PMID: 12769709May 29, 2003Paper

Inhibitors of farnesyltransferase and geranylgeranyltransferase-I for antitumor therapy: substrate-based design, conformational constraint and biological activity

Current Topics in Medicinal Chemistry
Christopher J Dinsmore, Ian M Bell

Abstract

The development of farnesyltransferase inhibitors, a novel approach to non-cytotoxic anticancer therapy, has been an active area of research over the past decade. Compounds that have advanced to clinical trials were evolved both from substrate-based design efforts and from compound library screening hits. This review focuses on the effort at Merck to evolve inhibitors from the protein substrate of farnesyltransferase, which resulted in the identification of a non-peptide inhibitor for clinical evaluation. X-ray crystal structures of farnesyltransferase complexed with early peptidomimetic as well as later non-peptide inhibitors have validated this design approach. NMR spectroscopic methods for studying enzyme-bound inhibitor structure, in conjunction with the use of conformational constraints, were critical components of subsequent efforts to provide potent inhibitors with varying levels of farnesyltransferase and geranylgeranyltransferase-I inhibitory specificity. Several of these compounds were important tools for investigating the use of prenyltransferase inhibitors to target Ki-Ras-mediated tumor growth.

Citations

Apr 15, 2004·Bioorganic & Medicinal Chemistry Letters·Xiao-Hui Liu, Glenn D Prestwich
Dec 17, 2015·Molecular Neurobiology·Shangfeng GaoXiuping Zhou
Nov 17, 2009·Journal of Enzyme Inhibition and Medicinal Chemistry·Aihua XieRobert J Doerksen
Jul 12, 2005·Angewandte Chemie·Matthew P GlennAndrew D Hamilton
May 24, 2007·Journal of Enzyme Inhibition and Medicinal Chemistry·Devendra S PuntambekarMange Ram Yadav
Mar 1, 2013·MedChemComm·Joshua D Ochocki, Mark D Distefano
Jul 6, 2014·Current Reviews in Musculoskeletal Medicine·Guilherme Figueiredo PintanMario Ferretti
Sep 24, 2005·The Oncologist·Natalie M G M AppelsJan H M Schellens
Jan 27, 2004·Bioorganic & Medicinal Chemistry Letters·Christopher J DinsmoreTheresa M Williams
Jun 25, 2018·Protein Expression and Purification·Lauren ProcterDominic Esposito

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