Melanoma Molecular Maps Projects



Title: List of IGF1R inhibitors
Legend: The insulin-like growth factor 1 receptor (IGF1R) is a receptor tyrosine kinase (RTK) that functions as a heterotetramer (2 extracellular ligand binding alpha subunits + 2 beta subunits comprising transmembrane and TK domains). Ligand binding induces TK activity. Docking proteins SRC homology 2 domain-containing (SHC) protein and insulin receptor substrates (IRS1, IRS2) are then activated by phosphorylation and the signal is propagated via the MAPK and the PI3K/Akt pathway, respectively. IGF1R is highly homologous to both splice variants of the insulin receptor (IR-A, IR-B), which allows formation of hybrid receptors and explains the strict interaction between the two signaling pathways. IGF1 is the main ligand for IGF1R and hybrid receptors. Insulin binds to its receptor and to hybrid receptors. IGF2 binds to IGF1R, hybrid receptors and insulin receptor. IGF1R is ubiquitously expressed. IGF1 is typically produced by fibroblasts upon activation of the growth hormone (GH) pathway; IGF binding proteins (IGFBP) regulate IGF1 and IGF2 transport to target tissues and interaction with receptors. In physiology IGF1R is mainly involved in body growth, development and metabolism. In oncology, according to preclinical cancer models (including melanoma), it promotes cell proliferation, antiapoptotic activity (> therapeutics resistance) and metastatic potential. Several anti-IGF1R therapeutics have been developed (mainly blocking antibodies and tyrosine kinase inhibitors, TKI). Examples: 19D12 (SCH 717454), AMG-479, AVE-1642, BIIB022, BMS-536,924 , BMS-554,417 , CP-751,851 , Di-diabody, EXEL-228, H7C10, IGF1R antisense, IGF1R interference, IMC-A12, Insm-18, MK0466, NVP-ADW742, NVP-AEW541, OSI-906, Picropodophyllin (cyclolignan PPP), PQ401, R1507, TAE226. REFERENCES: [1] Hartog H et al, Eur J Cancer 2007, 4 3:1895-904. [2] Clemmons DR, Nat Rev Drug Discov 2007, 6:821-33. [3] Larsson O et al, Br J Cancer 2007, 96 Suppl:R2-6. [4] Yeh AH et al, Oncogene 2006, 25:6574-81
Author: The MMMP Team (updated: Mar 2008)

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