Simultaneous inhibition of Vps34 kinase would enhance PI3Kδ inhibitor cytotoxicity in the B-cell malignancies.

Autor: Liu X; 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., Wang A; High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, 230031, Anhui, P. R. China.; University of Science and Technology of China, Anhui, Hefei, 230036, P. R. China., Liang X; High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, 230031, Anhui, P. R. China.; CHMFL-HCMTC Target Therapy Joint Laboratory, Hefei, 230031, Anhui, P. R. China., Liu J; High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, 230031, Anhui, P. R. China.; University of Science and Technology of China, Anhui, Hefei, 230036, P. R. China., Zou F; High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, 230031, Anhui, P. R. China.; CHMFL-HCMTC Target Therapy Joint Laboratory, Hefei, 230031, Anhui, P. R. China., Chen C; High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, 230031, Anhui, P. R. China.; CHMFL-HCMTC Target Therapy Joint Laboratory, Hefei, 230031, Anhui, P. R. China., Zhao Z; High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, 230031, Anhui, P. R. China.; CHMFL-HCMTC Target Therapy Joint Laboratory, Hefei, 230031, Anhui, P. R. China., Deng Y; High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, 230031, Anhui, P. R. China.; University of Science and Technology of China, Anhui, Hefei, 230036, P. R. China., Wu H; High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, 230031, Anhui, P. R. China.; University of Science and Technology of China, Anhui, Hefei, 230036, P. R. China., Qi Z; High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, 230031, Anhui, P. R. China.; CHMFL-HCMTC Target Therapy Joint Laboratory, Hefei, 230031, Anhui, P. R. China., Wang B; High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, 230031, Anhui, P. R. China.; CHMFL-HCMTC Target Therapy Joint Laboratory, Hefei, 230031, Anhui, P. R. China., Wang L; High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, 230031, Anhui, P. R. China.; CHMFL-HCMTC Target Therapy Joint Laboratory, Hefei, 230031, Anhui, P. R. China., Liu F; High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, 230031, Anhui, P. R. China.; University of Science and Technology of China, Anhui, Hefei, 230036, P. R. China., Xu Y; Department of Chemistry, University of Science and Technology of China, Anhui, Hefei, 230036, P. R. China., Wang W; High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, 230031, Anhui, P. R. China.; CHMFL-HCMTC Target Therapy Joint Laboratory, Hefei, 230031, Anhui, P. R. China., Fernandes SM; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA., Stone RM; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA., Galinsky IA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA., Brown JR; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA., Loh T; Department of Chemistry, University of Science and Technology of China, Anhui, Hefei, 230036, P. R. China., Griffin JD; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA., Zhang S; CHMFL-HCMTC Target Therapy Joint Laboratory, Hefei, 230031, Anhui, P. R. China.; Hefei Cosource Medicine Technology Co. Ltd. Hefei, 230031, Anhui, P. R.China., Weisberg EL; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA., Zhang X; High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, 230031, Anhui, P. R. China., Liu J; High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, 230031, Anhui, P. R. China.; CHMFL-HCMTC Target Therapy Joint Laboratory, Hefei, 230031, Anhui, P. R. China., Liu Q; High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, 230031, Anhui, P. R. China.; University of Science and Technology of China, Anhui, Hefei, 230036, P. R. China.; Hefei Science Center, Chinese Academy of Sciences, Hefei, 230031, Anhui, P. R. China.
Jazyk: angličtina
Zdroj: Oncotarget [Oncotarget] 2016 Aug 16; Vol. 7 (33), pp. 53515-53525.
DOI: 10.18632/oncotarget.10650
Abstrakt: 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.
Competing Interests: Dr. Shanchun Zhang is a shareholder of Hefei Cosource Medicine Technology Co. LTD.
Databáze: MEDLINE