HDM2004

HDM2004 is a selective, orally active HPK1 inhibitor that can cross the blood-brain barrier, with an IC50 of 1.89 nM. It exhibits anticancer activity against colon cancer and demonstrates synergistic effects in homologous mouse models when combined with anti-PD-L1 treatment. HDM2004 can be utilized in colon cancer research.

HPK1:1.89 nM

HDM2004 is a potent inhibitor of recombinant HPK1 with an IC₅₀ of 1.89 nM, and it demonstrates 31.88-fold selectivity for the homologous kinase GLK (GLK IC₅₀ = 60.29 nM). It enhances IL-2 secretion in human peripheral blood mononuclear cells (PBMC) following anti-CD3/anti-CD28 stimulation, showing an EC₅₀ of 38.9 nM. HDM2004 exhibits excellent stability in both mouse (t₁/₂ > 300 min) and human (t₁/₂ > 300 min) liver microsomes. At a concentration of 1 μM, HDM2004 shows moderate kinome selectivity, strongly inhibiting off-targets ROCK1 (inhibition rate 94.04%, IC₅₀ = 230.0 nM), VEGFR2 (inhibition rate 91.39%, IC₅₀ = 116.7 nM), and LCK (inhibition rate 78.25%, IC₅₀ = 300.1 nM), with no significant inhibition observed on the remaining 44 safety-related targets.

HDM2004 (administered orally; once daily; for 2 consecutive weeks; at a dose of 20-60 mg/kg) exhibits dose-dependent antitumor activity in the MC38 syngeneic colon cancer mouse model. When combined with anti-mouse PD-L1, HDM2004 shows synergistic antitumor effects, achieving a maximum TGI rate of 77.05% with a daily oral dose of 60 mg/kg.