Inhibition of CD45 phosphatase activity induces cell cycle arrest and apoptosis of CD451 lymphoid tumors ex vivo and in vivo

Abstract

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 compound 211 (2-[(4-acetylphenyl)amino]-3-chloronaphthoquinone), a selective inhibitor of CD45 phosphatase activity, could preferentially affect actively proliferating cells but spare resting lymphoid cells. Compound 211 inhibited CD45 and induced inappropriate SFK signaling, leading to a G2/M cell cycle arrest and apoptotic cell death. CD451 cell lines were sensitive to compound 211 cyto-toxicity at low micromolar LD50 while control CD452 cell lines and CD451 resting primary T cells were spared any toxicity. In two syngeneic tumor models in vivo, compound 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.