Design, Synthesis, and Structure–Activity Relationship Studies of 7 <i>H</i> -Pyrrolo[2,3- <i>d</i> ]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 7<i>H</i>-pyrrolo-[2,3-<i>d</i>]-pyrimidine scaffold. The structure-activity relationship was systematically summarized, and notably, compound <b>7a</b> 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 <b>7a</b> 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 <b>7a</b> may provide promising CK1α inhibitors with desirable drug-like properties for cancer treatment.