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

Wataru Asano, Kenji Yamanaka, Yasunori Ohara, Toru Uhara, Satoki Doi, Takuya Orita, Tomoko Iwanaga, Tsuyoshi Adachi, Shingo Fujioka, Tatsuo Akaki, Kazutaka Ikegashira, Yoshiji Hantani

Biochemistry 2023 Jul 18

filter terms:

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.

Citation

Wataru Asano, Kenji Yamanaka, Yasunori Ohara, Toru Uhara, Satoki Doi, Takuya Orita, Tomoko Iwanaga, Tsuyoshi Adachi, Shingo Fujioka, Tatsuo Akaki, Kazutaka Ikegashira, Yoshiji Hantani. Fragment-Based Discovery of Novel VE-PTP Inhibitors Using Orthogonal Biophysical Techniques. Biochemistry. 2023 Jul 18;62(14):2161-2169