2. Academic Validation
  3. Small-molecule inhibition of MLL activity by disruption of its interaction with WDR5

Small-molecule inhibition of MLL activity by disruption of its interaction with WDR5

  • Biochem J. 2013 Jan 1;449(1):151-9. doi: 10.1042/BJ20121280.
Guillermo Senisterra 1,  Hong Wu,  Abdellah Allali-Hassani,  Gregory A Wasney,  Dalia Barsyte-Lovejoy,  Ludmila Dombrovski,  Aiping Dong,  Kong T Nguyen,  David Smil,  Yuri Bolshan,  Taraneh Hajian,  Hao He,  Alma Seitova,  Irene Chau,  Fengling Li,  Gennadiy Poda,  Jean-François Couture,  Peter J Brown,  Rima Al-Awar,  Matthieu Schapira,  Cheryl H Arrowsmith,  Masoud Vedadi
Affiliations

Affiliation

  • 1 Structural Genomics Consortium, 101 College Street, Toronto, Ontario, Canada.
PMID: 22989411 DOI: 10.1042/BJ20121280
Abstract

WDR5 (WD40 repeat protein 5) is an essential component of the human trithorax-like family of SET1 [Su(var)3-9 enhancer-of-zeste trithorax 1] methyltransferase complexes that carry out trimethylation of histone 3 Lys4 (H3K4me3), play key roles in development and are abnormally expressed in many cancers. In the present study, we show that the interaction between WDR5 and Peptides from the catalytic domain of MLL (mixed-lineage leukaemia protein) (KMT2) can be antagonized with a small molecule. Structural and biophysical analysis show that this antagonist binds in the WDR5 peptide-binding pocket with a Kd of 450 nM and inhibits the catalytic activity of the MLL core complex in vitro. The degree of inhibition was enhanced at lower protein concentrations consistent with a role for WDR5 in directly stabilizing the MLL multiprotein complex. Our data demonstrate inhibition of an important protein-protein interaction and form the basis for further development of inhibitors of WDR5-dependent Enzymes implicated in MLL-rearranged leukaemias or other cancers.

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