Characterization of selective and potent PI3Kδ inhibitor (PI3KDIN- 015) for B-Cell malignances
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Xiaochuan Liu1,2,*, Aoli Wang2,3,*, Xiaofei Liang2,4,*, Cheng Chen2,4,*, Juanjuan Liu2,3, Zheng Zhao2,4, Hong Wu2,3, Yuanxin Deng2,3, Li Wang2,4, Beilei Wang2,4, Jiaxin Wu2,3, Feiyang Liu2,3, Stacey M. Fernandes5, Sophia Adamia5, Richard M. Stone5, Ilene A. Galinsky5, Jennifer R. Brown5, James D. Griffin5, Shanchun Zhang4,6, Teckpeng Loh1, Xin Zhang2, Wenchao Wang2,4, Ellen L. Weisberg5, Jing Liu2,4, Qingsong Liu2,4,7
1Department of Chemistry, University of Science and Technology of China, Hefei 230036, Anhui, P. R. China
2High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China
3University of Science and Technology of China, Hefei 230036, Anhui, 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
Wenchao Wang, email: [email protected]
Ellen L. Weisberg, email: [email protected]
Jing Liu, email: [email protected]
Qingsong Liu, email: [email protected]
Keywords: PI3Kδ, leukemia, B-cell malignances, PI3K, kinase inhibitors
Received: January 14, 2016 Accepted: March 28, 2016 Published: April 12, 2016
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.
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