Unknown

Dataset Information

0

Discovery of a potent, covalent BTK inhibitor for B-cell lymphoma.


ABSTRACT: BTK is a member of the TEC family of non-receptor tyrosine kinases whose deregulation has been implicated in a variety of B-cell-related diseases. We have used structure-based drug design in conjunction with kinome profiling and cellular assays to develop a potent, selective, and irreversible BTK kinase inhibitor, QL47, which covalently modifies Cys481. QL47 inhibits BTK kinase activity with an IC50 of 7 nM, inhibits autophosphorylation of BTK on Tyr223 in cells with an EC50 of 475 nM, and inhibits phosphorylation of a downstream effector PLC?2 (Tyr759) with an EC50 of 318 nM. In Ramos cells QL47 induces a G1 cell cycle arrest that is associated with pronounced degradation of BTK protein. QL47 inhibits the proliferation of B-cell lymphoma cancer cell lines at submicromolar concentrations.

SUBMITTER: Wu H 

PROVIDER: S-EPMC4027949 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

altmetric image

Publications


BTK is a member of the TEC family of non-receptor tyrosine kinases whose deregulation has been implicated in a variety of B-cell-related diseases. We have used structure-based drug design in conjunction with kinome profiling and cellular assays to develop a potent, selective, and irreversible BTK kinase inhibitor, QL47, which covalently modifies Cys481. QL47 inhibits BTK kinase activity with an IC50 of 7 nM, inhibits autophosphorylation of BTK on Tyr223 in cells with an EC50 of 475 nM, and inhib  ...[more]

Similar Datasets

| S-EPMC9879287 | biostudies-literature
| S-EPMC4987129 | biostudies-literature
| S-EPMC8155265 | biostudies-literature
| S-EPMC7667833 | biostudies-literature
| S-EPMC9812614 | biostudies-literature
| S-EPMC8445847 | biostudies-literature
| S-EPMC10461952 | biostudies-literature
| S-EPMC5298344 | biostudies-literature
| S-EPMC7549109 | biostudies-literature
| S-EPMC4007912 | biostudies-literature