Abstract 3967: ISM9182A, a novel HPK1 inhibitor, exhibits immune modulatory activity and robust monotherapy anti-tumor effects in preclinical studies

Abstract The hematopoietic progenitor kinase 1 (HPK1 or MAP4K1) is a member of the Ste20 serine/threonine kinase super family that negatively regulates immune cells, including T cells, B cells and dendritic cells (DCs). Thus HPK1 is an attractive immuno-oncology target in many tumor types. Here, we report ISM9182A as a novel, potent, and selective inhibitor of HPK1. ISM9182A demonstrated nanomolar enzymatic potency against HPK1 with 100-fold selectivity against other MAP4K family kinases. ISM9182A inhibited the phosphorylation of SLP-76 at Ser376 dose-dependently with an IC50 of 30nM in human peripheral blood mononuclear cells. Moreover, ISM9182A enhanced IL-2 and IFNγ secretion upon CD3/CD28 co-stimulation in a dose-dependent manner without affecting T cell proliferation. Treatment of human pan T cells with ISM9182A also significantly reversed PGE2-mediated immunosuppression of human pan T cell activation and further boosted IL-2 and IFNγ secretion compared to CD3/CD28 co-stimulation. In monocyte-derived DCs stimulated with TNF-α/IL-1β/PGE-2, ISM9182A significantly upregulated CD80, CD86, and CD83 expression, demonstrating its potency to promote DC maturation. ISM9182A showed no obvious toxicity towards human T cell, B cells, and monocytes without CD3/CD28 co-stimulation. In vivo PK data revealed favorable ADME properties and good oral bioavailability of ISM9182A across different species. In a CT-26 murine syngeneic mouse model, oral administration of ISM9182A exhibited potent antitumor effects with p-SLP76 inhibition in both murine spleen and tumor, without body weight loss. In summary, ISM9182A is a potent and selective HPK1 inhibitor and a promising immuno-oncology agent. Citation Format: Celia X. -J. Chen, Congying Pu, Jingjing Peng, Xiaoyu Ding, Hongfu Lu, Xiao Ding, Man Zhang, Supriya Bavadekar, Sujata Rao, Feng Ren, Alex Zhavoronkov. ISM9182A, a novel HPK1 inhibitor, exhibits immune modulatory activity and robust monotherapy anti-tumor effects in preclinical studies 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 (6Suppl): Abstract nr 3967.