GLEPP1/Protein-tyrosine Phosphatase ϕ Inhibitors Block Chemotaxis in Vitro and in Vivo and Improve Murine Ulcerative Colitis

Abstract

We describe novel, cell-permeable, and bioavailable salicylic acid derivatives that are potent and selective inhibitors of GLEPP1/protein-tyrosine phosphatase . Two previously described GLEPP1 substrates, paxillin and Syk, are both required for cytoskeletal rearrangement and cellular motility of leukocytes in chemotaxis. We show here that GLEPP1 inhibitors prevent dephosphorylation of Syk1 and paxillin in resting cells and block primary human monocyte and mouse bone marrow-derived macrophage chemotaxis in a gradient of monocyte chemotactic protein-1. In mice, the GLEPP1 inhibitors also reduce thioglycolate-induced peritoneal chemotaxis of neutrophils, lymphocytes, and macrophages. In murine disease models, the GLEPP1 inhibitors significantly reduce severity of contact hypersensitivity, a model for allergic dermatitis, and dextran sulfate sodium-induced ulcerative colitis, a model for inflammatory bowel disease. Taken together, our data provide confirmation that GLEPP1 plays an important role in controlling chemotaxis of multiple types of leukocytes and that pharmacological inhibition of this phosphatase may have therapeutic use.

Small molecule tools for functional interrogation of protein tyrosine phosphatases

“…Two novel salicylic acid derivatives (compounds 29 and 30 ; Fig. 9) have been described as competitive inhibitors of PTPRO, with an IC 50 of 123 and 340 n m , respectively [101]. These two compounds showed more than ten‐fold selectivity over PAC1, PTPβ, PTPH1 and PTPμ, and a modest selectivity (two to fivefold) against PTP1B, TC‐PTP, SHP1, SHP2 and VHR.…”

Targeting Protein Tyrosine Phosphatases for Anticancer Drug Discovery

“…These include a bidentate PTP1B inhibitor ( 11 ), (PTP1B Ki : 2.4 nM; Shp2 IC 50 : 10 μM) [47] and a bis(trifluoromethanesulfonamide) ( 12 ) (Shp2 IC 50 : 1.8 μM). Gobert et al synthesized two Glepp1 PTP inhibitors ( 13 and 14 , IC 50 : 0.12 μM, 0.34 μM ) that potently cross-inhibit Shp2 (IC 50 : 0.39 μM, 0.65 μM) [90]. Compounds ( 13 ) and ( 14 ) are orally bioavailable and have protective effect on dextran sulfate sodium-induced ulcerative colitis in mice [90].…”

“…Gobert et al synthesized two Glepp1 PTP inhibitors ( 13 and 14 , IC 50 : 0.12 μM, 0.34 μM ) that potently cross-inhibit Shp2 (IC 50 : 0.39 μM, 0.65 μM) [90]. Compounds ( 13 ) and ( 14 ) are orally bioavailable and have protective effect on dextran sulfate sodium-induced ulcerative colitis in mice [90]. In an effort to develop retinoid-derived orphan nuclear receptor small heterodimer partners that induce apoptosis in leukemic cells, compound ( 15 ) was found to inhibit Shp2 (IC 50 : 0.45 μM) [91].…”

PTPRO-Associated Hepatic Stellate Cell Activation Plays a Critical Role in Liver Fibrosis

“…Low or aberrant expression of PTPRO has been shown in many types of human cancer, including lung cancer, hepatocellular carcinoma, and breast cancer [18,32,33]. Research also shows that PTPRO inhibitors can significantly reduce the pathophysiological severity in a mouse model of allergic dermatitis and inflammatory bowel disease [34]. Other PTPs play a regulatory role in fibrosis.…”