Inhibiting the Insulin growth factor signaling by targeting IRS proteins for destruction is a potent anti-tumor strategy

Our laboratory has been developing tyrphostin inhibitors aimed at the IGF1R signaling pathway since 1997(1). Over the years we developed substrate competitive IGF1R kinase inhibitors (2-4). Based on these studies we discovered a family of tyrphostins, named NTs, which act as allosteric effectors of IGF1R. In metastatic melanoma cells, these IGF1R inhibitors lead to the translocation of the IGF1R substrates IRS1 and IRS2 from their IGF1R docking site to the cytosol, enabling Shc to replace it on the shared docking site. Shc binding leads to the activation of the Ras-Raf-ErkMAPK pathway, which leads to an inhibitory serine phosphorylation and irreversible degradation of the IRS proteins, resulting in long-lasting inhibition of the IGF1R pathway. These NT compounds inhibit the growth of a many cancer cell types, and possess potent anti-tumor effects on B-RAFV600E-driven and PLX4032-resistant metastatic melanoma, on ovarian and prostate cancer, in nude mice. These inhibitors may play a therapeutic role in significant number of cancers since IRS1 plays a crucial role in cancer cell proliferation in many human malignancies and its up-regulation mediates resistance to anti-cancer drugs, including signal transduction inhibitors such as Tarceva. Targeting IRS2 is also highly significant, since it is associated with cancer cell motility and metastasis.