Discovery of the first non-ATP competitive IGF-1R kinase inhibitors: Advantages in comparison with competitive inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 21, Issue 8, 2011, Pages 2224-2228

  Lesuisse, Dominique ^b   Mauger, Jacques ^a   Nemecek, Conception ^b   Maignan, Sébastien ^b   Boiziau, Janine ^b   Harlow, Greg ^a   Hittinger, Augustin ^b   Ruf, Swen ^c   Strobel, Hartmut ^c   Nair, Anil ^a   Ritter, Kurt ^c   Malleron, Jean Luc ^b   Dagallier, Anne ^b   El Ahmad, Youssef ^b   Guilloteau, Jean Pierre ^b   Guizani, Houlfa ^b   Bouchard, Hervé ^b   Venot, Corinne ^b  

^a Sanofi aventis   (United States)

^b SANOFI   (France)

^c SANOFI AVENTIS DEUTSCHLAND GMBH   (Germany)

Author keywords

ATP; IGF 1R; Kinase inhibitors; Noncompetitive; Slow binding inhibitor

Indexed keywords

HYDANTOIN DERIVATIVE; PROTEIN KINASE INHIBITOR; SOMATOMEDIN C RECEPTOR;

ARTICLE; BINDING COMPETITION; DRUG SELECTIVITY; DRUG SYNTHESIS; ENZYME INHIBITION; HIGH THROUGHPUT SCREENING;

ADENOSINE TRIPHOSPHATE; ANIMALS; BINDING SITES; BINDING, COMPETITIVE; COMPUTER SIMULATION; DRUG EVALUATION, PRECLINICAL; MICE; PROTEIN KINASE INHIBITORS; RECEPTOR, IGF TYPE 1;

EID: 79953291096     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2011.03.003     Document Type: Article

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10. 2, 50 mM NaCl, 3% glycerol, 0.025% Tween 20, 120 μM adenosine triphosphate. Enzyme reactions were terminated by the addition of 100 mM Hepes buffer pH 7.0, containing 0.4 M KF, 133 mM EDTA, BSA 0.1% containing an anti-GST antibody labelled with XL665 and an anti-phosphotyrosine antibody conjugated to a europium cryptate (Eu-K). Features of the two fluorophores, XL-665 and Eu-K are given in Mathis et al., Anticancer Res. 1997, 17, 3011. The specific long time signal of XL-665, produced only when the IGF1R enzyme is autophosphorylated, was measured on a Victor analyser (Perkin-Elmer). Inhibition of IGF1R kinase activity with compounds of the invention was expressed as percentage inhibition of control activity exhibited in the absence of test compounds.
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