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

• Published in: Oncotarget Vol. 6; no. 14; pp. 12128 - 12140
• Main Authors: Wang, Shuzhen, Xie, Weiquan, Wang, Duowei, Peng, Zhigang, Zheng, Yan, Liu, Nan, Dai, Wen, Wang, Yang, Wang, Zongqiang, Yang, Yong, Chen, Yijun
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 20.05.2015
• Subjects: Animals; Apoptosis; Cell Culture Techniques; Cell Line, Tumor; Cell Proliferation; Fusion Proteins, bcr-abl; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Mice, Inbred BALB C; Mutation; Protein Phosphatase 2 - genetics; Research Paper; Signal Transduction; Survival Analysis; Transfection; chronic myeloid leukemia; T315I mutation; SET; protein phosphatase 2A; BCR-ABL
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.3665

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.