Towards the Development of Novel Vav-Rac Inhibitors

 描述（由申请人提供）：癌症相关死亡的主要原因是恶性细胞从原发性肿瘤转移到其他组织。调节性Rho家族GTP酶的异常活性已被鉴定为引发这种细胞迁移发生的潜在生化过程之一。在我们的实验室里， 分子抑制剂EHop-016，并显示其能够抑制原癌基因Vav 2与Rho GTdR Rac 1的相互作用。当EHop-016与Rac结合时，它会阻止其被GEF Vav 2激活。这抑制了Rac刺激的过程，如板状伪足形成、细胞迁移和转移。我们已经表明，EHop-016在小鼠体内实验中减少肿瘤生长和转移。在本提案的第一个目标中，将对EHop-016进行结构优化，以获得具有增加的活性、降低的毒性和优化的药物化学参数的化合物。这有望产生一种适合临床前研究的化合物，最终可能成为一种新型抗癌药物。在该提案的第二个目标中，将设计抑制Vav-Rac相互作用的新试剂，其结合Vav而不是Rac。这将提供具有替代作用模式的Vav-Rac相互作用的小分子抑制剂。我们获得了三种不同的肿瘤细胞系，每种细胞系主要表达GEF的一种亚型，Vav 1、Vav 2或Vav 3。与Rac结合抑制剂EHop-016类似，假设Vav结合抑制剂抑制板状伪足形成、细胞迁移和转移。随着新的Vav结合剂的发现，用于研究GTdR活性的新的分子探针将变得可用。此外，这些新型抑制剂的进一步优化可能潜在地导致将与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.