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Drug-resistant menin variants retain high binding affinity and interactions with MLL1.
Ray, Joshua; Clegg, Bradley; Grembecka, Jolanta; Cierpicki, Tomasz.
Afiliación
  • Ray J; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Clegg B; Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Program in Chemical Biology, University of Michigan, Ann Arbor, MI, USA.
  • Grembecka J; Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Program in Chemical Biology, University of Michigan, Ann Arbor, MI, USA. Electronic address: jolantag@umich.edu.
  • Cierpicki T; Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Program in Chemical Biology, University of Michigan, Ann Arbor, MI, USA; Department of Biophysics, University of Michigan, Ann Arbor, MI, USA. Electronic address: tomaszc@umich.edu.
J Biol Chem ; : 107777, 2024 Sep 12.
Article en En | MEDLINE | ID: mdl-39276940
ABSTRACT
Menin is an essential oncogenic co-factor of MLL1 fusion proteins in acute leukemias and inhibitors of the menin-MLL1 interaction are under evaluation in clinical trials. Recent studies found emerging resistance to menin inhibitor treatment in leukemia patients as a result of somatic mutations in menin. To understand how patient mutations in menin affect the interaction with MLL1, we performed systematic characterization of the binding affinity of these menin mutants (T349M, M327I, G331R and G331D) and the N-terminal fragment of MLL1. We also determined the crystal structures of menin patient mutants and their complexes with MLL1-derived peptides. We found that drug-resistant mutations in menin occur at a site adjacent to the MLL1 binding site, but they do not affect MLL1 binding to menin. On the contrary, our structural analysis shows that all these point mutations in menin generate steric clash with menin inhibitors. We also found that mutation G331D results in a very slow dissociation of MLL1 from menin and this mutant might be particularly difficult to inhibit with small molecule drugs. This work provides structural information to support the development of a new generation of small molecule inhibitors that overcome resistance caused by menin mutations.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: J Biol Chem Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
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XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: J Biol Chem Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos