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  2. Therapeutic effects of the allosteric protein tyrosine phosphatase 1B inhibitor KY-226 on experimental diabetes and obesity via enhancements in insulin and leptin signaling in mice

Therapeutic effects of the allosteric protein tyrosine phosphatase 1B inhibitor KY-226 on experimental diabetes and obesity via enhancements in insulin and leptin signaling in mice

  • J Pharmacol Sci. 2018 May;137(1):38-46. doi: 10.1016/j.jphs.2018.03.001.
Yuma Ito 1 Masaki Fukui 2 Mamoru Kanda 2 Ko Morishita 2 Yoshimichi Shoji 2 Tatsuya Kitao 2 Eiichi Hinoi 3 Hiroaki Shirahase 4
Affiliations

Affiliations

  • 1 Drug Discovery Research Department, Kyoto Pharmaceutical Industries, Ltd., 38, Nishinokyo Tsukinowa-cho, Nakagyo-ku, Kyoto, 604-8444, Japan; Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School, Kanazawa, Ishikawa, 920-1192, Japan.
  • 2 Drug Discovery Research Department, Kyoto Pharmaceutical Industries, Ltd., 38, Nishinokyo Tsukinowa-cho, Nakagyo-ku, Kyoto, 604-8444, Japan.
  • 3 Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School, Kanazawa, Ishikawa, 920-1192, Japan.
  • 4 Drug Discovery Research Department, Kyoto Pharmaceutical Industries, Ltd., 38, Nishinokyo Tsukinowa-cho, Nakagyo-ku, Kyoto, 604-8444, Japan. Electronic address: shirahase@kyoto-pharm.co.jp.
Abstract

The anti-diabetic and anti-obesity effects of the allosteric protein tyrosine Phosphatase 1B (PTP1B) inhibitor 4-(biphenyl-4-ylmethylsulfanylmethyl)-N-(hexane-1-sulfonyl)benzoylamide (KY-226) were pharmacologically evaluated. KY-226 inhibited human PTP1B activity (IC50 = 0.28 μM), but did not exhibit Peroxisome Proliferator-activated Receptor γ (PPARγ) agonist activity. In rodent preadipocytes (3T3-L1), KY-226 up to 10 μM had no effects on adipocyte differentiation, whereas pioglitazone, a PPARγ Agonist, markedly promoted it. In human hepatoma-derived cells (HepG2), KY-226 (0.3-10 μM) increased the phosphorylated Insulin Receptor (pIR) produced by Insulin. In db/db mice, the oral administration of KY-226 (10 and 30 mg/kg/day, 4 weeks) significantly reduced plasma glucose and triglyceride levels as well as hemoglobin A1c values without increasing body weight gain, while pioglitazone exerted similar effects with increases in body weight gain. KY-226 attenuated plasma glucose elevations in the oral glucose tolerance test. KY-226 also increased pIR and phosphorylated Akt in the liver and femoral muscle. In high-fat diet-induced obese mice, the oral administration of KY-226 (30 and 60 mg/kg/day, 4 weeks) decreased body weight gain, food consumption, and fat volume gain with increases in phosphorylated STAT3 in the hypothalamus. In conclusion, KY-226 exerted anti-diabetic and anti-obesity effects by enhancing Insulin and Leptin signaling, respectively.

Keywords

Allosteric inhibitor; Diabetes; Obesity; PTP1B inhibitor; db/db mouse.

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