Abstract 1659: Development of HJC0152, its analogs and protein degraders to modulate STAT3 for triple-negative breast cancer therapy

Abstract

Abstract Breast cancer represents the most commonly diagnosed female malignancy worldwide. Although breast cancer screening and treatments have improved significantly over the last half-century, aggressive subtypes like triple-negative breast cancer (TNBC) as well as growing chemoresistance cases continue to evade frontline therapies. STAT3, a transcription factor involved in cell proliferation, survival, and malignant transformation, plays a key role in mammary carcinogenesis, resistance, and recurrence. Both STAT3 overexpression and aberrant activation are frequently observed in primary breast tumors and their metastatic lesions. Although STAT3 is recognized as an attractive preventive and therapeutic target, there are no FDA-approved STAT3 inhibitors in clinical use. Via structure- and fragment-based drug design strategies as well as in silico molecular modeling and docking, our team previously developed a putative STAT3 inhibitor, HJC0152. This study aims to further characterize the anticancer mechanism of HJC0152 as well as optimize its potency. Our results show that HJC0152 interacts with STAT3 with a similar specificity to an experimental STAT3 inhibitor, Stattic. To further improve its potency and efficacy, we developed several HJC0152 derivatives including HJC0152-based proteolysis targeting chimera (PROTAC) degraders. Several molecules showed comparable or improved potency to HJC0152 against several breast cancer cell lines including TNBC cells. While the total STAT3 protein level reduces moderately with HJC0152 treatment, several new compounds decrease STAT3 protein level more profoundly. In particular, the newly developed HJC0152-PROTACs showed a significant late inhibition of STAT3 phosphorylation at the Tyr705 and Ser727 residues as well as a reduction in total STAT3 protein. Our data indicate that HJC0152-based analogs and protein degraders can suppress breast cancer cell proliferation, likely through targeting STAT3 signaling pathway. Future experiments will determine the molecular prolife of promising molecules as well as assess their in vivo anticancer efficacy using xenograft models. This project is supported by NIH/NCI Awards R01CA226001 and R01CA231150 to Q.S. and J.Z. Citation Format: Gabrielle Vontz, Jun Li, Ruixia Ma, Jimin Xu, Mingxiang Zhou, Haiying Chen, Jia Zhou, Qiang Shen. Development of HJC0152, its analogs and protein degraders to modulate STAT3 for triple-negative breast cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1659.