Biochemical and Structural Characterization of a Novel Class of Inhibitors of the Type 1 Insulin-like Growth Factor and Insulin Receptor Kinases

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• 作者：Ian M. Bell ; Steven M. Stirdivant ; Janet Ahern ; J. Christopher Culberson ; Paul L. Darke ; Christopher J. Dinsmore ; Robert A. Drakas ; Steven N. Gallicchio ; Samuel L. Graham ; David C. Heimbrook ; Dawn L.
• 刊名：Biochemistry
• 出版年：2005
• 出版时间：July 12, 2005
• 年：2005
• 卷：44
• 期：27
• 页码：9430 - 9440
• 全文大小：284K
• 年卷期：v.44,no.27(July 12, 2005)
• ISSN：1520-4995

文摘

The type 1 insulin-like growth factor receptor (IGF-1R) is often overexpressed on tumor cellsand is believed to play an important role in anchorage-independent proliferation. Additionally, cell culturestudies have indicated that IGF-1R confers increased resistance to apoptosis caused by radiation orchemotherapeutic agents. Thus, inhibitors of the intracellular kinase domain of this receptor may haveutility for the clinical treatment of cancer. As part of an effort to develop clinically useful inhibitors ofIGF-1R kinase, a novel class of pyrrole-5-carboxaldehyde compounds was investigated. The compoundsexhibited selectivity against the closely related insulin receptor kinase intrinsically and in cell-based assays.The inhibitors formed a reversible, covalent adduct at the kinase active site, and treatment of such adductswith sodium borohydride irreversibly inactivated the enzyme. Analysis of a tryptic digest of a covalentlymodified IGF-1R kinase fragment revealed that the active site Lys1003 had been reductively alkylatedwith the aldehyde inhibitor. Reductive alkylation of the insulin receptor kinase with one of these inhibitorsled to a similarly inactivated enzyme which was examined by X-ray crystallography. The crystal structureconfirmed the modification of the active site lysine side chain and revealed details of the key interactionsbetween the inhibitor and enzyme.