title: Development of new insulin-like growth factor-1 receptor kinase inhibitors using catechol mimics.
abstract: Because insulin-like growth factor-1 (IGF-1) and its receptor play a pivotal role in many cancers, it is an attractive target for the design of inhibitors. Here we present a new family of bioisostere inhibitors, based on the structure of AG 538. AG 538 is a substrate-competitive inhibitor of the IGF-1 receptor (IGF-1R), with an IC50 = 61 nM in a cell-free kinase assay (Blum, G., Gazit, A., and Levitzki, A. (2000) Biochemistry 39, 15705-15712). AG 538 is a low molecular weight compound containing two catechol rings, which are sensitive to oxidation in cells. We have therefore prepared and examined catechol bioisosteres of AG 538. These AG 538 bioisosteres possess similar biological properties to AG 538; they inhibit IGF-1R by a substrate-competitive mechanism and are non-competitive vis à vis ATP. They inhibit IGF-1R kinase activity in the sub-micromolar concentration range in cell-free assays. IGF-1 induced IGF-1R autophosphorylation; IRS-1 phosphorylation and protein kinase B activation are inhibited at a low micromolar concentration range when applied to intact cells. These inhibitors also block the formation of colonies in soft agar by prostate and breast cancer cells. The ability to replace catechol groups with a moiety that is more stable in cells may aid in developing non-catechol-containing substrate-competitive inhibitors targeted toward IGF-1R and possibly against other protein-tyrosine kinases.
authors.affiliation: Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Givat Ram, Jerusalem 91904, Israel.
authors.forename: Galia
authors.initials: G
authors.lastname: Blum
authors.forename: Aviv
authors.initials: A
authors.lastname: Gazit
authors.forename: Alexander
authors.initials: A
authors.lastname: Levitzki
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D002396:Catechols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008956:Models, Chemical; D041681:NIH 3T3 Cells; D010100:Oxygen / Q000378:metabolism; D010766:Phosphorylation; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: C419770:AG 538; D002396:Catechols; D004791:Enzyme Inhibitors; D020032:Tyrphostins; D000255:Adenosine Triphosphate; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; C034221:catechol; D010100:Oxygen