Structure-Based Design and Synthesis of Potent, Ethylenediamine-Based, Mammalian Farnesyltransferase Inhibitors as Anticancer Agents
| Autor: | Sung Youn Chang, Lorena S. Beese, Matthew P. Glenn, Said M. Sebti, Michael A. Hast, Ryan J. Floyd, Erin Pusateri Keaney, William P. Katt, Christopher G. Cummings, Andrew D. Hamilton, Michael H. Gelb, Steven Fletcher, Cynthia Bucher, Wesley C. Van Voorhis, Michelle A. Blaskovich |
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| Rok vydání: | 2010 |
| Předmět: |
Models
Molecular Stereochemistry Farnesyltransferase Plasmodium falciparum Prenyltransferase Farnesyl pyrophosphate Antineoplastic Agents Crystallography X-Ray Article Cell Line Structure-Activity Relationship chemistry.chemical_compound Catalytic Domain Nitriles Drug Discovery Animals Farnesyltranstransferase Humans Structure–activity relationship Moiety chemistry.chemical_classification Sulfonamides Aniline Compounds Molecular Structure biology Active site Ethylenediamines In vitro Rats Enzyme chemistry Drug Design biology.protein Molecular Medicine Protein Binding |
| Zdroj: | Journal of Medicinal Chemistry. 53:6867-6888 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm1001748 |
| Popis: | A potent class of anticancer, human farnesyltransferase (hFTase) inhibitors has been identified by “piggy-backing” on potent, antimalarial inhibitors of Plasmodium falciparum farnesyltransferase (PfFTase). On the basis of a 4-fold substituted ethylenediamine scaffold, the inhibitors are structurally simple and readily derivatized, facilitating the extensive structure–activity relationship (SAR) study reported herein. Our most potent inhibitor is compound 1f, which exhibited an in vitro hFTase IC50 value of 25 nM and a whole cell H-Ras processing IC50 value of 90 nM. Moreover, it is noteworthy that several of our inhibitors proved highly selective for hFTase (up to 333-fold) over the related prenyltransferase enzyme geranylgeranyltransferase-I (GGTase-I). A crystal structure of inhibitor 1a co-crystallized with farnesyl pyrophosphate (FPP) in the active site of rat FTase illustrates that the para-benzonitrile moiety of 1a is stabilized by a π–π stacking interaction with the Y361β residue, suggesting a structural explanation for the observed importance of this component of our inhibitors. |
| Databáze: | OpenAIRE |
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