Discovery of Pyridine-2-Carboxamides Derivatives as Potent and Selective HPK1 Inhibitors for the Treatment of Cancer

Hematopoietic progenitor kinase 1 (HPK1) has emerged
as an attractive
target for immunotherapy due to its critical role in T cell activation
and proliferation. The major challenge in developing HPK1 inhibitors
lies in balancing kinase selectivity, pharmacokinetic (PK) properties,
and therapeutic efficacy. In this study, we report a series of pyridine-2-carboxamide
analogues demonstrating strong HPK1 inhibitory activity in enzymatic
and cellular assays, along with good kinase selectivity. Among these
analogues, compound 19 showed good in vitro HPK1 inhibitory
activity, excellent kinase selectivity (>637-fold vs GCK-like kinase
and >1022-fold vs LCK), and robust in vivo efficacy in the CT26
(tumor
growth inhibition (TGI) = 94.3%, 2/6 CRs) and MC38 murine colorectal
cancer models (TGI = 83.3%, 1/6 complete response) when administered
in combination with anti-PD-1. Compound 19 also demonstrated
adequate in vitro ADME and in vivo PK properties, displaying good
oral bioavailability across multiple species (F %
= 35–63). These findings summarize our compound’s favorable
safety and efficacy profiles, justifying its testing in future translational
studies.