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Structure-based design and synthesis of potent, ethylenediamine-based, mammalian farnesyltransferase inhibitors as anticancer agents.
Title | Structure-based design and synthesis of potent, ethylenediamine-based, mammalian farnesyltransferase inhibitors as anticancer agents. |
Publication Type | Journal Article |
Year of Publication | 2010 |
Authors | Fletcher, S, Keaney, EP, Cummings, CG, Blaskovich, MA, Hast, MA, Glenn, MP, Chang, S-Y, Bucher, CJ, Floyd, RJ, Katt, WP, Gelb, MH, Van Voorhis, WC, Beese, LS, Sebti, SM, Hamilton, AD |
Journal | J Med Chem |
Volume | 53 |
Issue | 19 |
Pagination | 6867-88 |
Date Published | 2010 Oct 14 |
ISSN | 1520-4804 |
Keywords | Aniline Compounds, Animals, Antineoplastic Agents, Catalytic Domain, Cell Line, Crystallography, X-Ray, Drug Design, Ethylenediamines, Farnesyltranstransferase, Humans, Models, Molecular, Molecular Structure, Nitriles, Plasmodium falciparum, Protein Binding, Rats, Structure-Activity Relationship, Sulfonamides |
Abstract | 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 IC(50) value of 25 nM and a whole cell H-Ras processing IC(50) 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. |
DOI | 10.1021/jm1001748 |
Alternate Journal | J. Med. Chem. |
PubMed ID | 20822181 |