The Src family of non-receptor tyrosine kinases regulate cell adhesion, growth, and differentiation through activation of multiple intracellular signaling pathways. Normally inactive, Src kinases are transiently activated during mitosis and constitutively activated by abnormal mutations. PP1 is a potent, reversible, ATP-competitive, and selective inhibitor of the Src family of protein tyrosine kinases. It inhibits p56lck (IC50 = 5 nM), p59fynT (IC50 = 6 nM), Hck (IC50 = 20 nM), and Src (IC50 = 170 nM) without significantly affecting the activity of EGFR kinase (IC50 = 250 nM), JAK2 (IC50 = 50 μM), or ZAP-70 (IC50 ≥ 0.6 μM). PP1 inhibits anti-CD3-induced tyrosine phosphorylation of human T cells with an IC50 value of 600 nM. It exhibits antitumor activity by antagonizing both proliferation and the inhibition of apoptosis mediated by a stem cell factor/mast cell growth factor in hematopoietic and small cell lung cancer cell lines. PP1 also blocks TGF-β-mediated cellular responses by directly inhibiting type I TGF-β receptors (IC50 = 50 nM) in a manner unrelated to Src signaling.
