A-831 (Amgen)

A-831 is a potent and selective small molecule inhibitor of Casein kinase I isoform alpha (CK1α), developed by Amgen for the treatment of hematological malignancies. CK1α is a serine/threonine kinase that plays a pivotal role in regulating the p53 and Wnt/β-catenin signaling pathways. By inhibiting CK1α, A-831 induces the degradation of MDMX and the stabilization of p53, leading to cell cycle arrest and apoptosis in p53-wildtype cancer cells. Additionally, CK1α inhibition can modulate the Wnt pathway, which is often dysregulated in leukemias. A-831 has shown significant preclinical activity in models of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), particularly in cases where p53 function is preserved but suppressed by overexpressed negative regulators.