KME-2780 (KME2780) is a potent and selective dual IRAK1 and IRAK4 (IRAK1/4) inhibitor with IC50 of 19 and 0.5 nM, respectively.
KME-2780 shows Kd values of 2.2 and 0.2 nM for IRAK1 and IRAK4, respectively.
KME-2780 is significantly more effective at suppressing TLR2-mediated activation of NF-κB and autophosphorylation of IRAK1 in AML cells as compared with the IRAK4 seleective inhibitor KME-3859.
KME-2780 downregulats genes in MAPK/AP1, ATF4, IGFBP, and EGFR signaling in AML cells.
KME-2780 suppresses eukemia stem/progenitor cells (LSPCs), suppresses OCI-AML3 cells, which is insensitive to the genetic inactivation of IRAK1 and IRAK4.
KME-2780 treatment also resulted in a greater expression of CD38, a glycoprotein expressed on mature immune cells.
KME-2780 (30 mg/kg, orally daily) suppresses MDS/AML in xenografted mice.
