27727-37-3Relevant articles and documents
Targeting enteropeptidase with reversible covalent inhibitors to achieve metabolic benefits
Sun, Weimei,Zhang, Xuqing,Cummings, Maxwell D.,Albarazanji, Kamal,Wu, Jiejun,Wang, Mina,Alexander, Richard,Zhu, Bin,Zhang, Yuemei,Leonard, James,Lanter, James,Lenhard, James
, p. 510 - 521 (2020/12/22)
Inhibition of the serine protease enteropeptidase (EP) opens a new avenue to the discovery of chemotherapeutics for the treatment of metabolic diseases. Camostat has been used clinically for treating chronic pancreatitis in Japan; however, the mechanistic basis of the observed clinical efficacy has not been fully elucidated. We demonstrate that camostat is a potent reversible covalent inhibitor of EP, with an inhibition potency (kinact/KI) of 1.5 × 104M-1s-1. High-resolution liquid chromatography-mass spectrometry (LC-MS) showed addition of 161.6 Da to EP after the reaction with camostat, consistent with insertion of the carboxyphenylguanidine moiety of camostat. Covalent inhibition of EP by camostat is reversible, with an enzyme reactivation half-life of 14.3 hours. Formation of a covalent adduct was further supported by a crystal structure resolved to 2.19 ?, showing modification of the catalytic serine of EP by a close analog of camostat, leading to formation of the carboxyphenylguanidine acyl enzyme identical to that expected for the reaction with camostat. Of particular note, minor structural modifications of camostat led to changes in the mechanism of inhibition. We observed from other studies that sustained inhibition of EP is required to effect a reduction in cumulative food intake and body weight, with concomitant improved blood glucose levels in obese and diabetic leptindeficient mice. Thus, the structure-activity relationship needs to be driven by not only the inhibition potency but also the mechanistic and kinetic characterization. Our findings support EP as a target for the treatment of metabolic diseases and demonstrate that reversible covalent EP inhibitors show clinically relevant efficacy. SIGNIFICANCE STATEMENT Interest in targeted covalent drugs has expanded in recent years, particularly so for kinase targets, but also more broadly. This study demonstrates that reversible covalent inhibition of the serine protease enteropeptidase is a therapeutically viable approach to the treatment of metabolic diseases and that mechanistic details of inhibition are relevant to clinical efficacy. Our mechanistic and kinetic studies outline a framework for detailed inhibitor characterization that is proving essential in guiding discovery efforts in this area.
INHIBITORY EFFECT OF LOW MOLECULAR WEIGHT COMPOUND ON CANCER AND FIBROSIS
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Paragraph 0022; 0106; 0118, (2020/01/08)
A novel therapeutic drug for malignant tumors, cancer stem cells, or fibrosis is obtained. A therapeutic drug for malignant tumors or cancer stem cells is used that includes at least one compound selected from the group consisting of compounds represented
Phosphonate-based irreversible inhibitors of human γ-glutamyl transpeptidase (GGT). GGsTop is a non-toxic and highly selective inhibitor with critical electrostatic interaction with an active-site residue Lys562 for enhanced inhibitory activity
Kamiyama, Akane,Nakajima, Mado,Han, Liyou,Wada, Kei,Mizutani, Masaharu,Tabuchi, Yukiko,Kojima-Yuasa, Akiko,Matsui-Yuasa, Isao,Suzuki, Hideyuki,Fukuyama, Keiichi,Watanabe, Bunta,Hiratake, Jun
supporting information, p. 5340 - 5352 (2016/10/24)
γ-Glutamyl transpeptidase (GGT, EC 2.3.2.2) that catalyzes the hydrolysis and transpeptidation of glutathione and its S-conjugates is involved in a number of physiological and pathological processes through glutathione metabolism and is an attractive phar
