Abstract C015: A STAT3 PROTAC Degrader SD-1240: the Structure-based Design, the Structure Mechanism of Potency and Selectivity, and the Mechanism of Action of Anti-tumor Activity

Abstract STAT3 is a transcription factor and a promising therapeutic target for cancer and other human diseases. We present here our structure-based design and development of the pre-clinical candidate (PCC) SD-1240, a highly potent, selective and efficacious STAT3 degraders. We first designed a series of novel, high-affinity, conformationally constrained VHL-1 ligands. Employing these novel VHL-1 ligands and our high-affinity STAT3 inhibitors, we successfully discovered a new class of STAT3 degraders, with SD-1240 being the best compound. SD-1240 effectively induces degradation of STAT3 with DC50 = 3 nM and Dmax >95% and is highly selective over other STAT proteins and >7,000 other proteins analyzed. To provide mechanistic insights into the highly selective and efficient STAT3 degradation, we have determined a cryo-electron microscopy (cryo-EM) structure of ternary complex STAT3-SD1240-VHL. SD-1240 displays an excellent pharmacokinetic profile across preclinical species and has no ADME and hERG liability. A single intravenous administration of SD-1240 at 1-10 mg/kg effectively induces complete and durable depletion of STAT3 in xenograft tumor and mouse native tissues. Induced degradation of STAT3 by SD-1240 results in a strong suppression of its STAT3 regulated transcription network in leukemia and lymphoma cells. SD-1240 potently inhibits the growth of a subset of acute myeloid leukemia and anaplastic large cell lymphoma cell lines. Weekly administration of SD-1240 at 1 mg/kg achieves complete and long-lasting tumor regression in leukemia and lymphoma xenograft models in mice. While SD-1240 shows no effect on the proliferation of TNBC cell lines and murine cancer cell lines in vitro, it exhibits strong antitumor activity in these tumor models in mice. SD-1240 was found to be well tolerated in mice, rats and dogs. Collectively, our data support SD-1240 as a promising development candidate for the treatment of human cancers and other human diseases. Citation Format: Haibin Zhou. A STAT3 PROTAC Degrader SD-1240: the Structure-based Design, the Structure Mechanism of Potency and Selectivity, and the Mechanism of Action of Anti-tumor Activity [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 C015.