CNP200137

CNP200137 is a potent, orally available, second-generation small molecule inhibitor and degrader of the menin-MLL (KMT2A) interaction. It is specifically designed to overcome acquired resistance mutations in the MEN1 gene, such as M327I, T349M, G331R, and E368K, which often limit the long-term efficacy of first-generation menin inhibitors like revumenib and ziftomenib. By disrupting the menin-MLL complex and inducing robust degradation of the menin protein, CNP200137 suppresses the expression of leukemogenic target genes, including MEIS1 and the HOX cluster. Preclinical studies have demonstrated nanomolar potency against both wild-type and mutant menin, showing significant anti-proliferative activity in KMT2A-rearranged and NPM1-mutant acute myeloid leukemia (AML) cell lines, as well as robust tumor growth suppression in xenograft models.