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Published on: December 1, 2020
Fragment-Based Discovery of Novel VE-PTP Inhibitors Using Orthogonal Biophysical Techniques
Wataru Asano1, Kenji Yamanaka1, Yasunori Ohara1
1Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
Abstract:
Tyrosine phosphorylation is an essential post-translational modification that regulates various biological events and is implicated in many diseases including cancer and atherosclerosis. Vascular endothelial protein tyrosine phosphatase (VE-PTP), which plays an important role in vascular homeostasis and angiogenesis, is therefore an attractive drug target for these diseases. However, there are still no drugs targeting PTP including VE-PTP. In this paper, we report the discovery of a novel VE-PTP inhibitor, Cpd-2, by fragment-based screening combining various biophysical techniques. Cpd-2 is the first VE-PTP inhibitor with a weakly acidic structure and high selectivity, unlike known strongly acidic inhibitors. We believe that this compound represents a new possibility for the development of bioavailable VE-PTP inhibitors.
Insights
Researchers discovered Cpd-2, a novel and selective inhibitor for vascular endothelial protein tyrosine phosphatase (VE-PTP). This weakly acidic compound offers a new avenue for developing bioavailable drugs targeting VE-PTP for diseases like cancer.
Area of Science:
- Biochemistry
- Pharmacology
- Molecular Biology
Background:
- Tyrosine phosphorylation is a critical post-translational modification regulating biological processes and implicated in diseases such as cancer and atherosclerosis.
- Vascular endothelial protein tyrosine phosphatase (VE-PTP) is crucial for vascular homeostasis and angiogenesis, making it a potential therapeutic target.
- Currently, no drugs effectively target protein tyrosine phosphatases (PTPs), including VE-PTP.
Purpose of the Study:
- To discover novel inhibitors of VE-PTP.
- To identify a lead compound for the development of bioavailable VE-PTP inhibitors.
- To explore new chemical scaffolds for PTP-targeted drug development.
Main Methods:
- Fragment-based screening was employed to identify potential inhibitors.
- Various biophysical techniques were utilized to characterize compound interactions.
- Structure-activity relationship studies were conducted to optimize inhibitor properties.
Main Results:
- A novel VE-PTP inhibitor, designated Cpd-2, was discovered.
- Cpd-2 exhibits a weakly acidic structure and high selectivity, distinguishing it from existing strongly acidic inhibitors.
- The compound represents a promising starting point for further drug development.
Conclusions:
- Cpd-2 is the first identified VE-PTP inhibitor with a weakly acidic profile and high selectivity.
- This discovery opens new possibilities for developing bioavailable VE-PTP inhibitors.
- Targeting VE-PTP with novel inhibitors like Cpd-2 may offer therapeutic benefits for vascular-related diseases.
