A non-covalent inhibitor XMU-MP-3 overrides ibrutinib-resistant Btk^C481S mutation in B-cell malignancies.

ABSTRACT:

Background and purpose

Bruton's tyrosine kinase (BTK) plays a key role in B-cell receptor signalling by regulating cell proliferation and survival in various B-cell malignancies. Covalent low-MW BTK kinase inhibitors have shown impressive clinical efficacy in B-cell malignancies. However, the mutant Btk^C481S poses a major challenge in the management of B-cell malignancies by disrupting the formation of the covalent bond between BTK and irreversible inhibitors, such as ibrutinib. The present studies were designed to develop novel BTK inhibitors targeting ibrutinib-resistant Btk^C481S mutation.

Experimental approach

BTK-Ba/F3, BTK(C481S)-Ba/F3 cells, and human malignant B-cells JeKo-1, Ramos, and NALM-6 were used to evaluate cellular potency of BTK inhibit

SUBMITTER: Gui F 

PROVIDER: S-EPMC6932946 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature