title: Characterization of selective and potent PI3Kδ inhibitor (PI3KDIN- 015) for B-Cell malignances.
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.
authors.affiliation: Department of Chemistry, University of Science and Technology of China, Hefei 230036, Anhui, P. R. China.|High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.
authors.forename: Xiaochuan
authors.initials: X
authors.lastname: Liu
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.|University of Science and Technology of China, Hefei 230036, Anhui, P. R. China.
authors.forename: Aoli
authors.initials: A
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Liang
authors.affiliation: 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.
authors.forename: Cheng
authors.initials: C
authors.lastname: Chen
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.|University of Science and Technology of China, Hefei 230036, Anhui, P. R. China.
authors.forename: Juanjuan
authors.initials: J
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.|University of Science and Technology of China, Hefei 230036, Anhui, P. R. China.
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.|University of Science and Technology of China, Hefei 230036, Anhui, P. R. China.
authors.forename: Yuanxin
authors.initials: Y
authors.lastname: Deng
authors.affiliation: 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.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Beilei
authors.initials: B
authors.lastname: Wang
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.|University of Science and Technology of China, Hefei 230036, Anhui, P. R. China.
authors.forename: Jiaxin
authors.initials: J
authors.lastname: Wu
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.|University of Science and Technology of China, Hefei 230036, Anhui, P. R. China.
authors.forename: Feiyang
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Stacey M
authors.initials: SM
authors.lastname: Fernandes
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Sophia
authors.initials: S
authors.lastname: Adamia
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Stone
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Ilene A
authors.initials: IA
authors.lastname: Galinsky
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Brown
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: James D
authors.initials: JD
authors.lastname: Griffin
authors.affiliation: CHMFL-HCMTC Target Therapy Joint Laboratory, Hefei 230031, Anhui, P. R. China.|Hefei Cosource Medicine Technology Co. LTD., Hefei 230031, Anhui, P.R.China.
authors.forename: Shanchun
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Chemistry, University of Science and Technology of China, Hefei 230036, Anhui, P. R. China.
authors.forename: Teckpeng
authors.initials: T
authors.lastname: Loh
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Wenchao
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Ellen L
authors.initials: EL
authors.lastname: Weisberg
authors.affiliation: 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.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: 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.|Hefei Science Center, Chinese Academy of Sciences, Hefei 230031, Anhui, P. R. China.
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Liu
mesh_terms: D000595:Amino Acid Sequence; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D015448:Leukemia, B-Cell / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008958:Models, Molecular; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors
keywords: B-cell malignances; PI3K; PI3Kδ; kinase inhibitors; leukemia