HPK1-IN-55 (compound 19) is a selective and orally active inhibitor of hematopoietic progenitor kinase 1 (HPK1) with an IC50 of less than 0.51 nM. It exhibits exceptional kinase selectivity, being over 637 times more selective for HPK1 compared to GCK kinase and over 1022 times compared to LCK. HPK1-IN-55 possesses anti-cancer properties.

HPK1:<0.51 nM

HPK1-IN-55 (0.5-10000 nM, 5 h) demonstrates HPK1 enzyme inhibition in human PBMCs, with an IC50 of less than 0.51 nM, and suppresses cellular IL-2 secretion with an EC50 of 43.3 nM [1]. Additionally, HPK1-IN-55 (0.001-100 nM) encourages the release of IL-2 and IFN-γ in human PBMCs, with EC50 values of 38.8 and 49.2 nM, respectively [1]. Moreover, HPK1-IN-55 (0.00457-10 μM, 72 h) enhances T cell proliferation in human immune T cells at low, medium, and high concentrations [1].

HPK1-IN-55, when administered at doses of 1.5-12 mg/kg orally twice daily for 5 weeks, demonstrates significant antitumor activity as a monotherapy and shows an additive effect when combined with anti-PD-1 in the CT26 model, while exhibiting a synergistic effect in the MC38 model [1]. In monkeys, HPK1-IN-55 at 1 mg/kg intravenously and 2 mg/kg orally shows a moderate clearance rate (Clp = 11.41 mL/min/kg), with satisfactory oral exposure (DNAUC (0−24 h) =560.5 h•ng/mL) and bioavailability (F % = 42.0) [1]. Additionally, HPK1-IN-55 demonstrates effective target engagement in the CT26 model at 1.5-12 mg/kg orally twice daily for 5 weeks.