| Autor: |
Nano N; Department of Biochemistry, University of Toronto, Toronto, ON M5G 1M1, Canada., Ugwu F; Department of Biochemistry, University of Toronto, Toronto, ON M5G 1M1, Canada., Seraphim TV; Department of Biochemistry, University of Toronto, Toronto, ON M5G 1M1, Canada., Li T; Department of Biochemistry, University of Toronto, Toronto, ON M5G 1M1, Canada., Azer G; Department of Biochemistry, University of Toronto, Toronto, ON M5G 1M1, Canada., Isaac M; Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada., Prakesch M; Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada., Barbosa LRS; Institute of Physics, University of São Paulo, São Paulo SP 05508-090, Brazil., Ramos CHI; Institute of Chemistry, University of Campinas UNICAMP, Campinas SP 13083-970, Brazil., Datti A; Department of Agriculture, Food, and Environmental Sciences, University of Perugia, 06121 Perugia, Italy., Houry WA; Department of Biochemistry, University of Toronto, Toronto, ON M5G 1M1, Canada.; Department of Chemistry, University of Toronto, Toronto, ON M5S 3H6, Canada. |
| Abstrakt: |
RUVBL1 and RUVBL2 are highly conserved ATPases that belong to the AAA+ (ATPases Associated with various cellular Activities) superfamily and are involved in various complexes and cellular processes, several of which are closely linked to oncogenesis. The proteins were implicated in DNA damage signaling and repair, chromatin remodeling, telomerase activity, and in modulating the transcriptional activities of proto-oncogenes such as c-Myc and β-catenin. Moreover, both proteins were found to be overexpressed in several different types of cancers such as breast, lung, kidney, bladder, and leukemia. Given their various roles and strong involvement in carcinogenesis, the RUVBL proteins are considered to be novel targets for the discovery and development of therapeutic cancer drugs. Here, we describe the identification of sorafenib as a novel inhibitor of the ATPase activity of human RUVBL2. Enzyme kinetics and surface plasmon resonance experiments revealed that sorafenib is a weak, mixed non-competitive inhibitor of the protein's ATPase activity. Size exclusion chromatography and small angle X-ray scattering data indicated that the interaction of sorafenib with RUVBL2 does not cause a significant effect on the solution conformation of the protein; however, the data suggested that the effect of sorafenib on RUVBL2 activity is mediated by the insertion domain in the protein. Sorafenib also inhibited the ATPase activity of the RUVBL1/2 complex. Hence, we propose that sorafenib could be further optimized to be a potent inhibitor of the RUVBL proteins. |
