Discovery of M-808 as a Highly Potent, Covalent, Small-Molecule Inhibitor of the Menin-MLL Interaction with Strong In Vivo Antitumor Activity

J Med Chem. 2020 May 14;63(9):4997-5010. doi: 10.1021/acs.jmedchem.0c00547. Epub 2020 Apr 27.


Targeting the menin-MLL protein-protein interaction is a new therapeutic strategy for the treatment of acute leukemia carrying MLL fusion (MLL leukemia). We describe herein the structure-based optimization of a class of covalent menin inhibitors, which led to the discovery of M-808 (16) as a highly potent and efficacious covalent menin inhibitor. M-808 effectively inhibits leukemia cell growth at low nanomolar concentrations and is capable of achieving partial tumor regression in an MV4;11 xenograft tumor model in mice at a well-tolerated dose schedule. Determination of the co-crystal structure of M-808 in complex with menin provides a structural basis for their high-affinity, covalent interactions. M-808 represents a promising, covalent menin inhibitor for further optimization and evaluation toward developing a new therapy for the treatment of MLL leukemia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Azetidines / chemical synthesis
  • Azetidines / pharmacology
  • Azetidines / therapeutic use*
  • Cell Line, Tumor
  • Crystallography, X-Ray
  • Drug Screening Assays, Antitumor
  • Female
  • Histone-Lysine N-Methyltransferase / antagonists & inhibitors*
  • Histone-Lysine N-Methyltransferase / metabolism
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy*
  • Mice, SCID
  • Molecular Structure
  • Myeloid-Lymphoid Leukemia Protein / antagonists & inhibitors*
  • Myeloid-Lymphoid Leukemia Protein / metabolism
  • Protein Binding / drug effects*
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Proto-Oncogene Proteins / metabolism
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • Azetidines
  • KMT2A protein, human
  • MEN1 protein, human
  • Proto-Oncogene Proteins
  • Myeloid-Lymphoid Leukemia Protein
  • Histone-Lysine N-Methyltransferase