Discovery of a small molecule targeting SET-PP2A interaction to overcome BCR-ABLT315I mutation of chronic myeloid leukemia

// Shuzhen Wang 1,* , Weiquan Xie 1,* , Duowei Wang 2,* , Zhigang Peng 1,* , Yan Zheng 2 , Nan Liu 1 , Wen Dai 1 , Yang Wang 1 , Zongqiang Wang 1 , Yong Yang 2 , Yijun Chen 1 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 Correspondence to: 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 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-p210 T315I cells. These findings demonstrate that TGI1002 is a novel SET inhibitor with important therapeutic potential for the treatment of drug-resistant CML.