title: Identification of Bidentate Salicylic Acid Inhibitors of PTP1B.
abstract: PTP1B is a master regulator in the insulin and leptin metabolic pathways. Hyper-activated PTP1B results in insulin resistance and is viewed as a key factor in the onset of type II diabetes and obesity. Moreover, inhibition of PTP1B expression in cancer cells dramatically inhibits cell growth in vitro and in vivo. Herein, we report the computationally guided optimization of a salicylic acid-based PTP1B inhibitor 6, identifying new and more potent bidentate PTP1B inhibitors, such as 20h, which exhibited a > 4-fold improvement in activity. In CHO-IR cells, 20f, 20h, and 20j suppressed PTP1B activity and restored insulin receptor phosphorylation levels. Notably, 20f, which displayed a 5-fold selectivity for PTP1B over the closely related PTPσ protein, showed no inhibition of PTP-LAR, PRL2 A/S, MKPX, or papain. Finally, 20i and 20j displayed nanomolar inhibition of PTPσ, representing interesting lead compounds for further investigation.
authors.affiliation: Department of Chemical and Physical Sciences, University of Toronto Mississauga , Mississauga, ON L5L 1C6, Canada.
authors.forename: Sina
authors.initials: S
authors.lastname: Haftchenary
authors.affiliation: Department of Chemical and Physical Sciences, University of Toronto Mississauga , Mississauga, ON L5L 1C6, Canada.
authors.forename: Andriana O
authors.initials: AO
authors.lastname: Jouk
authors.affiliation: McGill Goodman Cancer Research Centre and Department of Biochemistry, McGill University , Montreal, QC H3G 1Y6, Canada.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Aubry
authors.affiliation: Department of Chemical and Physical Sciences, University of Toronto Mississauga , Mississauga, ON L5L 1C6, Canada.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Lewis
authors.affiliation: McGill Goodman Cancer Research Centre and Department of Biochemistry, McGill University , Montreal, QC H3G 1Y6, Canada.
authors.forename: Melissa
authors.initials: M
authors.lastname: Landry
authors.affiliation: Department of Chemical and Physical Sciences, University of Toronto Mississauga , Mississauga, ON L5L 1C6, Canada.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Ball
authors.affiliation: Department of Chemical and Physical Sciences, University of Toronto Mississauga , Mississauga, ON L5L 1C6, Canada.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Shouksmith
authors.affiliation: Department of Chemical and Physical Sciences, University of Toronto Mississauga , Mississauga, ON L5L 1C6, Canada.
authors.forename: Catherine V
authors.initials: CV
authors.lastname: Collins
authors.affiliation: McGill Goodman Cancer Research Centre and Department of Biochemistry, McGill University , Montreal, QC H3G 1Y6, Canada.
authors.forename: Michel L
authors.initials: ML
authors.lastname: Tremblay
authors.affiliation: Department of Chemical and Physical Sciences, University of Toronto Mississauga , Mississauga, ON L5L 1C6, Canada.
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Gunning
keywords: PTP1B; PTPσ; bidentate inhibitors; diabetes; insulin receptor; salicylic acid; small molecule inhibitor