Zimlovisertib (PF-06650833) is an effective, selective and orally active inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4) (IC50s: 0.2 and 2.4 nM in the cell and PBMC assay).

IRAK4:0.2 nM

The kinome selectivity profile of PF06650833 (Compound 40) is assessed in a panel of 278 kinases at 200 nM inhibitor concentration using the ATP Km for each kinase. Approximately 100% inhibition is observed for IRAK4. Lactam PF06650833 is assessed in a whole-cell functional VEGF2R assay (PAE-KDR cell line). No activity is observed at concentrations up to and including 30 μM. In a voltage clamp assay, PF06650833 inhibits hERG current by 25% at 100 μM.

PF06650833 (0.3-30 mg/kg; p.o; for 2.5 hours; male SD rats) treatment significantly inhibits LPS-induced TNF-α in a dose dependent manner. Mean exposures of PF06650833 in plasma are 2.1 nM, 7.7 nM, 19 nM and 150 nM free, respectively, at 2.5 hours after oral administration of PF06650833 at 0.3, 1, 3, and 30 mg/kg. The fraction unbound in rat plasma of PF06650833 is 0.3.

Animal Model: Male Sprague-Dawley rats. Dosage: 0.1 mg/kg, 1 mg/kg, 3 mg/kg, 30 mg/kg. Administration: Oral administration; for 2.5 hours