Abstract 5825: SWA1211, a next generation HPK1 inhibitor exhibits superior anti tumor efficacy in preclinical studies

Abstract Immune oncology is an important breakthrough for cancer therapy represented by immune checkpoints inhibitors like PD-1/L1, CTLA4 antibody drugs. Although this type of drug has become the standard treatment for many kinds of cancers, a large proportion of patients fail to respond to them or become resistant eventually. Therefore, new mechanisms or targets remain urgent to further improve the therapeutic outcomes or overcome the resistance of immunotherapy.Hematopoietic progenitor kinase 1 (HPK1), also known as MAP4K1, belongs to the MAP4K family of protein serine/threonine kinases. HPK1 is a negative regulator of T-cell signaling and has been identified as a promising target to combat cancers by eliciting robust anti-tumor immunity. Many HPK1 inhibitors are under active clinical development.SWA1211 is a best-in-class (BIC) HPK1 inhibitor designed using Stonewise’s proprietary 3D molecular generation model. To conquer the challenge of selective inhibition on HPK1, a steric group was designed to extend toward the small hydrophobic pocket formed by Leu23 and Val31 in HPK1, which does not exist in GLK due to the different residue, Ile22. This unique molecular structure design significantly improved potency and selectivity of our compounds, and excellent immune cell activation was achieved (biochemical assay IC50=0.9nM @ATP 1mM; human T-cell activation EC50=9nM). Selectivity study showed a unique kinases inhibition profile with no obvious off-kinase activity related risk.More importantly, when compared to other HPK1 inhibitors developed by leading developers, SWA1211 stimulates T cell activation efficiently in an ever-known broadest concentration range without any exhaustive effect (up to a concentration of 1000 folds of EC50). This unique non-bell-shaped immune cell activation curve translates to unmatched efficacy as no other HPK1 inhibitors have shown in preclinical settings. Single agent of SWA1211 induces tumor shrinkage in Hepa1-6 and EMT6 mouse syngeneic tumor models. GLP toxicity studies indicated ideal therapeutic index was obtained. We believe SWA1211 to be a promising next generation immune therapy for cancer patients.We have completed all IND enabling studies for SWA1211 and the results demonstrated a favorable drug-like profile. We expect to receive the green light for a clinical trial from the FDA and NMPA by March 2025; the clinical trial will be initiated immediately afterward. Citation Format: Guanglong Sun, Yuyang Ge, Huting Wang, Desheng Kong, Carrie Xiang. SWA1211, a next generation HPK1 inhibitor exhibits superior anti tumor efficacy in preclinical studies [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 5825.