Journal
NATURE CHEMICAL BIOLOGY
Volume 14, Issue 9, Pages 895-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41589-018-0099-z
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Funding
- National Institutes of Health [R01 DA036887, R01 CA194864, R01 GM082856]
- US Department of Energy, Office of Biological and Environmental Research [DE-AC02-06CH11357]
- Laura and Isaac Perlmutter Cancer Center from the National Cancer Institute [P30CA016087]
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Rapidly determining the biological effect of perturbing a site within a potential drug target could guide drug discovery efforts, but it remains challenging. Here, we describe a facile target validation approach that exploits monobodies, small synthetic binding proteins that can be fully functionally expressed in cells. We developed a potent and selective monobody to WDR5, a core component of the mixed lineage leukemia (MLL) methyltransferase complex. The monobody bound to the MLL interaction site of WDR5, the same binding site for small-molecule inhibitors whose efficacy has been demonstrated in cells but not in animals. As a genetically encoded reagent, the monobody inhibited proliferation of an MLL-AF9 cell line in vitro, suppressed its leukemogenesis and conferred a survival benefit in an in vivo mouse leukemia model. The capacity of this approach to readily bridge biochemical, structural, cellular characterization and tests in animal models may accelerate discovery and validation of druggable sites.
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