Abstract 6057: Evaluation of a highly potent and selective STAT3 degrader as a new class of immunotherapy

Abstract STAT3 (signal transducer and activator of transcription 3) is a transcription factor and a promising therapeutic target for cancer and other human diseases. In addition to its role in regulation of tumor cells, STAT3 also plays a key role in regulation of immunity and is a promising therapeutic target for the development of new immuno-oncology drugs. Our laboratory has previously reported the development of potent and highly selective STAT3 degraders, including SD-36 and SD-91. Extensive optimization of SD-36 and SD-91 yielded new, highly potent, selective and efficacious STAT3 degraders. In direct comparison, our most potent, new STAT3 degrader (compound 1) is >50-times more potent than SD-36 in inducing STAT3 degradation in cells and demonstrates >500-fold degradation selectivity over other STAT members. A single intravenous administration of compound 1 in mice is highly effective in inducing complete depletion of STAT3 protein in tissues for 48-96 h without reducing the levels of other STAT proteins. Compound 1 is very effective in inhibition of tumor growth not only in tumor models responsive to immune checkpoint blockade (ICB) but also in tumor models resistant to ICB. Furthermore, combination of compound 1 with PD-1/PD-L1 antibodies greatly enhances the antitumor activity as compared to SD-1218 or ICB. Of significance, compound 1 is well tolerated in mice without any signs of toxicity in mice at highly efficacious doses. Our mechanistic studies show that STAT3 depletion has a major effect in modulation of the immune cells in mice. Collectively, our data suggest that selective STAT3 degradation hold great promise for new cancer immunotherapy. Citation Format: Longchuan Bai, Haibin Zhou, Jiajia Zhou, Dimin Wu, Ranjan Kumar Acharyya, Hoda Metwally, Donna McEachern, Bo Wen, Duxin Sun, Weiping Zou, Shaomeng Wang. Evaluation of a highly potent and selective STAT3 degrader as a new class of immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6057.