Abstract B132: SD-1240, a VHL-based STAT3 degrader, induces optent and selective STAT3 depletion and suppresses tumor growth in ALCL preclinical models

Abstract Dysregulated STAT3 signaling is a hallmark of tumorigenesis and therapeutic resistance across a wide spectrum of cancers, yet strategies for directly targeting STAT3 have, to date, met with limited clinical success. We have developed SD-1240, a rationally designed heterobifunctional PROTAC degrader that recruits the VHL E3 ligase to facilitate the selective and potent degradation of STAT3. In cellular models of anaplastic large cell lymphoma (ALCL), SD-1240 elicited rapid, robust and selective STAT3 protein depletion with low nanomolar potency (DC50 5–10 nM; Dmax >95%), leading to marked cytotoxicity (IC50: 5–50 nM in a panel of ALCL cell lines). Notably, SD-1240 achieved selective STAT3 depletion in both ALCL cell lines and human peripheral blood mononuclear cells (PBMCs), while sparing other STAT family members (STAT1/2/4/5/6), as demonstrated by both quantitative proteomics and immunoblotting. In vivo, systemic administration of SD-1240 induced rapid and durable STAT3 degradation in both tumor and normal tissues, with STAT3 depletion sustained up to 168 hours post-dose. This pharmacodynamic effect translated into profound, dose-dependent tumor growth inhibition in ALCL xenograft models at doses ranging from 1–10 mg/kg (IV, weekly), without observable toxicity or weight loss in treated mice. Mechanistic studies revealed that transcriptional profiling of SD-1240–treated tumors showed broad suppression of canonical STAT3 gene targets and inhibition of multiple oncogenic and pro-survival signaling pathways. Collectively, these data establish SD-1240 as a highly selective, potent, and well-tolerated degrader of STAT3, capable of inducing durable pharmacodynamic and antitumor responses in preclinical mouse tumor models. These findings support the advancement of SD-1240 as a promising clinical candidate for the treatment of STAT3-driven malignancies. This work is funded by NIH/NCI R01CA244509), Proteovant Therapeutics and Oncopia Therapeutics Citation Format: Longchuan Bai, Haibin Zhou, Dimin Wu, Ranjan Acharyya, Hoda Metwally, Donna McEachern, Bo Wen, Duxin Sun, Jeanne A. Stuckey, Shaomeng Wang. SD-1240, a VHL-based STAT3 degrader, induces optent and selective STAT3 depletion and suppresses tumor growth in ALCL preclinical models [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B132.