152-PROTACs showed a significantly late differential inhibition of STAT3 phosphorylation at the Tyr705 and Ser727 residues, and reduced the total STAT3 protein level at 72 hours of treatment. Our current results support the notion that HJC0152-based PROTAC degraders potently suppress breast cancer cell proliferation and induce apoptosis, via direct targeting of STAT3 and its protein degradation. These compounds are currently being investigated for breast cancer cell migration and invasion, and will be evaluated for the in vivo inhibition of tumor growth and metastasis in different mouse models. This project is supported by NIH/NCI Awards R01CA226001 and R01CA231150 to Q.S. and J.Z. Citation Format: Junhai Xu, Jimin Xu, Ruixia Ma, Mingxiang Zhou, Doerte R. Fricke, Haiying Chen, Hyejin Kim, Xi Liu, Jia Zhou, Qiang Shen. Development of HJC0152-based proteolysis-targeting chimera degraders for breast cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 424.