Structure-guided design of alpha-amino acid-derived Pin1 inhibitors.
The peptidyl prolyl cis/trans isomerase Pin1 is a promising molecular target for anti-cancer therapeutics. Here we report the structure-guided evolution of an indole 2-carboxylic acid fragment hit into a series of alpha-benzimidazolyl-substituted amino acids. Examples inhibited Pin1 activity with IC(50) <100nM, but were inactive on cells. Replacement of the benzimidazole ring with a naphthyl group resulted in a 10-50-fold loss in ligand potency, but these examples downregulated biomarkers of Pin1 activity and blocked proliferation of PC3 cells.
Potter
Andrew J
AJ
Vernalis (R&D) Ltd, Granta Park, Great Abington, Cambridge CB21 6GB, United Kingdom.
Ray
Stuart
S
Gueritz
Louisa
L
Nunns
Claire L
CL
Bryant
Christopher J
CJ
Scrace
Simon F
SF
Matassova
Natalia
N
Baker
Lisa
L
Dokurno
Pawel
P
Robinson
David A
DA
Surgenor
Allan E
AE
Davis
Ben
B
Murray
James B
JB
Richardson
Christine M
CM
Moore
Jonathan D
JD
D000596:Amino Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001562:Benzimidazoles / Q000737:chemistry; D001665:Binding Sites; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D007211:Indoles / Q000737:chemistry; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D000596:Amino Acids; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D007211:Indoles; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; C030374:indole; C031000:benzimidazole; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase