Structure-based design of imidazole-containing peptidomimetic inhibitors of protein farnesyltransferase.
A series of imidazole-containing peptidomimetic PFTase inhibitors and their co-crystal structures bound to PFTase and FPP are reported. The structures reveal that the peptidomimetics adopt a similar conformation to that of the extended CVIM tetrapeptide, with the imidazole group coordinating to the catalytic zinc ion. Both mono- and bis-imidazole-containing derivatives, 13 and 16, showed remarkably high enzyme inhibition activity against PFTase in vitro with IC50 values of 0.86 and 1.7 nM, respectively. The peptidomimetics were also highly selective for PFTase over PGGTase-I both in vitro and in intact cells. In addition, peptidomimetics and were found to suppress tumor growth in nude mouse xenograft models with no gross toxicity at a daily dose of 25 mg kg(-1).
Ohkanda
Junko
J
Department of Chemistry, Yale University, PO Box 208107, New Haven, CT 06520, USA.
Strickland
Corey L
CL
Blaskovich
Michelle A
MA
Carrico
Dora
D
Lockman
Jeffrey W
JW
Vogt
Andreas
A
Bucher
Cynthia J
CJ
Sun
Jiazhi
J
Qian
Yimin
Y
Knowles
David
D
Pusateri
Erin E
EE
Sebti
Saïd M
SM
Hamilton
Andrew D
AD
D000818:Animals; D002460:Cell Line; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000737:chemistry*; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
D004791:Enzyme Inhibitors; D007093:Imidazoles; D010455:Peptides; C029899:imidazole; D051231:Farnesyltranstransferase