Liu Xiaochuan, Wang Aoli, Liang Xiaofei, Liu Juanjuan, Zou Fengming, Chen Cheng, Zhao Zheng, Deng Yuanxin, Wu Hong, Qi Ziping, Wang Beilei, Wang Li, Liu Feiyang, Xu Yunhe, Wang Wenchao, Fernandes Stacey M, Stone Richard M, Galinsky Ilene A, Brown Jennifer R, Loh Teckpeng, Griffin James D, Zhang Shanchun, Weisberg Ellen L, Zhang Xin, Liu Jing, Liu Qingsong
Department of Chemistry, University of Science and Technology of China, Anhui, Hefei, 230036, P. R. China.
High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, 230031, Anhui, P. R. China.
Oncotarget. 2016 Aug 16;7(33):53515-53525. doi: 10.18632/oncotarget.10650.
PI3Kδ has been found to be over-expressed in B-Cell-related malignancies. Despite the clinical success of the first selective PI3Kδ inhibitor, CAL-101, inhibition of PI3Kδ itself did not show too much cytotoxic efficacy against cancer cells. One possible reason is that PI3Kδ inhibition induced autophagy that protects the cells from death. Since class III PI3K isoform PIK3C3/Vps34 participates in autophagy initiation and progression, we predicted that a PI3Kδ and Vps34 dual inhibitor might improve the anti-proliferative activity observed for PI3Kδ-targeted inhibitors. We discovered a highly potent ATP-competitive PI3Kδ/Vps34 dual inhibitor, PI3KD/V-IN-01, which displayed 10-1500 fold selectivity over other PI3K isoforms and did not inhibit any other kinases in the kinome. In cells, PI3KD/V-IN-01 showed 30-300 fold selectivity between PI3Kδ and other class I PI3K isoforms. PI3KD/V-IN-01 exhibited better anti-proliferative activity against AML, CLL and Burkitt lymphoma cell lines than known selective PI3Kδ and Vps34 inhibitors. Interestingly, we observed FLT3-ITD AML cells are more sensitive to PI3KD/V-IN-01 than the FLT3 wt expressing cells. In AML cell inoculated xenograft mouse model, PI3KD/V-IN-01 exhibited dose-dependent anti-tumor growth efficacies. These results suggest that dual inhibition of PI3Kδ and Vps34 might be a useful approach to improve the PI3Kδ inhibitor's anti-tumor efficacy.
已发现PI3Kδ在B细胞相关恶性肿瘤中过度表达。尽管首个选择性PI3Kδ抑制剂CAL-101取得了临床成功，但抑制PI3Kδ本身对癌细胞并未显示出太多细胞毒性功效。一个可能的原因是PI3Kδ抑制诱导了自噬，从而保护细胞免于死亡。由于III类PI3K亚型PIK3C3/Vps34参与自噬的起始和进展，我们预测PI3Kδ和Vps34双重抑制剂可能会提高针对PI3Kδ的抑制剂所观察到的抗增殖活性。我们发现了一种高效的ATP竞争性PI3Kδ/Vps34双重抑制剂PI3KD/V-IN-01，它对其他PI3K亚型具有10至1500倍的选择性，并且不抑制激酶组中的任何其他激酶。在细胞中，PI3KD/V-IN-01在PI3Kδ和其他I类PI3K亚型之间显示出30至300倍的选择性。PI3KD/V-IN-01对AML、CLL和伯基特淋巴瘤细胞系表现出比已知的选择性PI3Kδ和Vps34抑制剂更好的抗增殖活性。有趣的是，我们观察到FLT3-ITD AML细胞比表达FLT3野生型的细胞对PI3KD/V-IN-01更敏感。在接种AML细胞的异种移植小鼠模型中，PI3KD/V-IN-01表现出剂量依赖性的抗肿瘤生长功效。这些结果表明，双重抑制PI3Kδ和Vps34可能是提高PI3Kδ抑制剂抗肿瘤功效的一种有用方法。
