Design, Synthesis, and Structure-Activity Relationship Studies of 7H‑Pyrrolo[2,3‑d]pyrimidine Derivatives as Potent Casein Kinase 1α (CK1α) Inhibitors.

Casein kinase 1α (CK1α) is a serine/threonine kinase that plays a pivotal role in regulating p53 and other critical signaling pathways and is intimately involved in tumor initiation and progression. Inhibition of CK1α has been demonstrated to be a promising therapeutic strategy for certain types of cancers such as acute myeloid leukemia (AML). In this study, we designed and synthesized a series of novel CK1α inhibitors bearing a 7H-pyrrolo-[2,3-d]-pyrimidine scaffold. The structure-activity relationship was systematically summarized, and notably, compound 7a exhibited potent inhibitory activity against CK1α with an IC50 of 10.96 nM, representing a 9-fold increase in potency as compared to BTX-A51, the only CK1α inhibitor currently in clinical development. Additionally, compound 7a displayed favorable selectivity across a panel of kinases. It also dose-dependently stabilized p53 protein and effectively inhibited the growth of MV4-11 cells. Further optimization of 7a may provide promising CK1α inhibitors with desirable drug-like properties for cancer treatment.