Design and synthesis of benzofuro[3,2-b]pyridin-2(1H)-one derivatives as anti-leukemia agents by inhibiting Btk and PI3Kδ

Linyi Liu; Bingyu Shi; Xinyu Li; Xiangqian Wang; Xiang Lu; Xuerong Cai; Ali Huang; Guoshun Luo; Qidong You; Hua Xiang

doi:10.1016/j.bmc.2018.07.047

Design and synthesis of benzofuro[3,2-b]pyridin-2(1H)-one derivatives as anti-leukemia agents by inhibiting Btk and PI3Kδ

Bioorg Med Chem. 2018 Aug 15;26(15):4537-4543. doi: 10.1016/j.bmc.2018.07.047. Epub 2018 Jul 29.

Authors

Linyi Liu¹, Bingyu Shi¹, Xinyu Li¹, Xiangqian Wang¹, Xiang Lu¹, Xuerong Cai¹, Ali Huang¹, Guoshun Luo¹, Qidong You¹, Hua Xiang²

Affiliations

¹ Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
² Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address: xianghua@cpu.edu.cn.

PMID: 30077608
DOI: 10.1016/j.bmc.2018.07.047

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.

Keywords: Benzofuro[3,2-b]pyridin-2(1H)-one; Btk; Leukemia; PI3K; Synthesis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Agammaglobulinaemia Tyrosine Kinase / antagonists & inhibitors
Agammaglobulinaemia Tyrosine Kinase / metabolism*
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / pharmacology
Binding Sites
Cell Line, Tumor
Cell Proliferation / drug effects
Class I Phosphatidylinositol 3-Kinases / antagonists & inhibitors
Class I Phosphatidylinositol 3-Kinases / metabolism*
Drug Design*
Humans
Molecular Docking Simulation
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / pharmacology
Protein Structure, Tertiary
Structure-Activity Relationship

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Class I Phosphatidylinositol 3-Kinases
Agammaglobulinaemia Tyrosine Kinase
BTK protein, human