Abstract
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.
Highlights
Introduction of Substituents in Position5 of Compound 4— Primary sequence alignment of Protein-tyrosine phosphatases (PTPs) domains indicates that residues 47 and 48 potentially could be used to obtain selectivity for PTP and against PTP1B (Fig. 3)
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 PTP over PTP1B
The objective of the present study was to investigate if a general, low affinity, and active site-directed PTP inhibitor, which was previously optimized for PTP1B selectivity, could be used as a synthetic starting point for the design of compounds that selectively inhibit other PTPs but not PTP1B
Summary
Introduction of Substituents in Position5 of Compound 4— Primary sequence alignment of PTP domains indicates that residues 47 and 48 potentially could be used to obtain selectivity for PTP and against PTP1B (Fig. 3). Several different substituents capable of positioning suitable functional groups were introduced into the pyran ring of OATP, of which phthalimide-based side chains in position 5 were found to be promising (data not shown). Compound 5 (Fig. 2) with a phthalimide methyl side chain in this position of the pyran ring displays a significant improvement in affinity for PTP compared with the parent inhibitor, OATP (Table II). To our surprise this compound displays a nearly identical affinity for PTP1B (Table II). Most important, this compound still acts as a classical, reversible, and competitive inhibitor of both PTP and PTP1B (not shown)
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