Abstract 4304: Novel small molecule targeting cancer metabolism by inhibiting SCAP/SREBP pathway

Background: A critical component of oncogenesis and cancer progression is metabolic re-programming of cells to enable continuous growth. Oncogenic activated signaling pathways can drive de novo lipogenesis to provide ample lipids, e.g. cholesterol and fatty acids, to support the tumor cells heightened metabolic needs. The transcriptional regulation of lipogenesis is mediated by the sterol regulatory element-binding protein (SREBP) transcription factors, that are controlled by the regulatory SREBP cleavage activating protein (SCAP). Dysregulation of the SCAP/SREBP pathway has been documented in many tumor types, including breast, liver, and prostate cancer (Reviewed in Peck & Shulze, 2019). Activation of this pathway is inversely correlated with PFS and OS across tumor types, implicating the SCAP/SREBP pathway as a critical mediator of tumorigenesis and making it a good anti-cancer target. Historically, small molecule targeting of the SCAP/SREBP pathway has been difficult given the complexity of the pathway regulation and protein-protein interactions. Results: Utilizing an integrated drug discovery AI (Artificial Intelligence)-based platform to model SCAP/SREBP complex interactions and identify druggable domains to target with small molecules. Screening a total of ∼400 compounds across multiple scaffolds identified compounds with low nano-molar IC50 inhibition of SREBP pathway, and a pan-cancer cell line screen identified “responders” across cancer indications and subtypes. A comprehensive screening and SAR of in vitro ADME properties (LM stability, solubility) led to candidates for in vivo pharmacokinetics analysis. Several chemotypes with low clearance, long T1/2 in mice and good bioavailability were identified. Further testing of several Research Leads demonstrated robust tumor growth inhibition in breast (MCF7, 84.15%) and liver (HepG2, 45.5%) as a single agent, and synergistic activity with SoC in the HepG2 model (Sorafanib combination 76.1%). Probing publicly available datasets for glycolytic/lipogenic phenotypes across tumor types reveals heterogeneity across tumor types and the ability to stratify patients and indications by Glyco-/Lipo-genic score that may allow for patient selection in future clinical trials. Conclusion: We report here a novel small molecule that interacts with SCAP to prevent activation of SREBP pathway that was identified by computational modeling of a multi-protein complex of SCAP/SREBP. This molecule, CAP-1628987 specifically targets SCAP/SREBP pathway, has good drug-like properties, robust efficacy in multiple tumor models and favorable CMC properties. Citation Format: Jeffrey N. Lindquist, Michael Green, Ravi K. Muttineni, Hirdesh Uppal. Novel small molecule targeting cancer metabolism by inhibiting SCAP/SREBP pathway [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 4304.