Structure-based design and discovery of protein tyrosine phosphatase inhibitors incorporating novel isothiazolidinone heterocyclic phosphotyrosine mimetics.
Structure-based design led to the discovery of novel (S)-isothiazolidinone ((S)-IZD) heterocyclic phosphotyrosine (pTyr) mimetics that when incorporated into dipeptides are exceptionally potent, competitive, and reversible inhibitors of protein tyrosine phosphatase 1B (PTP1B). The crystal structure of PTP1B in complex with our most potent inhibitor 12 revealed that the (S)-IZD heterocycle interacts extensively with the phosphate binding loop precisely as designed in silico. Our data provide strong evidence that the (S)-IZD is the most potent pTyr mimetic reported to date.
Combs
Andrew P
AP
Discovery Chemistry, Incyte Corporation, Experimental Station, E336/132A, Route 141 and Henry Clay Road, Wilmington, DE 19880, USA. acombs@incyte.com
Yue
Eddy W
EW
Bower
Michael
M
Ala
Paul J
PJ
Wayland
Brian
B
Douty
Brent
B
Takvorian
Amy
A
Polam
Padmaja
P
Wasserman
Zelda
Z
Zhu
Wenyu
W
Crawley
Matthew L
ML
Pruitt
James
J
Sparks
Richard
R
Glass
Brian
B
Modi
Dilip
D
McLaughlin
Erin
E
Bostrom
Lori
L
Li
Mei
M
Galya
Laurine
L
Blom
Karl
K
Hillman
Milton
M
Gonneville
Lucie
L
Reid
Brian G
BG
Wei
Min
M
Becker-Pasha
Mary
M
Klabe
Ronald
R
Huber
Reid
R
Li
Yanlong
Y
Hollis
Gregory
G
Burn
Timothy C
TC
Wynn
Richard
R
Liu
Phillip
P
Metcalf
Brian
B
D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry; D015195:Drug Design; D008958:Models, Molecular; D018716:Molecular Mimicry; D019000:Phosphotyrosine / Q000737:chemistry*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship; D013237:Stereoisomerism; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry
D004151:Dipeptides; D013844:Thiazoles; D019000:Phosphotyrosine; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases