2. Academic Validation
  3. Discovery, Optimization, and Preclinical Pharmacology of EP652, a METTL3 Inhibitor with Efficacy in Liquid and Solid Tumor Models

Discovery, Optimization, and Preclinical Pharmacology of EP652, a METTL3 Inhibitor with Efficacy in Liquid and Solid Tumor Models

  • J Med Chem. 2025 Feb 13;68(3):2981-3003. doi: 10.1021/acs.jmedchem.4c02225.
Guillaume Dutheuil 1,  Killian Oukoloff 1,  Julien Korac 1,  François Lenoir 1,  Mohamed El Bousmaqui 1,  Nicolas Probst 1,  Alexey Lapin 1,  Galina Nakhabina 1,  Catherine Sorlet 1,  Nicolas Parmentier 1,  Delphine Karila 2,  Nugzar Ghavtadze 2,  Paméla Casault 2,  Stephen Claridge 2,  Selma Sapmaz 3,  Martin J Slater 3,  Graeme L Fraser 1
Affiliations

Affiliations

  • 1 Epics Therapeutics SA, rue Adrienne Bolland 47, Gosselies 6041, Belgium.
  • 2 Paraza Pharma, Inc., 2525 Avenue Marie Curie, Montréal H4S 2E1, Canada.
  • 3 Cresset Biomolecular Discovery Limited, New Cambridge House, Bassingbourn Road, Litlington, Cambridgeshire SG8 0SS, United Kingdom.
PMID: 39883878 DOI: 10.1021/acs.jmedchem.4c02225
Abstract

METTL3 is the RNA methyltransferase predominantly responsible for the addition of N6-methyladenosine (m6A), the most abundant modification to mRNA. The prevalence of m6A and the activity and expression of METTL3 have been linked to the appearance and progression of acute myeloid leukemia (AML), thereby making METTL3 an attractive target for Cancer therapeutics. We report herein the discovery and optimization of small-molecule inhibitors of METTL3, culminating in the selection of EP652 as an in vivo proof-of-concept compound. EP652 potently inhibits the enzymatic activity of METTL3, has favorable PK parameters, and demonstrates efficacy in preclinical oncology models, indicating that pharmacological inhibition of METTL3 is a viable strategy for the treatment of liquid and solid tumors.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-168878
    METTL3抑制剂
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