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.
The development of publicly available small molecule inhibitors against the oncoprotein MgcRacGAP will prove valuable on several levels. First, basic researchers like our research group will be able to use these inhibitors to improve our understanding of MgcRacGAP and its role in carcinogenesis as well as normal biology. Second, these inhibitors may turn out to be used as starting points for the development of novel cancer drugs. Third, these experiments, if successful, can serve as a proof-of-principle for other proteins of the same type as MgcRacGAP but with different functions as potential drug targets.
|Li, Yonghe; Lu, Wenyan; Chen, Dongquan et al. (2015) KIFC1 is a novel potential therapeutic target for breast cancer. Cancer Biol Ther 16:1316-22|
|van Adrichem, Arjan J; Fagerholm, Annika; Turunen, Laura et al. (2015) Discovery of MINC1, a GTPase-activating protein small molecule inhibitor, targeting MgcRacGAP. Comb Chem High Throughput Screen 18:3-17|