AZ3246 is an orally active, selective inhibitor of HPK1 with an IC50 of less than 3 nM. It induces IL-2 secretion in T cells with an EC50 of 90 nM. AZ3246 also functions as a low-volume, low-clearance antitumor compound.

AZ3246 (100 nM) exhibits greater selectivity for HPK1 over STK3, STK4, and TNIK kinases, showing more than 80% inhibition of HPK1 and MYLK, and over 50% inhibition of ROS1, YSK4, and TNIK [1]. It has excellent metabolic stability in human liver microsomes [1]. AZ3246 promotes IL-2 secretion by T cells with an EC50 value of 90 nM while not inhibiting antagonistic kinases. In primary human, rat, and dog hepatocytes, AZ3246 demonstrates low intrinsic clearance (CLint) values. A low turnover rate is also observed in H μ REL co-cultures of hepatocytes from rats, dogs, monkeys, and humans [1].

AZ3246, administered orally at a dose of 30 mg/kg twice daily, inhibits tumor growth in the EMT6 mouse model without affecting animal body weight at doses ranging from 30-150 mg/kg [1]. In mice, AZ3246 exposure increases linearly up to 30 mg/kg but shows limited increase at 100 mg/kg [1]. This compound is characterized by low volume and clearance, similar to neutral molecules, and is not extensively metabolized by the liver.