期刊
PROTEIN SCIENCE
卷 30, 期 8, 页码 1535-1553出版社
WILEY
DOI: 10.1002/pro.4125
关键词
cancer biology; drug discovery; kinase; structural biology
资金
- National Cancer Institute [R01CA116020, R01CA201049, R35CA242461]
- University at Buffalo
Precision oncology focuses on identifying and targeting key proteins and pathways driving tumorigenesis or tumor cell survival. Historical and recent efforts in developing inhibitors targeting these nodes emphasize the role of understanding protein structure and regulation in inhibitor discovery and characterization. Structural biology has also revealed new avenues in precision cancer drug discovery by uncovering mechanisms of allosteric regulation and vulnerabilities to activating oncogenic mutations.
Precision oncology is premised on identifying and drugging proteins and pathways that drive tumorigenesis or are required for survival of tumor cells. Across diverse cancer types, the signaling pathway emanating from receptor tyrosine kinases on the cell surface to RAS and the MAP kinase pathway is the most frequent target of oncogenic mutations, and key proteins in this signaling axis including EGFR, SHP2, RAS, BRAF, and MEK have long been a focus in cancer drug discovery. In this review, we provide an overview of historical and recent efforts to develop inhibitors targeting these nodes with an emphasis on the role that an understanding of protein structure and regulation has played in inhibitor discovery and characterization. Beyond its well-established role in structure-based drug design, structural biology has revealed mechanisms of allosteric regulation, distinct effects of activating oncogenic mutations, and other vulnerabilities that have opened new avenues in precision cancer drug discovery.
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