Discovery of a small molecule targeting SET-PP2A interaction to overcome BCR-ABLT315I mutation of chronic myeloid leukemia
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Shuzhen Wang1,*, Weiquan Xie1,*, Duowei Wang2,*, Zhigang Peng1,*, Yan Zheng2, Nan Liu1, Wen Dai1, Yang Wang1, Zongqiang Wang1, Yong Yang2, Yijun Chen1
1 State Key Laboratory of Natural Medicines and Laboratory of Chemical Biology, China Pharmaceutical University, Nanjing, China
2 State Key Laboratory of Natural Medicines and Institute of Pharmaceutical Science, China Pharmaceutical University, Nanjing, China
* These authors contributed equally to this work
Yijun Chen, email:
Yong Yang, email:
Keywords: chronic myeloid leukemia, BCR-ABL, T315I mutation, SET, protein phosphatase 2A
Received: February 06, 2015 Accepted: March 02, 2015 Published: March 26, 2015
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.
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