NDLI: Novel SHP-1 inhibitors TPI-1 and analogs with pre-clinical anti-tumor activities as tolerated oral agents

Content Provider	PubMed Central
Author	Kundu, Suman Fan, Keke Cao, Mingli Lindner, Daniel J. Zhao, Zhizhaung Joe Borden, Ernest Yi, Taolin
Abstract	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.
Related Links	http://dx.doi.org/10.4049/jimmunol.0903562
Ending Page	6536
Page Count	8
Starting Page	6529
File Format	PDF
ISSN	00221767
e-ISSN	15506606
Journal	Journal of immunology (Baltimore, Md. : 1950)
Issue Number	11
Volume Number	184
Language	English
Publisher Date	2010-06-01
Access Restriction	Open
Subject Keyword	Medicine(all) Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Immunology

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