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Facile target validation in an animal model with intracellularly expressed monobodies.
Gupta, Ankit; Xu, Jing; Lee, Shirley; Tsai, Steven T; Zhou, Bo; Kurosawa, Kohei; Werner, Michael S; Koide, Akiko; Ruthenburg, Alexander J; Dou, Yali; Koide, Shohei.
Afiliação
  • Gupta A; Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY, USA.
  • Xu J; Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL, USA.
  • Lee S; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Tsai ST; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Zhou B; Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY, USA.
  • Kurosawa K; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
  • Werner MS; Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY, USA.
  • Koide A; Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL, USA.
  • Ruthenburg AJ; Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, IL, USA.
  • Dou Y; Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY, USA.
  • Koide S; Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL, USA.
Nat Chem Biol ; 14(9): 895-900, 2018 09.
Article em En | MEDLINE | ID: mdl-30013062
ABSTRACT
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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Oligopeptídeos / Proteínas / Proteínas de Homeodomínio Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2018 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Oligopeptídeos / Proteínas / Proteínas de Homeodomínio Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2018 Tipo de documento: Article