Inhibition of CD45 phosphatase activity induces cell cycle arrest and apoptosis of CD45+ lymphoid tumors ex vivo and in vivo

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摘要：

Src-family kinases (SFK) govern cellular proliferation of bone marrow derived cells. SFKs are regulated by the protein tyrosine phosphatase enzymatic activity of CD45. All lymphoid cells express CD45 but only proliferating cells are dependent on CD45 activity. We postulated that a selective inhibitor of CD45 phosphatase activity, compound 211, could preferentially affect actively proliferating cells, but spare resting lymphoid cells. Compound 211 inhibited CD45 and induced inappropriate SFK signalling, leading to a G2/M cell cycle arrest and apoptotic cell death. CD45+ cell lines were sensitive to 211 cytotoxicity at low M LD50 while control CD45- cell lines and CD45+ resting primary T cells were spared any toxicity. In two syngeneic tumor models in vivo 211 delayed the growth of established primary tumors, and reduced tumor metastasis; without causing depletion of resting T cells. This work validates targeting CD45 phosphatase enzymatic activity, which may be a druggable target for cancer therapy.

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DOI：

10.1124/mol.117.110908

年份：

2018