Optimization of METTL3 Inhibitors for the Treatment of Solid Tumors and AML

  • J Med Chem. 2026 Apr 23;69(8):9585-9602. doi: 10.1021/acs.jmedchem.6c00474.
Guillaume Dutheuil  1 ,  Killian Oukoloff  1 ,  François Lenoir  1 ,  Julien Korac  1 ,  Mohamed El Bousmaqui  1 ,  Nicolas Probst  1 ,  Alexey Lapin  1 ,  Galina Nakhabina  1 ,  Nicolas Parmentier  1 ,  Catherine Sorlet  1 ,  Graeme L Fraser  1
Affiliations
  • 1. Epics Therapeutics SA, rue Adrienne Bolland 47, 6041 Gosselies, Belgium.
PMID: 41978353 DOI: 10.1021/acs.jmedchem.6c00474
Abstract

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.

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