Abstract 1882: Development of hit compounds targeting STAT3 for autoimmune diseases and cancers using a chemoproteomics-driven approach

Abstract Signal transducer and activator of transcription 3 (STAT3) is a critical regulator of immune responses, cellular proliferation, and survival, positioning it as a promising therapeutic target in autoimmune diseases and cancer. In this study, we present a chemoproteomics-based approach for the discovery and optimization of small-molecule inhibitors targeting STAT3. A series of novel small molecules capable of selectively modulating STAT3 activity were identified. By integrating structure-based design with our chemoproteomics platform, we not only validated the interactions of these compounds with STAT3 but also elucidated their downstream signaling effects in disease-relevant autoimmune models. Our chemoproteomics platform facilitates the unbiased identification of drug targets and off-target effects at a proteome-wide scale, significantly accelerating the lead optimization process. These findings highlight the potential of our STAT3 inhibitors as a novel class of therapeutics for autoimmune diseases. Ongoing studies are focused on optimizing these compounds for clinical trials by using the chemoproteomics platform to identify their molecular mechanisms of action and to predict potential off-target effects. Citation Format: Heejung Yang, Hojin Yoo, Sang-Jun Han, Sijin Kim, Donggyun Hong, Jeongyeon Kang, Birang Jeong, Go-Yeon Jung, Namgil Lee, Hoguen Kwak, Byung-Seok Kim. Development of hit compounds targeting STAT3 for autoimmune diseases and cancers using a chemoproteomics-driven approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1882.