Project Title: Inhibitors of the GTPases Rac1 and Cdc42 as disease modulators.
Research overview. Our laboratory is interested in developing novel, selective inhibitors of the Rho GTPases Rac1 and Cdc42. These relatively small proteins function as an on/off switch in the regulation of cell migration. In the “OFF” state, the nucleotide GDP is occupying the nucleotide binding site. When a member of regulating proteins called guanine nucleotide exchange factors (GEFs) binds to the GTPases, the GDP is replaced for a GTP, leading to a change of protein conformation to an “ON” state. This change of conformation of the GTPase activates downstream kinases and subsequently leads to formation of lamellipodia and invadopodia on the cell surface. This eventually results in migration of the cells from its origin and invasion of the cells in other tissues. Overexpression of either the GEFs or the GTPases has been found to disrupt the regulation of cell migration and has been implicated in different diseases, including metastatic cancer, malaria, and auto-immune disease. Therefore, inhibitors of Rac1 and/or Cdc42 are promising novel pharmaceutical drugs, of which MBQ-167 is our most advanced pre-clinical candidate for the treatment of metastatic cancer. Our current goal aims to develop a second generation of compounds with increased potency, selectivity and bioavailability which will improve drug properties and specific targeting to different diseases.
Skills/Techniques: PR-CLIMB participants will learn to use computer-based drug design, organic synthesis and purification methods, and analytical techniques such as NMR and Mass spectrometry.
Skills/Techniques: PR-CLIMB participants will learn to use computer-based drug design, organic synthesis and purification methods, and analytical techniques such as NMR and Mass spectrometry.