CMPD0431: A Promising HPK1 Inhibitor Unleashing Anti-Tumor Immune Responses in Oncology

The study introduces CMPD0431, a novel small molecule inhibitor of Hematopoietic Progenitor Kinase 1 (HPK1), which is a serine/threonine kinase involved in immune regulation. CMPD0431 has been shown to have a dual impact on the immune system, enhancing T cell activation and improving antigen-presenting cell (APC) function, particularly in dendritic cells. The compound exhibits high potency with an IC50 value in the nanomolar range and has been formulated for oral administration with favorable pharmacokinetic properties.

In vitro experiments have demonstrated that CMPD0431 effectively inhibits the phosphorylation of SLP76, a key substrate in T cell activation, leading to sustained T cell activity. This has been associated with an increase in the proliferation of human primary T cells and elevated production of pro-inflammatory cytokines such as interferon-gamma (IFN-γ) and interleukin-2 (IL-2). Additionally, the compound has been found to boost the functionality of dendritic cells in antigen presentation and cytokine production.

In vivo studies using a syngeneic mouse model have illustrated the anti-tumor potential of CMPD0431, with evidence of tumor growth inhibition, increased infiltration of CD3+ lymphocytes, and heightened production of pro-inflammatory cytokines. Remarkably, high-dose treatment resulted in tumor regression and a lack of tumor regrowth for an extended period without further treatment. Furthermore, the treated mice developed an immunological memory, as evidenced by an enhanced response to CT-26 specific antigen stimulation and increased IFN-γ secretion by splenic T lymphocytes.

These findings support the continued development of CMPD0431 as a first-in-class HPK1 inhibitor with a unique mechanism of action, suggesting its potential use as a standalone therapy or in combination with existing checkpoint inhibitors for cancer treatment. The research was presented at the American Association for Cancer Research Annual Meeting in 2019.