Structure-based design of novel human Pin1 inhibitors (I).
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.
Guo
Chuangxing
C
Pfizer Global Research and Development, 10770 Science Center Drive, San Diego, CA 92121, USA. alex.guo@pfizer.com
Hou
Xinjun
X
Dong
Liming
L
Dagostino
Eleanor
E
Greasley
Samantha
S
Ferre
Roseann
R
Marakovits
Joseph
J
Johnson
M Catherine
MC
Matthews
David
D
Mroczkowski
Barbara
B
Parge
Hans
H
Vanarsdale
Todd
T
Popoff
Ian
I
Piraino
Joseph
J
Margosiak
Stephen
S
Thomson
James
J
Los
Gerrit
G
Murray
Brion W
BW
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
D004791:Enzyme Inhibitors; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase