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Design, synthesis, and evaluation of 4,5,6,7-tetrahydrobenzo[d]thiazole-based novel dual kinase inhibitors of CK2 and GSK3?.

ABSTRACT: Casein kinase 2 (CK2) and glycogen synthase kinase-3beta (GSK3?) are responsible for the phosphorylation of a tumor suppressor protein (PTEN) in a cooperative manner which causes its deactivation. Thus, it is essential to inhibit both kinases simultaneously to prevent PTEN deactivation more efficiently. In this study, we have designed a novel lead from Hit15 which was identified in silico as a dual kinase inhibitor against CK2 and GSK3? through our previous study. The dataset of structural analogs of the lead was designed and confirmed by pharmacophore mapping and molecular docking. The screened analogs were considered further and a series of "tetrahydrobenzo[d]thiazoles" were synthesized. Compound 1g has shown highest dual kinase inhibitory activity at a concentration of 1.9 ?M against CK2 and 0.67 ?M against GSK3?. Our results suggest that the presence of a carboxyl group at the meta position of the phenyl ring plays a vital role in dual kinase inhibition.

SUBMITTER: Pardhi TR 

PROVIDER: S-EPMC6148497 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Design, synthesis, and evaluation of 4,5,6,7-tetrahydrobenzo[<i>d</i>]thiazole-based novel dual kinase inhibitors of CK2 and GSK3β.

Pardhi Triveni R TR   Patel Manishkumar S MS   Sudarsanam V V   Vasu Kamala K KK  

MedChemComm 20180726 9

Casein kinase 2 (CK2) and glycogen synthase kinase-3beta (GSK3β) are responsible for the phosphorylation of a tumor suppressor protein (PTEN) in a cooperative manner which causes its deactivation. Thus, it is essential to inhibit both kinases simultaneously to prevent PTEN deactivation more efficiently. In this study, we have designed a novel lead from Hit15 which was identified <i>in silico</i> as a dual kinase inhibitor against CK2 and GSK3β through our previous study. The dataset of structura  ...[more]

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