[Todos CMAT] [Cursos Pasteur] Ciclo de Seminarios: "From molecules to mice: optimization of WDR5 inhibitors" - Jueves 6 de abril - 9:30hs - Salón de Actos "Guillermo Dighiero"

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Vie Mar 31 16:52:18 UYT 2017


Ciclo de Seminarios: Jueves 6 de abril - 9:30hs - Salón de Actos "Guillermo Dighiero"

Título: "From molecules to mice: optimization of WDR5 inhibitors"

Expone: Matias Casas Selves, PhD. Senior Biologist
Drug Discovery Group
Ontario Institute for Cancer Research
MaRS Centre


WD repeat-containing protein 5 (WDR5) is an important scaffolding component of the COMPASS and COMPASS-like multiprotein complexes, essential for activating mixed-lineage leukemia (MLL) family members. MLL’s encode a family of histone methyltransferases (HMT) that activate gene expression through the methylation of histone H3 on lysine 4 (H3K4). 
Importantly, rearrangement of the MLL1 gene (and other MLL members) has been associated with onset and progression of acute myeloid and lymphoblastic leukemia. Depletion of WDR5 in preclinical models   strongly reduces MLL1 HMT activity and blocks oncogene-mediated cell proliferation, suggesting that WDR5 inhibition may be an effective strategy for therapeutic intervention.
Here we report the SAR optimization of a series of WDR5-MLL1 protein-protein inhibitors, advancing from cellular leads, to a highly potent and selective clinical candidate; which presents enhanced pharmacokinetic and pharmacodynamic properties.

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