Terreic acid, a quinone epoxide inhibitor of Bruton’s tyrosine kinase

Terreic acid, a quinone epoxide inhibitor of Bruton’s tyrosine kinase

Divisions of ^*Allergy and ^¶Immunochemistry, La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego, CA 92121; ^‡Pharmaceutical Research Laboratory, Kirin Brewery Co., Ltd., Takasaki, Gunma 370–12, Japan; ^§Department of Pharmacology, Gifu Pharmaceutical University, Gifu 502, Japan; and ^‖National Research Institute of Vegetables, Ornamental Plants, and Tea, Kanaya, Shizuoka 428, Japan

Communicated by Kimishige Ishizaka, Kirin Brewery Co., Tokyo, Japan (received for review November 11, 1998)

Abstract

Bruton’s tyrosine kinase (Btk) plays pivotal roles in mast cell activation as well as in B cell development. Btk mutations lead to severe impairments in proinflammatory cytokine production induced by cross-linking of high-affinity IgE receptor on mast cells. By using an in vitro assay to measure the activity that blocks the interaction between protein kinase C and the pleckstrin homology domain of Btk, terreic acid (TA) was identified and characterized in this study. This quinone epoxide specifically inhibited the enzymatic activity of Btk in mast cells and cell-free assays. TA faithfully recapitulated the phenotypic defects of btk mutant mast cells in high-affinity IgE receptor-stimulated wild-type mast cells without affecting the enzymatic activities and expressions of many other signaling molecules, including those of protein kinase C. Therefore, this study confirmed the important roles of Btk in mast cell functions and showed the usefulness of TA in probing into the functions of Btk in mast cells and other immune cell systems. Another insight obtained from this study is that the screening method used to identify TA is a useful approach to finding more efficacious Btk inhibitors.

Footnotes

↵ † Y.K., S.E.H., and E.K. contributed equally to this study.
↵ ** To whom reprint requests should be addressed. e-mail: toshi_kawakami{at}liai.org.
ABBREVIATIONS:

BCR,

B cell receptor;

Btk,

Bruton’s tyrosine kinase;

FcɛRI,

high-affinity IgE receptor;

GST,

glutathione S-transferase;

IL,

interleukin;

MAP,

mitogen-activated protein;

PH,

pleckstrin homology;

PKC,

protein kinase C;

PTK,

protein-tyrosine kinase;

TA,

terreic acid;

TNF,

tumor necrosis factor