MSC2530818

MSC2530818 is a potent, selective, and orally bioavailable small molecule inhibitor of the Mediator complex-associated kinases CDK8 and CDK19. Developed by Merck KGaA in collaboration with the Institute of Cancer Research (ICR), it was identified as a structurally distinct back-up candidate to CCT251921. The compound functions by inhibiting the kinase module of the Mediator complex, which leads to the modulation of WNT signaling and the inhibition of STAT1 phosphorylation at Ser727. Although MSC2530818 demonstrated antiproliferative activity in preclinical models of colorectal cancer and acute myeloid leukemia (AML), its development was significantly hindered by a widespread adverse safety profile observed at therapeutically relevant exposures in preclinical tolerability studies, leading to the conclusion that clinical development would be extremely challenging.