Serine/arginine protein kinase (SRPK) inhibition as a potential therapeutic strategy against leukemia cells

• Ano de defesa: 2018
• Autor(a) principal: Siqueira, Raoni Pais
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: eng
• Instituição de defesa: Universidade Federal de Viçosa
• Palavras-chave em Português: Inibidor de quinase; Leucemia; Serine/arginine; Serine/arginine protein kinase; Biologia Molecular
• Link de acesso: http://www.locus.ufv.br/handle/123456789/18831

Serine/Arginine protein kinase (SRPK) are key components of the splicing machinery trough the phospho­regulation of SR Proteins, which are crucial for exon selection in the alternative splicing. However, SRPK have frequently been found overexpressed or/and with altered activity in a number of cancers, including leukemias. Thus, the discovery of small molecule inhibitors against these kinases is of potential interest to identify novel therapeutic opportunities. Here, it is described the pharmacological inhibition of SRPK by N­(2­(piperidin­1­yl)­5­ (trifluoromethyl)phenyl)isonicotinamide (SRPIN340) on the viability of lymphoid and myeloid leukemia cell lines. Along with significant cytotoxic activity, the effect of treatments in regulating the phosphorylation of the SR protein family and in altering the expression of MAP2K1, MAP2K2, VEGF and FAS genes were also assessed. Furthermore, it was found that pharmacological inhibition of SRPKs can trigger early and late events of apoptosis. Finally, intrinsic tryptophan fluorescence emission, molecular docking and molecular dynamics were analyzed to gain structural information on the SRPK/SRPIN340 complex. In a second study, it is described the synthesis of a series of twenty­two trifluoromethyl arylamides based on the SRPIN340 scaffold and the evaluation of their antileukemia effects. Some derivatives presented superior cytotoxic effects against myeloid and lymphoid leukemia cell lines compared to SRPIN340. In particular, compounds N­(2­(4­bromophenylamino)­5­(trifluoromethyl)phenyl)­2­chloronicotinamide (24), N­(2­(4­bromophenylamino)­5­(trifluoromethyl)phenyl)nicotinamide (30), and N­(2­(4­ bromophenylamino)­5­(trifluoromethyl)phenyl)benzamide (36) presented IC 50 values within the 6.0 – 35.7 μM (μmol L ­1 ) range. In addition, these three compounds were able to trigger apoptosis and autophagy, and they exhibited synergistic effects in combination with the chemotherapeutic agent vincristine. Moreover, compound 30 was more efficient than SRPIN340 in impairing the intracellular phosphorylation status of SR proteins as well as the expression of MAP2K1, MAP2K2, VEGF, and RON oncogenic isoforms in leukemia cells. Taken together, these results suggest that SRPK pharmacological inhibitors may be considered for the development of novel therapeutic strategies against leukemias and other types of cancers.