Carlos Zepeda-Velázquez
Ontario Institute for Cancer Research,Canada
Title: The discovery and evaluation of OICR-9429: A small molecule antagonist of the Wdr5-Mll interaction
Biography
Biography: Carlos Zepeda-Velázquez
Abstract
At a fundamental level, gene expression is regulated by epigenetic histone modifications. Histone methyltransferases catalyze the transfer of the methyl group from S adenosylmethionine to specific lysine residues on histones. Mixed lineage leukemia 1 (MLL1) is a methyltransferase that methylates lysine 4 on histone H3 (H3K4me3) and is an important regulator of the haemopoietic system. Dysregulation of MLL1 is often associated with acute myeloid and lymphoid leukemias, making it an attractive therapeutic target. WD40 repeat protein 5 (WDR5) is a component of the multiprotein MLL1 complex that is essential for its methyltransferase activity, and disruption of the WDR5/MLL1 interaction may therefore present a viable therapeutic option for the treatment of MLL-dependent leukemias. Employing structure-based design principles and cheminformatic tools, compounds that bind to WDR5 with low nanomolar affinities were synthesized. Of the various small molecules assessed, OICR-9429 demonstrated the most potent activity with KD values of 51 nM (Biacore), 64 nM (FP) and 52 nM (ITC). OICR9429 also disrupts the interaction of WDR5 with MLL1 and RbBP5 in cells with IC50 values below 1 µM