Towards the Development of Novel Vav-Rac Inhibitors

 描述(申请人提供)：癌症相关死亡的一个主要原因是恶性肿瘤细胞从原发肿瘤转移到其他组织。调节性Rho家族GTP酶的异常活性被认为是启动这种细胞迁移的潜在生化过程之一。在我们的实验室里，我们发现了小的 分子抑制剂EHop-016，并表明它能抑制原癌基因Vav2与Rho GTP酶rac1的相互作用。当EHop-016与RAC结合时，它会阻止全球环境基金Vav2激活它。这抑制了RAC刺激的过程，如板脂形成、细胞迁移和转移。我们已经在小鼠体内实验中证明了EHop-016可以减少肿瘤的生长和转移。在本提案的第一个目标中，将对EHop-016进行结构优化，以获得具有更高活性、降低毒性和优化药物化学参数的化合物。这有望导致一种适合临床前研究的化合物，最终可能成为一种新型的抗癌药物。在该提案的第二个目标中，将设计与Vav结合而不是Rac结合的新的抑制Vav-Rac相互作用的药物。这将为Vav-Rac相互作用的小分子抑制剂提供另一种作用模式。我们可以接触到三种不同的肿瘤细胞系，每一种都主要表达环境基金的一种亚型，Vav1，Vav2或Vav3。与RAC结合抑制剂EHop-016类似，Vav结合抑制剂被认为可以抑制片状脂膜的形成、细胞迁移和转移。随着新的Vav结合蛋白的发现，一种新的用于研究GTP酶活性的分子探针将成为可能。此外，对这些新型抑制剂的进一步优化可能会产生与EHop-016或其改进的衍生物具有互补或相加作用的治疗剂。

 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.