title: Structure-guided design of alpha-amino acid-derived Pin1 inhibitors.
abstract: 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.
authors.affiliation: Vernalis (R&D) Ltd, Granta Park, Great Abington, Cambridge CB21 6GB, United Kingdom.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Potter
authors.forename: Stuart
authors.initials: S
authors.lastname: Ray
authors.forename: Louisa
authors.initials: L
authors.lastname: Gueritz
authors.forename: Claire L
authors.initials: CL
authors.lastname: Nunns
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Bryant
authors.forename: Simon F
authors.initials: SF
authors.lastname: Scrace
authors.forename: Natalia
authors.initials: N
authors.lastname: Matassova
authors.forename: Lisa
authors.initials: L
authors.lastname: Baker
authors.forename: Pawel
authors.initials: P
authors.lastname: Dokurno
authors.forename: David A
authors.initials: DA
authors.lastname: Robinson
authors.forename: Allan E
authors.initials: AE
authors.lastname: Surgenor
authors.forename: Ben
authors.initials: B
authors.lastname: Davis
authors.forename: James B
authors.initials: JB
authors.lastname: Murray
authors.forename: Christine M
authors.initials: CM
authors.lastname: Richardson
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Moore
mesh_terms: 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
chemical_list: 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