title: Structure-based design and synthesis of potent, ethylenediamine-based, mammalian farnesyltransferase inhibitors as anticancer agents.
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.
authors.affiliation: Department of Chemistry, Yale University, 225 Prospect Street, New Haven, Connecticut 06511, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Fletcher
authors.forename: Erin Pusateri
authors.initials: EP
authors.lastname: Keaney
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Cummings
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Blaskovich
authors.forename: Michael A
authors.initials: MA
authors.lastname: Hast
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Glenn
authors.forename: Sung-Youn
authors.initials: SY
authors.lastname: Chang
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Bucher
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Floyd
authors.forename: William P
authors.initials: WP
authors.lastname: Katt
authors.forename: Michael H
authors.initials: MH
authors.lastname: Gelb
authors.forename: Wesley C
authors.initials: WC
authors.lastname: Van Voorhis
authors.forename: Lorena S
authors.initials: LS
authors.lastname: Beese
authors.forename: Said M
authors.initials: SM
authors.lastname: Sebti
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Hamilton
mesh_terms: D000814:Aniline Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain; D002460:Cell Line; D018360:Crystallography, X-Ray; D015195:Drug Design; D005029:Ethylenediamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000201:enzymology; D011485:Protein Binding; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D005029:Ethylenediamines; D009570:Nitriles; D013449:Sulfonamides; C031234:ethylenediamine; D051231:Farnesyltranstransferase
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