2. Academic Validation
  3. Optimization of novel benzofuro[3,2-b]pyridin-2(1H)-one derivatives as dual inhibitors of BTK and PI3Kδ

Optimization of novel benzofuro[3,2-b]pyridin-2(1H)-one derivatives as dual inhibitors of BTK and PI3Kδ

  • Eur J Med Chem. 2019 Feb 15:164:304-316. doi: 10.1016/j.ejmech.2018.12.055.
Linyi Liu 1,  Xinyu Li 2,  Yu Cheng 2,  Lianjian Wang 2,  Huizhu Yang 2,  Jiurong Li 2,  Siying He 2,  Shuangjie Wu 3,  Qianqian Yin 4,  Hua Xiang 5
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China; Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Pudong, Shanghai, 201210, China.
  • 2 Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China.
  • 3 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China.
  • 4 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Pudong, Shanghai, 201210, China. Electronic address: yinqq@shanghaitech.edu.cn.
  • 5 Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China. Electronic address: xianghua@cpu.edu.cn.
PMID: 30605829 DOI: 10.1016/j.ejmech.2018.12.055
Abstract

Btk and PI3Kδ play crucial roles in the progression of leukemia, and studies confirmed that the dual inhibition against Btk and PI3Kδ could provide superior Anticancer agents to single targeted therapies. Herein, a new series of novel benzofuro[3,2-b]pyridin-2(1H)-one derivatives were optimized based on a Btk/PI3Kδ Inhibitor 2 designed by our group. Biological studies clarified that compound 6f exhibited the most potent inhibitory activity (BTK: IC50 = 74 nM; PI3Kδ: IC50 = 170 nM) and better selectivity than 2. Moreover, 6f significantly inhibited the proliferation of Raji and Ramos cells with IC50 values of 2.1 μM and 2.65 μM respectively by blocking Btk and PI3K signaling pathways. In brief, 6f possessed of the potency for further optimization as an anti-leukemic drug by inhibiting Btk and PI3Kδ kinase.

Keywords

B-cell malignancies; BTK; Dual inhibitor; Oncology; PI3Kδ.

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