Fragment-Based Discovery of Novel VE-PTP Inhibitors Using Orthogonal Biophysical Techniques

  • Biochemistry. 2023 Jul 18;62(14):2161-2169. doi: 10.1021/acs.biochem.3c00079.
Wataru Asano  1 ,  Kenji Yamanaka  1 ,  Yasunori Ohara  1 ,  Toru Uhara  1 ,  Satoki Doi  2 ,  Takuya Orita  2 ,  Tomoko Iwanaga  2 ,  Tsuyoshi Adachi  2 ,  Shingo Fujioka  2 ,  Tatsuo Akaki  2 ,  Kazutaka Ikegashira  2 ,  Yoshiji Hantani  1
Affiliations
  • 1. Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
  • 2. Chemical Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.
PMID: 37414577 DOI: 10.1021/acs.biochem.3c00079
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.

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