Further lead optimization of our series of METTL3 inhibitors is disclosed where aggregative replacements of the α-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.
Dutheuil et al. (Mon,) studied this question.