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

  • Oncotarget. 2016 May 31;7(22):32641-51. doi: 10.18632/oncotarget.8702.
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
Affiliations
  • 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.
PMID: 27081697 DOI: 10.18632/oncotarget.8702
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.

Keywords
B-cell malignances; PI3K; PI3Kδ; kinase inhibitors; leukemia.
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