Structure-based design and synthesis of potent, ethylenediamine-based, mammalian farnesyltransferase inhibitors as anticancer agents.
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.
Fletcher
Steven
S
Department of Chemistry, Yale University, 225 Prospect Street, New Haven, Connecticut 06511, USA.
Keaney
Erin Pusateri
EP
Cummings
Christopher G
CG
Blaskovich
Michelle A
MA
Hast
Michael A
MA
Glenn
Matthew P
MP
Chang
Sung-Youn
SY
Bucher
Cynthia J
CJ
Floyd
Ryan J
RJ
Katt
William P
WP
Gelb
Michael H
MH
Van Voorhis
Wesley C
WC
Beese
Lorena S
LS
Sebti
Said M
SM
Hamilton
Andrew D
AD
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
D000814:Aniline Compounds; D000970:Antineoplastic Agents; D005029:Ethylenediamines; D009570:Nitriles; D013449:Sulfonamides; C031234:ethylenediamine; D051231:Farnesyltranstransferase
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