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ALK5抑制剂的设计、合成及其生物学活性评价

许涛, 王小伟, 刘晓蓉, 王亚洲, 李志裕

许涛, 王小伟, 刘晓蓉, 王亚洲, 李志裕. ALK5抑制剂的设计、合成及其生物学活性评价[J]. 中国药科大学学报, 2020, 51(4): 441-448. DOI: 10.11665/j.issn.1000-5048.20200408
引用本文: 许涛, 王小伟, 刘晓蓉, 王亚洲, 李志裕. ALK5抑制剂的设计、合成及其生物学活性评价[J]. 中国药科大学学报, 2020, 51(4): 441-448. DOI: 10.11665/j.issn.1000-5048.20200408
shu
XU Tao, WANG Xiaowei, LIU Xiaorong, WANG Yazhou, LI Zhiyu. Design, synthesis and biological evaluation of ALK5 inhibitors[J]. Journal of China Pharmaceutical University, 2020, 51(4): 441-448. DOI: 10.11665/j.issn.1000-5048.20200408
Citation: XU Tao, WANG Xiaowei, LIU Xiaorong, WANG Yazhou, LI Zhiyu. Design, synthesis and biological evaluation of ALK5 inhibitors[J]. Journal of China Pharmaceutical University, 2020, 51(4): 441-448. DOI: 10.11665/j.issn.1000-5048.20200408
shu

ALK5抑制剂的设计、合成及其生物学活性评价

  • 1.

    中国药科大学药学院，南京 210009

  • 2.

    南京圣和药业股份有限公司，南京 211100

基金项目: 国家“重大新药创制”科技重大专项资助项目(No.2018ZX09301014-006, No.2019ZX09201001-003-005)

Design, synthesis and biological evaluation of ALK5 inhibitors

  • 1.

    School of Pharmacy, China Pharmaceutical University, Nanjing 210009

  • 2.

    Nanjing Sanhome Pharmaceutical Co. , Ltd. , Nanjing 211100，China

Funds: This study was supported by the National Science and Technology Major Project for Drug Innovation (No.2018ZX09301014-006; No.2019ZX09201001-003-005)

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    摘要
  • 摘要: 以ALK5抑制剂LY-3200882作为先导化合物，利用生物电子等排和构象限制等药物设计策略，结合分子对接技术，设计并合成了10个结构新颖的化合物，其结构经1H NMR、HR-MS表征。体外活性筛选结果显示，大多数化合物具有良好的激酶抑制活性。其中，化合物B4表现出显著优于LY-3200882的ALK5抑制活性(IC50 = 1.4 nmol/L vs 41.1 nmol/L)，同时对NIH3T3细胞中TGFβ-ALK5-SMAD2/3信号通路具有良好的抑制活性(IC50 = 14.2 nmol/L)。进一步研究表明，化合物B4的药代动力学性质良好，口服暴露量及生物利用度满足成药性要求，值得进一步开发。
    Abstract: Using ALK5 inhibitor LY-3200882 as a lead compound, ten structurally novel compounds were designed by bioisosterism, conformational restriction and molecular docking technology. All structures were synthesized and confirmed by 1H NMR and HR-MS. The results of in vitro activity screening showed that most compounds had good kinase inhibitory activity. Among them, compound B4 showed significantly better ALK5 inhibitory activity than LY-3200882 (IC50 = 1.4 nmol/L vs 41.1 nmol/L), and had good inhibitory activity against TGFβ-ALK5-SMAD2/3 signaling pathway in NIH3T3 cells (IC50 = 14.2 nmol/L). Besides, compound B4 had good pharmacokinetic properties, such as oral exposure and bioavailability, which is worthy of further development.
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    • 参考文献(9)
  • [1] Morikawa M，Derynck R, Miyazono K. TGF-β and the TGF-β family: context-dependent roles in cell and tissue physiology[J]. Cold Spring Harb Perspect Biol, 2016, 8(5):a021873.
    [2] Horbelt D, Denkis A, Knaus P. A portrait of transforming growth factor β superfamily signalling: background matters[J]. Int J Biochem Cell Biol, 2012, 44(3):469-474.
    [3] Xiaoling T, Wencai G, Lingyun Z, et al. Physical interaction of STAT1 isoforms with TGF-β receptors leads to functional crosstalk between two signaling pathways in epithelial ovarian cancer[J]. J Exp Clin Canc Res, 2018, 37(1):103.
    [4] Heldin CH, Moustakas A. Signaling receptors for TGF-β family members[J]. Cold Spring Harb Perspect Biol, 2016, 8(8):a022053.
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    [7] Batlle E, Massague J. Transforming growth factor-beta signaling in immunity and cancer[J]. Immunity, 2019, 50(4):924-940.
    [8] Pei H, Parthasarathy S, Joseph S, et al. LY3200882, a novel, highly selective TGFβRI small molecule inhibitor[J]. Cancer Res, 2017, 77:955.
    [9] Goldberg FW , Ward RA , Powell SJ , et al. Rapid generation of a high quality lead for transforming growth factor-β (TGF-β) type I receptor (ALK5)[J]. J Med Chem, 2009, 52(23):7901-7905.
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出版历程
  • 收稿日期:  2020-04-16
  • 刊出日期:  2020-08-24

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