PF-06650833

PF-06650833 is an inhibitor of IL-1 receptor-associated kinase 4 (IRAK4; IC₅₀ = 0.2 nM).¹ It is selective for IRAK4 over a panel of 268 kinases at 200 nM but also inhibits IRAK1, MAP kinase-interacting serine/threonine protein kinase 2 (MNK2), leucine-rich repeat kinase 2 (LRRK2), CDC-like kinase 4 (Clk4), and casein kinase 1γ1 (CK1γ1) by greater than 70% at 200 nM. PF-06650833 (100 nM) reduces secretion of DNA from primary human neutrophils stimulated by the toll-like receptor 7 (TLR7) agonist R-837 (imiquimod; Item No. 14956) and decreases IFN regulatory factor 5 (IRF5) nuclear translocation induced by the synthetic TLR7/8 ligand R-848 (Item No. 14806) in primary human peripheral blood mononuclear cells (PMBCs).² It decreases paw volume in a rat model of collagen-induced arthritis when administered at a dose of 100 mg/kg once per day.¹ Dietary administration of PF-06650833 reduces serum levels of the autoantibodies anti-dsDNA, anti-SSA, and anti-RNP and decreases kidney glomerular tuft area in a mouse model of systemic lupus erythematosus (SLE) induced by the isoprenoid alkane pristane.²

WARNING This product is not for human or veterinary use.

1. Lee, K.L., Ambler, C.M., Anderson, D.R., et al. Discovery of clinical candidate 1-{[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide (PF-06650833), a potent, selective inhibitor of interleukin-1 receptor associated kinase 4 (IRAK4), by fragment-based drug design. J. Med. Chem. 60(13), 5521-5542 (2017).

2. Winkler, A., Sun, W., De, S., et al. The interleukin-1 receptor-associated kinase 4 inhibitor PF-06650833 blocks inflammation in preclinical models of rheumatic disease and in humans enrolled in a randomized clinical trial. Arthritis Rheumatol. 73(12), 2206-2218 (2021).