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Anastassiadis T , Duong-Ly KC , Deacon SW , Lafontant A , Ma H , Devarajan K , Dunbrack RL Jr , Wu J , Peterson JR
A highly selective dual insulin receptor (IR)/insulin-like growth factor 1 receptor (IGF-1R) inhibitor derived from an extracellular signal-regulated kinase (ERK) inhibitor
J Biol Chem. 2013 Sep 27;288(39) :28068-77
PMID: 23935097    PMCID: PMC3784719   
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Dual inhibitors of the closely related receptor tyrosine kinases insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor (IR) are promising therapeutic agents in cancer. Here, we report an unusually selective class of dual inhibitors of IGF-1R and IR identified in a parallel screen of known kinase inhibitors against a panel of 300 human protein kinases. Biochemical and structural studies indicate that this class achieves its high selectivity by binding to the ATP-binding pocket of inactive, unphosphorylated IGF-1R/IR and stabilizing the activation loop in a native-like inactive conformation. One member of this compound family was originally reported as an inhibitor of the serine/threonine kinase ERK, a kinase that is distinct in the structure of its unphosphorylated/inactive form from IR/IGF-1R. Remarkably, this compound binds to the ATP-binding pocket of ERK in an entirely different conformation to that of IGF-1R/IR, explaining the potency against these two structurally distinct kinase families. These findings suggest a novel approach to polypharmacology in which two or more unrelated kinases are inhibited by a single compound that targets different conformations of each target kinase.
Anastassiadis, Theonie Duong-Ly, Krisna C Deacon, Sean W Lafontant, Alec Ma, Haiching Devarajan, Karthik Dunbrack, Roland L Jr Wu, Jinhua Peterson, Jeffrey R GM083025/GM/NIGMS NIH HHS/United States P30 CA006927/CA/NCI NIH HHS/United States T32 CA009035-36/CA/NCI NIH HHS/United States Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't United States J Biol Chem. 2013 Sep 27;288(39):28068-77. doi: 10.1074/jbc.M113.505032. Epub 2013 Aug 9.