Novel SHP-1 inhibitors tyrosine phosphatase inhibitor-1 and analogs with preclinical anti-tumor activities as tolerated oral agents.
Novel SHP-1 inhibitors tyrosine phosphatase inhibitor-1 and analogs with preclinical anti-tumor activities as tolerated oral agents.
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DOI：
10.4049/jimmunol.0903562
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发表时间：
2010-06-01
期刊：
影响因子：
--
通讯作者：
Yi T
中科院分区：
文献类型：
--
作者：
Kundu S;Fan K;Cao M;Lindner DJ;Zhao ZJ;Borden E;Yi T
SHP-1 has been implicated as a potential cancer therapeutic target by its negative regulation of immune cell activation and the activity of the SHP-1 inhibitor SSG that induced IFNγ+ cells for anti-tumor action. To develop more potent SHP-1-targeted anti-cancer agents, inhibitory leads were identified from a library of 34,000 drug-like compounds. Among the leads and active at low nM for recombinant SHP-1, tyrosine phosphatase inhibitor-1 (TPI-1) selectively increased SHP-1 phospho-substrates (pLck-pY394, pZap70 and pSlp76) in Jurkat T cells but had little effects on pERK1/2 or pLck-pY505 regulated by phosphatases SHP-2 or CD45, respectively. TPI-1 induced mouse splenic-IFNγ+ cells in vitro, ~58-fold more effective than SSG, and increased mouse splenic-pLck-pY394 and -IFNγ+ cells in vivo. TPI-1 also induced IFNγ+ cells in human peripheral blood in vitro. Significantly, TPI-1 inhibited (~83%, p <0.002) the growth of B16 melanoma tumors in mice at a tolerated oral dose in a T cell-dependent manner but had little effects on B16 cell growth in culture. TPI-1 also inhibited B16 tumor growth and prolonged tumor mice survival as a tolerated s.c. agent. TPI-1 analogs were identified with improved activities in IFNγ+ cell induction and in anti-tumor actions. In particular, analog TPI-1a4 as a tolerated oral agent completely inhibited the growth of K1735 melanoma tumors and was more effective than the parental lead against MC-26 colon cancer tumors in mice. These results designate TPI-1 and the analogs as novel SHP-1 inhibitors with anti-tumor activity likely via an immune mechanism, supporting SHP-1 as a novel target for cancer treatment.
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DOI：
10.1038/newbio242148a0
发表时间：
1973-01-01
期刊：
NATURE-NEW BIOLOGY
影响因子：
--
作者：
FIDLER, IJ
通讯作者：
FIDLER, IJ
影响因子：
10.3
作者：
Carlomagno, F;Anaganti, S;Santoro, M
通讯作者：
Santoro, M
影响因子：
1.5
作者：
Aguado, Enrique;Martinez-Florensa, Mario;Aparicio, Pedro
通讯作者：
Aparicio, Pedro
影响因子：
2.2
作者：
Favre, N;Bordmann, G;Rudin, W
通讯作者：
Rudin, W
影响因子：
4.8
作者：
Chiang, GG;Sefton, BM
通讯作者：
Sefton, BM