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Sorafenib as an Inhibitor of RUVBL2

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Autor(es):
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Nano, Nardin [1] ; Ugwu, Francisca [1, 2] ; Seraphim, V, Thiago ; Li, Tangzhi [3, 4] ; Azer, Gina [3, 4] ; Isaac, Methvin [5] ; Prakesch, Michael [5] ; Barbosa, Leandro R. S. [6] ; Ramos, I, Carlos H. ; Datti, Alessandro [7] ; Houry, Walid A. [8, 3, 4]
Número total de Autores: 11
Afiliação do(s) autor(es):
[1] Univ Toronto, Dept Biochem, Toronto, ON M5G 1M1 - Canada
[2] Houry, Walid A., Univ Toronto, Dept Chem, Toronto, ON M5S 3H6, Canada.Nano, Nardin, Univ Toronto, Dept Biochem, Toronto, ON M5G 1M1 - Canada
[3] Seraphim, Thiago, V, Univ Toronto, Dept Biochem, Toronto, ON M5G 1M1 - Canada
[4] Seraphim, Thiago, V, Houry, Walid A., Univ Toronto, Dept Chem, Toronto, ON M5S 3H6, Canada.Nano, Nardin, Univ Toronto, Dept Biochem, Toronto, ON M5G 1M1 - Canada
[5] Ontario Inst Canc Res, Drug Discovery Program, Toronto, ON M5G 0A3 - Canada
[6] Univ Sao Paulo, Inst Phys, BR-05508090 Sao Paulo, SP - Brazil
[7] Univ Perugia, Dept Agr Food & Environm Sci, I-06121 Perugia - Italy
[8] Univ Toronto, Dept Chem, Toronto, ON M5S 3H6 - Canada
Número total de Afiliações: 8
Tipo de documento: Artigo Científico
Fonte: BIOMOLECULES; v. 10, n. 4 APR 2020.
Citações Web of Science: 0
Resumo

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 beta-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. (AU)

Processo FAPESP: 16/05019-0 - A influência termodinâmica e estrutural de líquidos iônicos em sistemas biomiméticos de membrana
Beneficiário:Natália Fernandes de Oliveira
Linha de fomento: Bolsas no Brasil - Iniciação Científica
Processo FAPESP: 15/15822-1 - Estudo das propriedades físico-químicas e estruturais de fármacos e líquidos iônicos com sistemas de relevância biológica
Beneficiário:Leandro Ramos Souza Barbosa
Linha de fomento: Auxílio à Pesquisa - Regular
Processo FAPESP: 12/50161-8 - Estudo da estrutura e função da chaperona Hsp90 com ênfase no seu papel em homeostase celular
Beneficiário:Carlos Henrique Inacio Ramos
Linha de fomento: Auxílio à Pesquisa - Temático
Processo FAPESP: 12/01953-9 - Proteínas em condição de fibrilação: caracterização estrutural e espectroscópica em função de agentes desnaturantes
Beneficiário:Leandro Ramos Souza Barbosa
Linha de fomento: Auxílio à Pesquisa - Regular