Journal of Clinical & Experimental OncologyISSN: 2324-9110

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The discovery and evaluation of OICR-9429: A small molecule antagonist of the Wdr5-Mll interaction

Carlos Zepeda-Velazquez, Matthaus Getlik, David Smil, Yuri Bolshan, Gennadiy Poda, Guillermo Senisterra, Hong Wu, Abdellah Allali-Hassani,
Gregory A Wasney, Dalia Barsyte-Lovejoy, Ludmila Dombrovski, Aiping Dong, Hao He, Alma Seitova, Irene Chau, Fengling Li, Jean-Francois
Couture, Ekat

Ontario Institute for Cancer Research,Canada
University of Toronto, Canada

: J Clin Exp Oncol


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). OICR- 9429 also disrupts the interaction of WDR5 with MLL1 and RbBP5 in cells with IC50 values below 1 μM.


Carlos Zepeda-Velázquez earned his BSc degree in Pharmaceutical Chemistry from La Salle University and his M.Sc. in Organic Chemistry from National Autonomous University of Mexico in 2003 and 2006 respectively. Subsequently, he worked as a process chemist at Signa, SA de CV (Apotex Pharmachem INC). For his doctoral studies he moved to Canada in 2009 and joined the group of Dr McNulty at McMaster University where he completed the total synthesis of the anticancer natural product (+)-trans-Dihydrolycoricidine. He then moved to the Ontario Institute for Cancer Research under Dr Rima Al-awar, working on novel anti-tumor agents and in 2016 he was promoted to Research Scientist. His research focuses on chemical biology of chromatin regulation and drug discovery.

E-mail: [email protected]

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