AZD1080 is a selective orally active brain permeable GSK3 inhibitor

by Selleckchem | Nov 11 2013

The insulin-like growth factor signaling pathway plays an important role in various cellular processes, including proliferation and differentiation . Components of this pathway include azd1080 the ligands IGF1 and IGF2, which exhibit a high degree of sequence homology to insulin; insulin-like growth factor-1 receptor , which contains an extracellular domain that binds both IGFs and an intracellular tyrosine kinase domain that initiates signaling; and IGF2R, which lacks a tyrosine kinase domain and binds IGF2 without initiating signal transduction . The IGF1R and insulin receptor pathways are closely related. IGF1R and IR exhibit extensive sequence similarity, including sequence identity in their ATP binding clefts and at residues that contact the peptide ligands in their binding sites as well as 84% homology in the kinase domain . In both cases, ligand binding results in a conformational change that leads to autophosphorylation of the receptor tyrosine kinase domain; increased phosphorylation of the receptor substrates Shc, IRS-1 and IRS-2; and activation of the same downstream signaling cascades, including the mitogen-activated protein kinase and phosphatidylinositol-3 urb597 kinase /Akt pathways . Indeed, IGF1R and IR are so similar that IGF1R and IR isoform A , a splice variant that is overexpressed in certain carcinomas, can heterodimerize to form hybrid receptors that signal after binding IGF1, IGF2 or insulin at physiologic levels . Moreover, IR-A homodimers can bind IGF2 and, to a lesser extent, IGF1 , suggesting that proliferative IGF signaling can occur through IGF1R homodimers, IGF1R/IR-A heterodimers and IR-A homodimers . In contrast, hybrid receptors containing IGF1R and IR isoform B are orders of magnitude less sensitive to IGF2 and insulin . Uncontrolled IGF1R signaling, which stimulates proliferation and protects cells from apoptosis , has been implicated in the development and maintenance of various neoplasms . As a result, the IGF1/IGF1R axis has become a target for anticancer drug development. Tivantinib Agents currently undergoing preclinical or clinical testing include neutralizing IGF1 antibodies, antagonistic IGF1R antibodies, and small molecule IGF1R tyrosine kinase inhibitors . In view of signaling by IGF1R/IR-A hybrids and IR-A homodimers , as well as the high sequence homology of IGF1R and IR, there has also been recent interest in dual receptor inhibitors. The dual IGF1R/IR inhibitor BMS-554417 exhibited antiproliferative and proapoptotic activity in vitro and in vivo with modest effects on glucose tolerance . BMS-536924 , which is used in the present work, is likewise an ATP-competitive inhibitor of IGF1R and IR that has shown activity against neoplastically transformed cell lines . Although the role of the IGF1 system has been extensively investigated in various solid tumors, less is known about the role of IGF1R and IR in AML. Earlier reports demonstrated that IGF1 enhances colony formation by committed normal myeloid and erythroid progenitors , but more primitive CD34+ normal progenitors lack IGF1R expression and are resistant to IGF1R downregulation . In addition, IGF1 enhances proliferation of human AML cell lines and clonogenic growth of AML progenitors in vitro . More recently, expression of IR as well as IGF1R was demonstrated in AML cell lines and a handful of primary AML specimens. In addition, it was reported that insulin and IGF1 both enhanced the proliferation of AML cells and that downregulation of either IR or IGFR modestly diminished proliferation of U937 cells , raising the possibility that IR signaling also contributes to survival and proliferation of AML cells.