Simultaneous inhibition of Vps34 kinase would enhance PI3Kδ inhibitor cytotoxicity in the B-cell malignancies
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Xiaochuan Liu1,2,*, Aoli Wang2,3,*, Xiaofei Liang2,4,*, Juanjuan Liu2,3,*, Fengming Zou2,4,*, Cheng Chen2,4,*, Zheng Zhao2,4, Yuanxin Deng2,3, Hong Wu2,3, Ziping Qi2,4, Beilei Wang2,4, Li Wang2,4, Feiyang Liu2,3, Yunhe Xu1, Wenchao Wang2,4, Stacey M. Fernandes5, Richard M. Stone5, Ilene A. Galinsky5, Jennifer R. Brown5, Teckpeng Loh1, James. D. Griffin5, Shanchun Zhang4,6, Ellen L. Weisberg5, Xin Zhang2, Jing Liu2,4, Qingsong Liu2,3,7
1Department of Chemistry, University of Science and Technology of China, Anhui, Hefei, 230036, P. R. China
2High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, 230031, Anhui, P. R. China
3University of Science and Technology of China, Anhui, Hefei, 230036, P. R. China
4CHMFL-HCMTC Target Therapy Joint Laboratory, Hefei, 230031, Anhui, P. R. China
5Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
6Hefei Cosource Medicine Technology Co. LTD. Hefei, 230031, Anhui, P.R.China
7Hefei Science Center, Chinese Academy of Sciences, Hefei, 230031, Anhui, P. R. China
*These authors have contributed equally to this work
Ellen L. Weisberg, email: Ellen_weisberg@dfci.harvard.edu
Xin Zhang, email: email@example.com
Jing Liu, email: firstname.lastname@example.org
Qingsong Liu, email: email@example.com
Keywords: PI3Kδ, Vps34, combination, chronic lymphatic leukemia, acute myeloid leukemia
Received: April 19, 2016 Accepted: June 03, 2016 Published: July 18, 2016
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.
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