Discovery of small molecule inhibitors of the oncogenic and cytokinetic protein M

发现致癌和细胞因子蛋白 M 的小分子抑制剂

• 批准号: 8449605
• 负责人: Krister Wennerberg
• 金额: $ 4.64万
• 依托单位: SOUTHERN RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8449605
• 关键词: Affect; Antineoplastic Agents; Binding; Biochemical; Biological Assay; Biology; Cells; Clinical; Complex; Cytokinesis; Data; Development; Dissociation; Drug Targeting; Ensure; Exhibits; Family; Finland; Funding; GTP-Binding Proteins; Guanine Nucleotide Exchange Factors; Human; Institutes; Kinesin; Kinetics; Label; Laboratories; Malignant Neoplasms; Microtubules; Molecular Medicine; Molecular Motors; Molecular Probes; Molecular Target; Monomeric GTP-Binding Proteins; Oncogene Proteins; Oncogenic; Proteins; Protocols documentation; Research; Research Institute; Research Personnel; Role; Site; Solid; Sorting - Cell Movement; Source; Specificity; Testing; Time; Work; base; carcinogenesis; improved; inhibitor/antagonist; meetings; multiple myeloma M Protein; novel; operation; outcome forecast; overexpression; programs; protein complex; research study; rho; rho GTPase-activating protein; screening; small molecule; tumorigenesis

DESCRIPTION (provided by applicant): Discovery of small molecule inhibitors of the oncogenic and cytokinetic protein MgcRacGAP The MKLP1/MgcRacGAP/Ect2 protein complex is well established as an essential regulator of cytokinesis. MKLP1 is a microtubule-driven molecular motor (kinesin), MgcRacGAP is a GTPase-activating protein for Rho family small G-proteins (RhoGAP), and Ect2 is a guanine nucleotide exchange factor for Rho proteins (RhoGEF). Interestingly, this complex also appears to contribute to human oncogenesis and cancer malignancy. The proteins of the complex are overexpressed in many human cancers and the expression levels are directly correlated with a poor clinical prognosis. Therefore, development of small molecule inhibitors of this protein complex would be very valuable to further understand its biology of this protein and they may serve as leads for a novel class of anti-cancer drugs. Here we propose to utilize the assays and protocols we have established to identify and develop potent and selective inhibitors of MgcRacGAP with the support of one or more MLPCN centers.

描述（由申请人提供）：发现肿瘤和细胞动力学蛋白MGCRACGAP的小分子抑制剂MKLP1/MGCRACGAP/ECT2蛋白复合物已被很好地确定为细胞因子的必不可少的调节剂。 MKLP1是微管驱动的分子运动（驱动蛋白），MGCRACGAP是Rho家族小G蛋白（RHOGAP）的GTPase激活蛋白（RHOGAP），ECT2是Rho蛋白（Rhogef）的鸟嘌呤核苷酸交换因子。有趣的是，这种复合物似乎也有助于人类的肿瘤发生和癌症恶性肿瘤。在许多人类癌症中，该复合物的蛋白质过表达，表达水平与临床预后不良直接相关。因此，这种蛋白质复合物的小分子抑制剂的发展对于进一步了解其对该蛋白的生物学非常有价值，并且可以作为新型抗癌药物的铅。在这里，我们建议利用我们确定的分析和协议来识别和开发MGCRACGAP的有效和选择性抑制剂，并在一个或多个MLPCN中心的支持下。

项目成果

Discovery of MINC1, a GTPase-activating protein small molecule inhibitor, targeting MgcRacGAP.

• DOI: 10.2174/1386207318666141205112730
• 发表时间: 2015
• 期刊: Combinatorial chemistry & high throughput screening
• 影响因子: 1.8
• 作者: van Adrichem AJ;Fagerholm A;Turunen L;Lehto A;Saarela J;Koskinen A;Repasky GA;Wennerberg K
• 通讯作者: Wennerberg K