Targeting SHP-1,2 and SHIP pathways – a novel strategy for cancer treatment?

Well balanced levels of tyrosine phosphorylation, maintained by the reversible and coordinated actions of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs), are critical for a wide range of cellular processes including growth, differentiation, metabolism, migration, and survival. Aberrant tyrosine phosphorylation, as a result of a perturbed balance between the activities of PTKs and PTPs, however, is linked to the pathogenesis of numerous human diseases, including cancer, suggesting that PTPs may be innovative molecular targets for cancer treatment. Two PTPs that have an important inhibitory role in lymphocytes and other haematopoietic cells are SHP-1 and SHP-2 (SH2 domain-containing phosphatases 1 and 2), SHP-1,2 have been shown to promote cell growth and act by both upregulating positive signaling pathways and by downregulating negative signaling pathways. SHIP (SH2 domain-containing inositol phosphatase) is another inhibitory phosphatase that is rather specific for the inositol phospholipid phosphatidylinositol-3,4,5-trisphosphate (PIP3). SHIP acts as a negative regulator of immune response by hydrolysing PIP3, and, as a result, a SHIP defiency results in myeloproliferation and B cell lymphoma in mice. This strong validation of SHP-1,2 and SHIP as oncology targets has generated considerable interest in the development of small molecule inhibitors as potential therapeutic agents for haematologic malignancies and solid tumours, however, SHP-1,2 and SHIP have proven to be an extremely difficult target for drug discovery, due primarily to the highly conserved and positively charged nature of its PTP active site. The majority of reported PTP inhibitors lack either appropriate selectivity or membrane permeability, limiting their utility in modulating the activity of the intracellular PTPs. In order to overcome these caveats novel techniques have been employed to synthesise new inhibitors that specifically attentuate the PTP-dependent signaling inside the cell and amongst them some are already in clinical development (e.g., SHP-1 inhibitor sodium stibogluconate; SHP-2 inhibitor TNO155; SHIP-1 activator AQX-1125). In this review the mechanisms of action and the clinical development of newly available SHP-1,2 and SHIP inhibitors and activators are decribed and the major issues facing this rapidly evolving field are discussed.