Abstact

Further lead optimization of our series of METTL3 inhibitors is disclosed where aggregative replacements of the alpha-methylpyridone core and 5-dimethylaminopyridin-3-yl-1,2,3-triazole hinge moiety with an oxetan-3-yl-pyridin-3-yl core and 5-cyclopropylpyridin-3-yl-1,3,4-thiadiazol-2-yl hinge moiety, respectively, improved oral bioavailability while decreasing lipophilicity, thereby translating into oral efficacy in mouse tumor models. This research culminates in the discovery of EP102, a compound with a clear selectivity profile and a favorable ADME/PK profile in addition to robust efficacy in AML and solid tumor models. EP102 has entered clinical development for the treatment of advanced solid tumors.