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The lymphoid tyrosine phosphatase LYP,encoded by the PTPN22 gene,is a critical regulator of signaling in T cells.A single-nucleotide polymorphism(SNP)in the PTPN22 gene correlates with various autoimmune diseases such as type 1 diabetes,rheumatoid arthritis,and systemic lupus erythematosus.Currently,Lyp has become a potential drug target for autoimmune diseases.Herein we applied a combination of high sensitivity pharmacophore-and docking-based virtual screening methodology to identify novel Lyp inhibitors.Nine novel Lyp inhibitors were identified with IC50 ranging from 1.01~55.95μM,and among them four xcompounds shown significant efficacious cellular activity in T-cells.Specially,selectivity profiling against closely related tyrosine phosphatases indicated that compound B12 is a potent selective inhibitor of LYP with a Ki value of 10.03μM and more than 6-fold selectivity over a large panel of PTPs.