FM-381

FM-381 is a potent covalent reversible inhibitor of JAK3 targeting the unique Cys909. FM-381 has an IC₅₀ of 127 pM for JAK3, with 410, 2700 and 3600-fold selectivity over JAK1, JAK2 and TYK2, respectively. IC50 & Target: IC50: 127 pM (JAK3)^[1] In Vitro: FM-381 is screened against a panel of 410 kinases at concentrations of 100 nM and 500 nM. FM-381 has no relevant effect on the activity of any tested kinases except JAK3 at a concentration of 100 nM. At 500 nM, FM-381 moderately inhibits 11 other kinases besides JAK3 with residual activities below 50%. FM-381 is found to be inactive in a selectivity panel of frequently hit BRDs (BRD4, BRPF, CECR, FALZ, TAF1, BRD9). FM-381 selectively inhibits JAK3 signaling in human CD4⁺ T Cells. FM-381 shows an apparent EC₅₀ of 100 nM in a dose dependent BRET assay and blocks IL2 stimulated (JAK3/JAK1 dependent) STAT5 phosphorylation at 100 nM, but not JAK3 independent IL6 (JAK1/2/TYK dependent) stimulated STAT3 signalling in human CD4⁺ T cells up to 1 µM^[1].