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Activation and Regulation Mechanisms of the RAF Kinase Family

RAF激酶家族的激活和调节机制

基本信息

批准号：
10798593
负责人：
Zhihong Wang
金额：
$ 2.76万
依托单位：
ROWAN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-10 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10798593
关键词：
Address Affinity Allosteric Regulation BRAF gene Binding Binding Sites Biochemical Biological Assay Biological Process Biology CDK4 gene Cells Chemicals Client Clinical Co-Immunoprecipitations Complex Computing Methodologies Development Dimerization Disease Dissociation Drug resistance Elements Engineering Enzymes Event Family Goals Growth Factor Receptors Health Human In Vitro Intervention Kinetics Knowledge Length MAP Kinase Gene MAPK Signaling Pathway Pathway Malignant Neoplasms Mass Spectrum Analysis Measures Mediating Membrane Modeling Molecular Molecular Conformation Mutate Mutation Mutation Analysis N-terminal Nucleotides Oncogenic Outcome Output Pathologic Pathway interactions Peptides Pharmaceutical Preparations Phosphorylation Phosphotransferases Photoaffinity Labels Physiological Positioning Attribute Proliferating Protein Family Protein Isoforms Protein Kinase Protein-Serine-Threonine Kinases Proteins Proto-Oncogene Proteins B-raf RAS genes Ras/Raf Regulation Research Second Primary Cancers Serine Signal Transduction Sirolimus Specificity Structure System Tacrolimus Binding Proteins Therapeutic Variant Work X-Ray Crystallography biochemical tools biophysical tools cellular imaging chaperone machinery dimer inhibitor insight interdisciplinary approach live cell imaging member molecular dynamics multicatalytic endopeptidase complex mutant novel therapeutic intervention paralogous gene pharmacologic phosphoproteomics preference protein degradation prototype raf Kinases recruit success synergism targeted cancer therapy tumor tumorigenesis

项目摘要

BRAF, a member of the RAF family protein kinases, works in the MAPK signaling pathway, which controls broad cellular events like proliferation and differentiation. BRAF is the most frequently mutated kinase in human cancers. Furthermore, tumors lacking BRAF mutations are contingent on BRAF activity when there are mutations in upstream pathway members, such as RAS or growth factor receptors. Thus, BRAF represents an important target for cancer therapy. Despite three decades of intense research, only recently has a sufficient understanding of BRAF's mechanism creaked open the door to BRAF therapy. However, the current clinical BRAF inhibitors, vemurafenib and dabrafenib, are limited to the class I mutant BRAFV600E. Vemurafenib and dabrafenib, the two ATP-competitive inhibitors, can paradoxically activate non-BRAFV600E and wild-type BRAF, suggesting that BRAF has functions that are independent of its kinase activity. Therapeutic strategies for tumors with non- BRAFV600E mutations and wild-type BRAF are still lacking. Gaps in our knowledge contributed to the limitations of ATP-competitive BRAF drugs. The proposed work centers around three questions regarding RAF activation and regulation in health and disease states. Q1: how BRAF structural elements and ATP binding mediate the catalytic-independent functions of non-BRAFV600E and wild-type BRAF? Q2: what is the mechanism of action of the first BRAF allosteric inhibitor developed by our group and how can inhibitors targeting the catalytic and non- catalytic functions of BRAF be developed? Q3: What factors contribute to the non-overlapping functions of RAF isoforms, despite their structural similarity? The PI and her team will address these questions through multidisciplinary approaches, including X-ray crystallography, binding kinetics, phosphoproteomics, live cell imaging, chemical biology, and computational methods. Our findings will not only facilitate a better understanding of the complex biochemical mechanisms of the RAF kinase family, also provide a molecular basis for novel therapeutic approaches targeting BRAF-driven tumors.

BRAF是RAF家族蛋白激酶的一员，在MAPK信号通路中起作用