期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 111, 期 21, 页码 7531-7536出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1402393111
关键词
helix mimics; hypoxia signaling; synthetic inhibitors of transcription
资金
- National Science Foundation [CHE-1161644, CHE-1151554]
- NYU Cancer Center Support Grant [5P30CA16087-33]
- Direct For Mathematical & Physical Scien
- Division Of Chemistry [1151554] Funding Source: National Science Foundation
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 a-helices. We designed mimics of a key a-helical domain at the interface of hypoxia-inducible factor 1 alpha 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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