Characterization of selective and potent PI3Kδ inhibitor (PI3KDIN- 015) for B-Cell malignances.

// Xiaochuan Liu 1, 2, * , Aoli Wang 2, 3, * , Xiaofei Liang 2, 4, * , Cheng Chen 2, 4, * , Juanjuan Liu 2, 3 , Zheng Zhao 2, 4 , Hong Wu 2, 3 , Yuanxin Deng 2, 3 , Li Wang 2, 4 , Beilei Wang 2, 4 , Jiaxin Wu 2, 3 , Feiyang Liu 2, 3 , Stacey M. Fernandes 5 , Sophia Adamia 5 , Richard M. Stone 5 , Ilene A. Galinsky 5 , Jennifer R. Brown 5 , James D. Griffin 5 , Shanchun Zhang 4, 6 , Teckpeng Loh 1 , Xin Zhang 2 , Wenchao Wang 2, 4 , Ellen L. Weisberg 5 , Jing Liu 2, 4 , Qingsong Liu 2, 4, 7 1 Department of Chemistry, University of Science and Technology of China, Hefei 230036, Anhui, P. R. China 2 High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China 3 University of Science and Technology of China, Hefei 230036, Anhui, P. R. China 4 CHMFL-HCMTC Target Therapy Joint Laboratory, Hefei 230031, Anhui, P. R. China 5 Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA 6 Hefei Cosource Medicine Technology Co. LTD., Hefei 230031, Anhui, P. R. China 7 Hefei Science Center, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China * These authors have contributed equally to this work Correspondence to: Wenchao Wang, email: wwcbo@hmfl.cas.cn Ellen L. Weisberg, email: Ellen_weisberg@dfci.harvard.edu Jing Liu, email: jingliu@hmfl.ac.cn Qingsong Liu, email: qsliu97@hmfl.ac.cn Keywords: PI3Kδ, leukemia, B-cell malignances, PI3K, kinase inhibitors Received: January 14, 2016     Accepted: March 28, 2016     Published: April 12, 2016 ABSTRACT 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.