title: Structure-based design of novel human Pin1 inhibitors (I).
abstract: Pin1 is a member of the cis-trans peptidyl-prolyl isomerase family with potential anti-cancer therapeutic value. Here we report structure-based de novo design and optimization of novel Pin1 inhibitors. Without a viable lead from internal screenings, we designed a series of novel Pin1 inhibitors by interrogating and exploring a protein crystal structure of Pin1. The ligand efficiency of the initial concept molecule was optimized with integrated SBDD and parallel chemistry approaches, resulting in a more attractive lead series.
authors.affiliation: Pfizer Global Research and Development, 10770 Science Center Drive, San Diego, CA 92121, USA. alex.guo@pfizer.com
authors.forename: Chuangxing
authors.initials: C
authors.lastname: Guo
authors.forename: Xinjun
authors.initials: X
authors.lastname: Hou
authors.forename: Liming
authors.initials: L
authors.lastname: Dong
authors.forename: Eleanor
authors.initials: E
authors.lastname: Dagostino
authors.forename: Samantha
authors.initials: S
authors.lastname: Greasley
authors.forename: Roseann
authors.initials: R
authors.lastname: Ferre
authors.forename: Joseph
authors.initials: J
authors.lastname: Marakovits
authors.forename: M Catherine
authors.initials: MC
authors.lastname: Johnson
authors.forename: David
authors.initials: D
authors.lastname: Matthews
authors.forename: Barbara
authors.initials: B
authors.lastname: Mroczkowski
authors.forename: Hans
authors.initials: H
authors.lastname: Parge
authors.forename: Todd
authors.initials: T
authors.lastname: Vanarsdale
authors.forename: Ian
authors.initials: I
authors.lastname: Popoff
authors.forename: Joseph
authors.initials: J
authors.lastname: Piraino
authors.forename: Stephen
authors.initials: S
authors.lastname: Margosiak
authors.forename: James
authors.initials: J
authors.lastname: Thomson
authors.forename: Gerrit
authors.initials: G
authors.lastname: Los
authors.forename: Brion W
authors.initials: BW
authors.lastname: Murray
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D020650:Combinatorial Chemistry Techniques; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase