MK256 (MK-256) is a potent, selective CDK8 inhibitor with IC50 of 2.5 nM and 3.3 nM against CDK8/cyclin C and CDK19/cyclin C, respectively.
MK256 does not inhibit other 13 CDKs at 200 nM, with exception of CDK9 (IC50=105 nM, 40-fold selectivity for CDK8).
MK256 bonds in the ATP binding pocket of CDK8, two hydrogen bonds were formed between MK256 and hinge region residues Asp98 and Ala100.
MK256 (50-500 nM) induces differentiation/maturation in CD34+/CD38- human leukemic cell line (TEX) cells.
MK256 shows a wide range of sensitivity to a panel of AML cell lines, ranging from highly sensitive (<30 nM) to highly resistant (>5 uM).
MK256 is sensitive to MV- 4-11 (IC50=23 nM) and MOLM-14 (IC50=24 nM), both of which harbor mixed lineage leukemia (MLL) fusions.
MK256 also shows relatively potent growth inhibition against SKNO-1 (IC50=73 nM) and KG-1 (IC50=80 nM).
MK256 downregulates phosphorylation of STAT1 and STAT5 in AML cell lines MV-4-11 and MOLM-14, also downregulates MCL-1 and CCL2 mRNA expression.
MK256 (50 mg/kg, oral) showed great efficacy in MOLM-14 mice xenograft model, the combination of MK256 and venetoclax lowered the effective concentration for both compounds.