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In vivo modulation of hypoxia-inducible signaling by topographical helix mimetics.
Lao, Brooke Bullock; Grishagin, Ivan; Mesallati, Hanah; Brewer, Thomas F; Olenyuk, Bogdan Z; Arora, Paramjit S.
Afiliação
  • Lao BB; Department of Chemistry, New York University, New York, NY 10003; and.
  • Grishagin I; Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089.
  • Mesallati H; Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089.
  • Brewer TF; Department of Chemistry, New York University, New York, NY 10003; and.
  • Olenyuk BZ; Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089 arora@nyu.edu bogdan@usc.edu.
  • Arora PS; Department of Chemistry, New York University, New York, NY 10003; and arora@nyu.edu bogdan@usc.edu.
Proc Natl Acad Sci U S A ; 111(21): 7531-6, 2014 May 27.
Article em En | MEDLINE | ID: mdl-24821806
ABSTRACT
Development of small-molecule inhibitors of protein-protein interactions is a fundamental challenge at the interface of chemistry and cancer biology. Successful methods for design of protein-protein interaction inhibitors include computational and experimental high-throughput and fragment-based screening strategies to locate small-molecule fragments that bind protein surfaces. An alternative rational design approach seeks to mimic the orientation and disposition of critical binding residues at protein interfaces. We describe the design, synthesis, biochemical, and in vivo evaluation of a small-molecule scaffold that captures the topography of α-helices. We designed mimics of a key α-helical domain at the interface of hypoxia-inducible factor 1α and p300 to develop inhibitors of hypoxia-inducible signaling. The hypoxia-inducible factor/p300 interaction regulates the transcription of key genes, whose expression contributes to angiogenesis, metastasis, and altered energy metabolism in cancer. The designed compounds target the desired protein with high affinity and in a predetermined manner, with the optimal ligand providing effective reduction of tumor burden in experimental animal models.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Biomimética / Bibliotecas de Moléculas Pequenas / Domínios e Motivos de Interação entre Proteínas / Descoberta de Drogas Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2014 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Biomimética / Bibliotecas de Moléculas Pequenas / Domínios e Motivos de Interação entre Proteínas / Descoberta de Drogas Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2014 Tipo de documento: Article