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Towards the Development of Novel Vav-Rac Inhibitors

致力于开发新型 Vav-Rac 抑制剂

基本信息

批准号：
8998770
负责人：
CORNELIS P VLAAR
金额：
$ 11.25万
依托单位：
UNIVERSITY OF PUERTO RICO MED SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-01 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8998770
关键词：
Actins Adverse effects Area Binding Biochemical Process Breast Cancer Etiology Cancer cell line Cell Migration Inhibition function Cell Proliferation Cells Cessation of life Clinical Complement Complex Development Disseminated Malignant Neoplasm Docking Dose Family Guanine Nucleotide Exchange Factors Guanosine Triphosphate Phosphohydrolases Hydrogen Bonding Implant In Vitro Investigation Laboratories Lead Leukemic Cell MDA MB 435 Malignant Neoplasms Molecular Molecular Probes Molecular Weight Mus Neoplasm Metastasis New Agents Oncogenes Oncogenic Outcome Plasma Primary Neoplasm Procedures Process Property Protein Databases Protein Isoforms Proteins Proto-Oncogenes Recommendation Regulation Research Structure Surface Testing Therapeutic Therapeutic Agents Time Tissues Toxic effect Tumor Cell Line Up-Regulation Vav guanine-nucleotide exchange factor Xenograft procedure cancer cell cancer therapy cell growth cell motility clinical investigation design drug candidate drug development improved in vivo inhibitor/antagonist migration nanomolar neoplastic cell novel novel therapeutics overexpression polymerization pre-clinical prevent process optimization programs protein protein interaction public health relevance research study rho rho GTP-Binding Proteins screening small molecule small molecule inhibitor targeted cancer therapy targeted treatment tumor tumor growth virtual water solubility

项目摘要

DESCRIPTION (provided by applicant): A major cause of cancer related deaths is due to the metastasis of malignant cells from the primary tumor to other tissues. Aberrant activity of the regulatory Rho family GTPases has been identified as one of the underlying biochemical processes for initiation of this cell migration to occur. In our laboratory we discovered the small molecule inhibitor EHop-016, and showed that it was able to inhibit the interaction of the proto-oncogene Vav2 with the Rho GTPase Rac1. When EHop-016 binds to Rac, it prevents its activation by the GEF Vav2. This inhibits Rac-stimulated processes such as lamellipodia formation, cell migration, and metastasis. We have shown that EHop-016 reduces tumor growth and metastasis in in vivo experiments in mice. In the first aim of this proposal, a structural optimization of EHop-016 will be carried to obtain a compound with increased activity, reduced toxicity and optimized pharmacochemical parameters. This is expected lead to a compound that is suitable for pre-clinical investigation that could eventually become a novel pharmacotherapeutic agent against cancer. In the second aim of the proposal, new agents that inhibit Vav-Rac interaction will be designed that bind to Vav instead of to Rac. This will provide small molecule inhibitors of Vav-Rac interaction with an alternative mode of action. We have access to three different tumor cell lines that each predominantly express one of the isoforms of the GEF, Vav1, Vav2 or Vav3. Similar as the Rac-binding inhibitor EHop-016, Vav-binding inhibitors are hypothesized to inhibit lamellipodia formation, cell migration and metastasis. With the discovery of new Vav binders, a new molecular probe for the investigation of GTPase activities will become available. Moreover, further optimization of these novel inhibitors could potentially lead to therapeutic agents that will have a complementary or additive effect with EHop-016 or its improved derivatives.