Design, Synthesis, and Evaluation of 2-(arylsulfonyl)oxiranes as Cell-permeable Covalent Inhibitors of Protein Tyrosine Phosphatases

• Published in: Chemical biology & drug design 2012-10, Vol.80 (4), p.489-499
• Main Authors: Dana, Dibyendu, Das, Tirtha K., Kumar, Ish, Davalos, Anibal R., Mark, Kevin J., Ramai, Daryl, Chang, Emmanuel J., Talele, Tanaji T., Kumar, Sanjai
• Format: Article
• Language: English
• Subjects: Binding Sites; Catalytic Domain; Cell Line, Tumor; covalent PTP inhibitor; Drug Design; Epoxy Compounds - chemical synthesis; Epoxy Compounds - chemistry; Epoxy Compounds - pharmacokinetics; Epoxy Compounds - pharmacology; Humans; irreversible PTP inhibitor; mechanism-based inhibitors of PTP; Models, Molecular; protein tyrosine phosphatase inhibitor; Protein Tyrosine Phosphatases - antagonists & inhibitors; Protein Tyrosine Phosphatases - chemistry; Protein Tyrosine Phosphatases - metabolism; Structure-Activity Relationship
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/j.1747-0285.2012.01437.x

A structure‐based design approach has been applied to develop 2‐(arylsulfonyl)oxiranes as potential covalent inhibitors of protein tyrosine phosphatases. A detailed kinetic analysis of inactivation by these covalent inhibitors reveals that this class of compounds inhibits a panel of protein tyrosine phosphatases in a time‐ and dose‐dependent manner, consistent with the covalent modification of the enzyme active site. An inactivation experiment in the presence of sodium arsenate, a known competitive inhibitor of protein tyrosine phosphatase, indicated that these inhibitors were active site bound. This finding is consistent with the mass spectrometric analysis of the covalently modified protein tyrosine phosphatase enzyme. Additional experiments indicated that these compounds remained inert toward other classes of arylphosphate‐hydrolyzing enzymes, and alkaline and acid phosphatases. Cell‐based experiments with human A549 lung cancer cell lines indicated that 2‐(phenylsulfonyl)oxirane (1) caused an increase in intracellular pTyr levels in a dose‐dependent manner thereby suggesting its cell‐permeable nature. Taken together, the newly identified 2‐(arylsulfonyl)oxiranyl moiety could serve as a novel chemotype for the development of activity‐based probes and therapeutic agents against protein tyrosine phosphatase superfamily of enzymes. A computer‐assisted design approach has been undertaken to develop 2‐(arylsulfonyl)oxiranes as covalent inhibitors of Protein Tyrosine Phosphatases (PTPs). Enzyme kinetics and mass spectrometric analysis indicate that these agents are active site‐directed and covalent inhibitors of PTPs. Furthermore, these inhibitors remain inert towards strong nucleophile such as sodium azide and other arylphosphate‐hydrolyzing enzymes such as alkaline and acid phosphatases. Cell‐based experiments on human A549 cancer cell line indicate that they are cell permeable and cause an increase in intracellular pTyr levels.