title: Discovery of a small molecule targeting SET-PP2A interaction to overcome BCR-ABLT315I mutation of chronic myeloid leukemia.
abstract: Despite the great success in using tyrosine kinase inhibitors (TKIs) to treat chronic myeloid leukemia (CML), the frequent development of multi-drug resistance, particularly the T315I mutation of BCR-ABL, remains a challenging issue. Enhancement of protein phosphatase 2A (PP2A) activity by dissociating its endogenous inhibitor SET is an effective approach to combat TKI-based resistance. Here, we report the identification of a novel 2-phenyloxypyrimidine compound TGI1002 to specifically disrupt SET-PP2A interaction. By binding to SET, TGI1002 inhibits SET-PP2A interaction and increases PP2A activity. In addition, knocking-down SET expression decreases tumor cell sensitivity to TGI1002. TGI1002 treatments also markedly increase dephosphorylation of BCR-ABL. Moreover, TGI1002 significantly inhibits tumor growth and prolongs survival of xenografted mice implanted with BaF3-p210T315I cells. These findings demonstrate that TGI1002 is a novel SET inhibitor with important therapeutic potential for the treatment of drug-resistant CML.
authors.affiliation: State Key Laboratory of Natural Medicines and Laboratory of Chemical Biology, China Pharmaceutical University, Nanjing, China.
authors.forename: Shuzhen
authors.initials: S
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines and Laboratory of Chemical Biology, China Pharmaceutical University, Nanjing, China.
authors.forename: Weiquan
authors.initials: W
authors.lastname: Xie
authors.affiliation: State Key Laboratory of Natural Medicines and Institute of Pharmaceutical Science, China Pharmaceutical University, Nanjing, China.
authors.forename: Duowei
authors.initials: D
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines and Laboratory of Chemical Biology, China Pharmaceutical University, Nanjing, China.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Peng
authors.affiliation: State Key Laboratory of Natural Medicines and Institute of Pharmaceutical Science, China Pharmaceutical University, Nanjing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Natural Medicines and Laboratory of Chemical Biology, China Pharmaceutical University, Nanjing, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Natural Medicines and Laboratory of Chemical Biology, China Pharmaceutical University, Nanjing, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Dai
authors.affiliation: State Key Laboratory of Natural Medicines and Laboratory of Chemical Biology, China Pharmaceutical University, Nanjing, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines and Laboratory of Chemical Biology, China Pharmaceutical University, Nanjing, China.
authors.forename: Zongqiang
authors.initials: Z
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines and Institute of Pharmaceutical Science, China Pharmaceutical University, Nanjing, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Natural Medicines and Laboratory of Chemical Biology, China Pharmaceutical University, Nanjing, China.
authors.forename: Yijun
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016044:Fusion Proteins, bcr-abl; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy; D008807:Mice, Inbred BALB C; D009154:Mutation; D054648:Protein Phosphatase 2 / Q000235:genetics*; D015398:Signal Transduction; D016019:Survival Analysis; D014162:Transfection
chemical_list: D016044:Fusion Proteins, bcr-abl; D054648:Protein Phosphatase 2
keywords: BCR-ABL; SET; T315I mutation; chronic myeloid leukemia; protein phosphatase 2A