Liu Xiaochuan, Wang Aoli, Liang Xiaofei, Chen Cheng, Liu Juanjuan, Zhao Zheng, Wu Hong, Deng Yuanxin, Wang Li, Wang Beilei, Wu Jiaxin, Liu Feiyang, Fernandes Stacey M, Adamia Sophia, Stone Richard M, Galinsky Ilene A, Brown Jennifer R, Griffin James D, Zhang Shanchun, Loh Teckpeng, Zhang Xin, Wang Wenchao, Weisberg Ellen L, Liu Jing, Liu Qingsong
Department of Chemistry, University of Science and Technology of China, Hefei 230036, Anhui, P. R. China.
High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.
Oncotarget. 2016 May 31;7(22):32641-51. doi: 10.18632/oncotarget.8702.
PI3Kδ is predominately expressed in leukocytes and has been found overexpressed in B-cell related malignances such as CLL and AML. We have discovered a highly selective ATP competitive PI3Kd inhibitor PI3KD-IN-015, which exhibits a high selectivity among other PI3K isoforms in both biochemical assays and cellular assay, meanwhile did not inhibit most of other protein kinases in the kinome. PI3KD-IN-015 demonstrates moderately anti-proliferation efficacies against a variety of B-cell related cancer cell lines through down-regulate the PI3K signaling significantly. It induced both apoptosis and autophagy in B-cell malignant cell lines. In addition, combination of autophagy inhibitor Bafilomycin could potentiate the moderate anti-proliferation effect of PI3KD-IN-015. PI3KD-IN-015 shows anti-proliferation efficacy against CLL and AML patient primary cells. Collectively, these results indicate that PI3KD-IN-015 may be useful drug candidate for further development of anti-B-cell related malignances therapies.
PI3Kδ主要在白细胞中表达，并且已发现在B细胞相关恶性肿瘤如慢性淋巴细胞白血病（CLL）和急性髓细胞白血病（AML）中过表达。我们发现了一种高度选择性的ATP竞争性PI3Kδ抑制剂PI3KD-IN-015，其在生化测定和细胞测定中对其他PI3K亚型均表现出高选择性，同时不抑制激酶组中的大多数其他蛋白激酶。PI3KD-IN-015通过显著下调PI3K信号传导，对多种B细胞相关癌细胞系表现出适度的抗增殖功效。它在B细胞恶性细胞系中诱导凋亡和自噬。此外，自噬抑制剂巴弗洛霉素的联合使用可增强PI3KD-IN-015的适度抗增殖作用。PI3KD-IN-015对CLL和AML患者原代细胞显示出抗增殖功效。总体而言，这些结果表明PI3KD-IN-015可能是用于抗B细胞相关恶性肿瘤治疗进一步开发的有用候选药物。
