CCT251921

CCT251921 is a potent, selective, and orally bioavailable small-molecule inhibitor of the Mediator complex-associated kinases **Cyclin-Dependent Kinase 8 (CDK8)** and **Cyclin-Dependent Kinase 19 (CDK19)**. Developed by the **Institute of Cancer Research (ICR)**, it serves as a chemical probe and therapeutic candidate primarily investigated for the treatment of **Acute Myeloid Leukemia (AML)**. CCT251921 works by blocking the phosphorylation of **STAT5** (specifically at Ser726/731), which is critical for maintaining the self-renewal and survival of leukemic stem cells (LSCs). Inhibition of the CDK8/19 kinase module by CCT251921 induces a shift in the epigenetic and transcriptional landscape, promoting myeloid and erythroid-like differentiation and ultimately triggering apoptosis in sensitive leukemia models. Preclinical research has demonstrated that CCT251921 exhibits synergistic anti-leukemic activity when combined with BET bromodomain inhibitors such as pelabresib.