Targeting the KIT activating switch control pocket: a novel mechanism to inhibit neoplastic mast cell proliferation and mast cell activation

被引：27

作者：

Bai, Y. ^{[1
]}

Bandara, G. ^{[1
]}

Chan, E. Ching ^{[1
]}

Maric, I. ^{[2
]}

Simakova, O. ^{[2
]}

Bandara, S. N. ^{[1
]}

Lu, W-P ^{[3
]}

Wise, S. C. ^{[3
]}

Flynn, D. L. ^{[3
]}

Metcalfe, D. D. ^{[1
]}

Gilfillan, A. M. ^{[1
]}

Wilson, T. M. ^{[1
]}

机构：

[1] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA

[2] Ctr Clin, Dept Lab Med, Bethesda, MD USA

[3] Deciphera Pharmaceut, Lawrence, KS USA

来源：

LEUKEMIA | 2013年 / 27卷 / 02期

关键词：

mastocytosis; switch pocket; KIT; KIT D816V; tyrosine kinase inhibitor; mast cell; TYROSINE KINASE INHIBITORS; C-KIT; DEPENDENT ACTIVATION; STI-571; INHIBITION; RI; MUTATIONS; PKC412; GROWTH; MASTOCYTOSIS; DASATINIB;

D O I：

10.1038/leu.2012.218

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Activating mutations in the receptor tyrosine kinase KIT, most notably KIT D816V, are commonly observed in patients with systemic mastocytosis. Thus, inhibition of KIT has been a major focus for treatment of this disorder. Here we investigated a novel approach to such inhibition. Utilizing rational drug design, we targeted the switch pocket (SP) of KIT, which regulates its catalytic conformation. Two SP inhibitors thus identified, DP-2976 and DP-4851, were examined for effects on neoplastic mast cell proliferation and mast cell activation. Autophosphorylation of both wild-type and, where also examined, KIT D816V activation was blocked by these compounds in transfected 293T cells, HMC 1.1 and 1.2 human mast cell lines, and in CD34(+)-derived human mast cells activated by stem cell factor (SCF). Both inhibitors induced apoptosis in the neoplastic mast cell lines and reduced survival of primary bone marrow mast cells from patients with mastocytosis. Moreover, the SP inhibitors more selectively blocked SCF potentiation of Fc epsilon RI-mediated degranulation. Overall, SP inhibitors represent an innovative mechanism of KIT inhibition whose dual suppression of KIT D816V neoplastic mast cell proliferation and SCF-enhanced mast cell activation may provide significant therapeutic benefits. Leukemia (2013) 27, 278-285; doi:10.1038/leu.2012.218

引用

页码：278 / 285

页数：8

共 34 条

[1] Effects of tyrosine kinase inhibitor STI571 on human mast cells bearing wild-type or mutated c-kit [J].