AZ3246 is an orally active and selective inhibitor of HPK1 with an IC50 of < 3 nM. AZ3246 induces IL-2 secretion in T cells with an EC 50 of 90 nM. AZ3246 is a low-clearance antitumor compound that can be used for the study of breast cancer [1].
In Vivo, AZ3246 (30 mg/kg; p.o.; twice daily) inhibits tumor growth in EMT6 mouse model, AZ3246 (30-150 mg/kg) shows no effect on animal bodyweight [1]. AZ3246 (10-100 mg/kg; p.o.) exposure in mouse is linear up to 30 mg/kg with a limited increase in exposure at 100 mg/kg[1]. AZ3246 is a low-clearance compound, consistent with a neutral molecule that is not heavily metabolized by the liver[1].
In Vitro, AZ3246 (100 nM) is highly selective for HPK1 over STK3, STK4, and TNIK, hits only HPK1 and MYLK at >80% inhibition, hits ROS1, YSK4 and TNIK at >50% inhibition[1]. AZ3246 has excellent metabolic stability in human liver microsomes[1]. AZ3246 induces IL-2 secretion in T cells with an EC50 of 90 nM without inhibiting antagonistic kinases[1]. AZ3246 exhibits low CLint values in primary human, rat, and dog hepatocytes. Low turnover was also observed in HμREL cocultures for rat, dog, monkey, and human hepatocytes[1].
References:
[1]. Shields JD, et al. Discovery and Optimization of Pyrazine Carboxamide AZ3246, a Selective HPK1 Inhibitor. J Med Chem. 2025 Feb 27;68(4):4582-4595.
In Vivo, AZ3246 (30 mg/kg; p.o.; twice daily) inhibits tumor growth in EMT6 mouse model, AZ3246 (30-150 mg/kg) shows no effect on animal bodyweight [1]. AZ3246 (10-100 mg/kg; p.o.) exposure in mouse is linear up to 30 mg/kg with a limited increase in exposure at 100 mg/kg[1]. AZ3246 is a low-clearance compound, consistent with a neutral molecule that is not heavily metabolized by the liver[1].
In Vitro, AZ3246 (100 nM) is highly selective for HPK1 over STK3, STK4, and TNIK, hits only HPK1 and MYLK at >80% inhibition, hits ROS1, YSK4 and TNIK at >50% inhibition[1]. AZ3246 has excellent metabolic stability in human liver microsomes[1]. AZ3246 induces IL-2 secretion in T cells with an EC50 of 90 nM without inhibiting antagonistic kinases[1]. AZ3246 exhibits low CLint values in primary human, rat, and dog hepatocytes. Low turnover was also observed in HμREL cocultures for rat, dog, monkey, and human hepatocytes[1].
References:
[1]. Shields JD, et al. Discovery and Optimization of Pyrazine Carboxamide AZ3246, a Selective HPK1 Inhibitor. J Med Chem. 2025 Feb 27;68(4):4582-4595.