2ZM3

Complex Structure of Insulin-like Growth Factor Receptor and Isoquinolinedione Inhibitor

Summary for 2ZM3

• Entry DOI: 10.2210/pdb2zm3/pdb
• Related: 1JQH
• Descriptor: Insulin-like growth factor 1 receptor, (4Z)-6-bromo-4-({[4-(pyrrolidin-1-ylmethyl)phenyl]amino}methylidene)isoquinoline-1,3(2H,4H)-dione (3 entities in total)
• Functional Keywords: igfr, protein-inhibitor complex, tyrosine kinase, atp-binding, cleavage on pair of basic residues, disease mutation, glycoprotein, membrane, nucleotide-binding, phosphoprotein, polymorphism, receptor, transferase, transmembrane, tyrosine-protein kinase
• Biological source: Homo sapiens (Human)
• Cellular location: Membrane; Single-pass type I membrane protein: P08069
• Total number of polymer chains: 4
• Total formula weight: 143073.80

Authors

Xu, W.,Mayer, S.C.,Boschelli, F.,Johnson, M.,Dwyer, B. (deposition date: 2008-04-10, release date: 2008-06-10, Last modification date: 2024-10-30)

Primary citation

Mayer, S.C.,Banker, A.L.,Boschelli, F.,Di, L.,Johnson, M.,Kenny, C.H.,Krishnamurthy, G.,Kutterer, K.,Moy, F.,Petusky, S.,Ravi, M.,Tkach, D.,Tsou, H.R.,Xu, W.
Lead identification to generate isoquinolinedione inhibitors of insulin-like growth factor receptor (IGF-1R) for potential use in cancer treatment
Bioorg.Med.Chem.Lett., 18:3641-3645, 2008

PubMed Abstract: Insulin-like growth factor receptor (IGF-1R) is a growth factor receptor tyrosine kinase that acts as a critical mediator of cell proliferation and survival. This receptor is over-expressed or activated in tumor cells and is emerging as a novel target in cancer therapy. Efforts in our "Hit to Lead" group have generated a novel series of submicromolar IGF-1R inhibitors based on a isoquinolinedione template originating from a Lance enzyme HTS screen. Chemical triage and parallel synthesis incorporating focused library arrays were instrumental in moving these investigations through the Wyeth exploratory medicinal chemistry process. The strategies, synthesis, and SAR behind this interesting kinase scaffold will be described.

PubMed: 18501599
DOI: 10.1016/j.bmcl.2008.04.044

Experimental method

X-RAY DIFFRACTION (2.5 Å)