Structure-based design of selective and potent inhibitors of protein-tyrosine phosphatase beta.
Protein-tyrosine phosphatases (PTPs) are considered important therapeutic targets because of their pivotal role as regulators of signal transduction and thus their implication in several human diseases such as diabetes, cancer, and autoimmunity. In particular, PTP1B has been the focus of many academic and industrial laboratories because it was found to be an important negative regulator of insulin and leptin signaling, and hence a potential therapeutic target in diabetes and obesity. As a result, significant progress has been achieved in the design of highly selective and potent PTP1B inhibitors. In contrast, little attention has been given to other potential drug targets within the PTP family. Guided by x-ray crystallography, molecular modeling, and enzyme kinetic analyses with wild type and mutant PTPs, we describe the development of a general, low molecular weight, non-peptide, non-phosphorus PTP inhibitor into an inhibitor that displays more than 100-fold selectivity for PTPbeta over PTP1B. Of note, our structure-based design principles, which are based on extensive bioinformatics analyses of the PTP family, are general in nature. Therefore, we anticipate that this strategy, here applied to PTPbeta, in principle can be used in the design and development of selective inhibitors of many, if not most PTPs.
Lund
Ida Katrine
IK
Signal Transduction, Protein Science, Novo Nordisk A/S, DK-2880 Bagsvaerd, Denmark.
Andersen
Henrik Sune
HS
Iversen
Lars Fogh
LF
Olsen
Ole Hvilsted
OH
Møller
Karin Bach
KB
Pedersen
Anja Kallesøe
AK
Ge
Yu
Y
Holsworth
Daniel D
DD
Newman
Michael J
MJ
Axe
Frank U
FU
Møller
Niels Peter Hundahl
NP
D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006860:Hydrogen Bonding; D007328:Insulin / Q000378:metabolism; D007700:Kinetics; D020738:Leptin / Q000378:metabolism; D008024:Ligands; D008956:Models, Chemical; D008958:Models, Molecular; D009154:Mutation; D010797:Phthalimides / Q000737:chemistry; D011487:Protein Conformation; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D013696:Temperature
D004791:Enzyme Inhibitors; D007328:Insulin; D020738:Leptin; D008024:Ligands; D010797:Phthalimides; C037431:phthalimide; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases