Zhao Y, Masiello D, McMillian M, Nguyen C, Wu Y, Melendez E, Smbatyan G, Kida A, He Y, Teo J-L, Kahn M
Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.
Oncogene. 2016 Jul 14;35(28):3705-17. doi: 10.1038/onc.2015.438. Epub 2015 Dec 14.
CREB-binding protein (CBP) and p300 are highly homologous transcriptional coactivators with unique, non-redundant roles that bind a wide array of proteins, including catenins-β and γ. ICG-001 is a small-molecule inhibitor that specifically inhibits the CBP/catenin interaction. Importantly, ICG-001 does not inhibit the p300/catenin interaction. We demonstrate that specifically inhibiting the interaction between CBP and catenin with ICG-001 results in the differentiation of quiescent drug-resistant chronic myelogenous leukemia-initiating cells (CML LICs), thereby sensitizing them to BCR-ABL tyrosine kinase inhibitors, for example, Imatinib. Using ICG-001 in a NOD/SCID/IL2Rγ(-/-) mouse model of engrafted human chronic myelogenous leukemia, we now demonstrate the complete elimination of engrafted leukemia after only one course of combined chemotherapy. Combination-treated animals live as long as their non-engrafted littermates. Results from these studies demonstrate that specifically antagonizing the CBP/catenin interaction with ICG-001 can eliminate drug-resistant CML LICs without deleterious effects to the normal endogenous hematopoietic stem cell population.
CREB结合蛋白（CBP）和p300是高度同源的转录共激活因子，具有独特的、非冗余的作用，可结合多种蛋白质，包括β连环蛋白和γ连环蛋白。ICG - 001是一种小分子抑制剂，可特异性抑制CBP/连环蛋白的相互作用。重要的是，ICG - 001不抑制p300/连环蛋白的相互作用。我们证明，用ICG - 001特异性抑制CBP与连环蛋白之间的相互作用会导致静止的耐药性慢性粒细胞白血病起始细胞（CML LICs）分化，从而使它们对BCR - ABL酪氨酸激酶抑制剂（例如伊马替尼）敏感。在植入人慢性粒细胞白血病的NOD/SCID/IL2Rγ（-/-）小鼠模型中使用ICG - 001，我们现在证明仅经过一个疗程的联合化疗后即可完全消除植入的白血病。联合治疗的动物与未植入的同窝幼崽寿命一样长。这些研究结果表明，用ICG - 001特异性拮抗CBP/连环蛋白的相互作用可以消除耐药性CML LICs，而不会对正常内源性造血干细胞群体产生有害影响。
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