PIM serine/threonine kinases in the pathogenesis and therapy of hematologic malignancies and solid cancers

被引:320
作者
Brault, Laurent [1 ]
Gasser, Christelle [1 ]
Bracher, Franz [2 ]
Huber, Kilian [2 ]
Knapp, Stefan [3 ]
Schwaller, Juerg [1 ]
机构
[1] Univ Basel Hosp, Dept Biomed, CH-4031 Basel, Switzerland
[2] Univ Munich, Dept Pharm, Munich, Germany
[3] Univ Oxford, Nuffield Dept Clin Med, Struct Genom Consortium, Oxford OX3 7DQ, England
来源
HAEMATOLOGICA-THE HEMATOLOGY JOURNAL | 2010年 / 95卷 / 06期
基金
加拿大健康研究院; 新加坡国家研究基金会; 英国惠康基金;
关键词
PIM kinases; leukemia; solid cancer; structure; small molecule inhibitors; CHRONIC LYMPHOCYTIC-LEUKEMIA; HALF-SANDWICH COMPLEXES; PROVIRAL INSERTION SITE; CELL-CYCLE PROGRESSION; C-MYC; PROTOONCOGENE PIM-1; SUBSTRATE-SPECIFICITY; TRANSCRIPTION FACTORS; HEMATOPOIETIC-CELLS; SIGNALING PATHWAYS;
D O I
10.3324/haematol.2009.017079
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The identification as cooperating targets of Proviral Integrations of Moloney virus in murine lymphomas suggested early on that PIM serine/threonine kinases play an important role in cancer biology. Whereas elevated levels of PIM1 and PIM2 were mostly found in hematologic malignancies and prostate cancer, increased PIM3 expression was observed in different solid tumors. PIM kinases are constitutively active and their activity supports in vitro and in vivo tumor cell growth and survival through modification of an increasing number of common as well as isoform-specific substrates including several cell cycle regulators and apoptosis mediators. PIM1 but not PIM2 seems also to mediate homing and migration of normal and malignant hematopoietic cells by regulating chemokine receptor surface expression. Knockdown experiments by RNA interference or dominant-negative acting mutants suggested that PIM kinases are important for maintenance of a transformed phenotype and therefore potential therapeutic targets. Determination of the protein structure facilitated identification of an increasing number of potent small molecule PIM kinase inhibitors with in vitro and in vivo anticancer activity. Ongoing efforts aim to identify isoform-specific PIM inhibitors that would not only help to dissect the kinase function but hopefully also provide targeted therapeutics. Here, we summarize the current knowledge about the role of PIM serine/threonine kinases for the pathogenesis and therapy of hematologic malignancies and solid cancers, and we highlight structural principles and recent progress on small molecule PIM kinase inhibitors that are on their way into first clinical trials.
引用
收藏
页码:1004 / 1015
页数:12
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