1. Design and synthesis of benzofuro[3,2-b]pyridin-2(1H)-one derivatives as anti-leukemia agents by inhibiting Btk and PI3Kδ
- Author
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Xiang Lu, Ali Huang, Qidong You, Xinyu Li, Xiangqian Wang, Shi Bingyu, Linyi Liu, Hua Xiang, Xuerong Cai, and Guoshun Luo
- Subjects
0301 basic medicine ,Class I Phosphatidylinositol 3-Kinases ,HL60 ,Clinical Biochemistry ,Pharmaceutical Science ,Antineoplastic Agents ,Biochemistry ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,immune system diseases ,Cell Line, Tumor ,hemic and lymphatic diseases ,Drug Discovery ,Agammaglobulinaemia Tyrosine Kinase ,medicine ,Humans ,Bruton's tyrosine kinase ,Protein Kinase Inhibitors ,Molecular Biology ,PI3K/AKT/mTOR pathway ,Cell Proliferation ,Binding Sites ,biology ,Kinase ,Organic Chemistry ,medicine.disease ,In vitro ,Protein Structure, Tertiary ,Molecular Docking Simulation ,Leukemia ,030104 developmental biology ,chemistry ,Docking (molecular) ,Drug Design ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Molecular Medicine ,K562 cells - Abstract
Btk inhibitors and PI3Kδ inhibitors play crucial roles in the treatment of leukemia, and studies confirmed that the synergetic inhibition against Btk and PI3Kδ could gain an optimal response. Herein, a series of novel benzofuro[3,2-b]pyridin-2(1H)-one derivatives were designed and synthesized as dual Btk/PI3Kδ kinases inhibitors for the treatment of leukemia. Studies indicated that most compounds could suppress the proliferation of multiple leukemia or lymphoma cells (Raji, HL60 and K562 cells) at low micromolar concentrations in vitro. Further kinase assays identified several compounds could simultaneously inhibit Btk kinase and PI3Kδ kinase. Thereinto, compound 16b exhibited the best inhibitory activity (Btk: IC50 = 139 nM; PI3Kδ: IC50 = 275 nM) and showed some selectivity against PI3Kδ compared to PI3Kβ/γ. Finally, the SAR of target compounds was preliminarily discussed combined with docking results. In brief, 16b possessed of the potency for the further optimization as anti-leukemia drugs by inhibiting simultaneously Btk kinase and PI3Kδ kinase.
- Published
- 2018
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