2. Academic Validation
  3. Application of deep generative model for design of Pyrrolo[2,3-d] pyrimidine derivatives as new selective TANK binding kinase 1 (TBK1) inhibitors

Application of deep generative model for design of Pyrrolo[2,3-d] pyrimidine derivatives as new selective TANK binding kinase 1 (TBK1) inhibitors

  • Eur J Med Chem. 2023 Feb 5:247:115034. doi: 10.1016/j.ejmech.2022.115034.
Shukai Song 1,  Haotian Tang 2,  Ting Ran 3,  Feng Fang 4,  Linjiang Tong 4,  Hongming Chen 5,  Hua Xie 6,  Xiaoyun Lu 7
Affiliations

Affiliations

  • 1 School of Pharmacy, Jinan University, #855 Xingye Avenue, Guangzhou, 510632, China.
  • 2 Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, #555 Zuchongzhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, No.19(A) Yuquan Road, Shijingshan District, Beijing, 100049, China.
  • 3 Division of Drug and Vaccine Research, Guangzhou Laboratory, Guangzhou, 510530, China.
  • 4 Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, #555 Zuchongzhi Road, Shanghai, 201203, China.
  • 5 Division of Drug and Vaccine Research, Guangzhou Laboratory, Guangzhou, 510530, China. Electronic address: chen_hongming@gzlab.ac.cn.
  • 6 Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, #555 Zuchongzhi Road, Shanghai, 201203, China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Cuiheng New District, Zhongshan City, China. Electronic address: hxie@simm.ac.cn.
  • 7 School of Pharmacy, Jinan University, #855 Xingye Avenue, Guangzhou, 510632, China. Electronic address: luxy2016@jnu.edu.cn.
PMID: 36603506 DOI: 10.1016/j.ejmech.2022.115034
Abstract

The deep conditional transformer neural network SyntaLinker was applied to identify compounds with pyrrolo[2,3-d]pyrimidine scaffold as potent selective TBK1 Inhibitor. Further medicinal chemistry optimization campaign led to the discovery of the most potent compound 7l, which exhibited strong enzymatic inhibitory activity against TBK1 with an IC50 value of 22.4 nM 7l had a superior inhibitory activity in human monocytic THP1-Blue cells reporter gene assay than MRT67307. Furthermore, 7l significantly inhibited TBK1 downstream target genes cxcl10 and ifnβ expression in THP1 and RAW264.7 cells induced by poly (I:C) and lipopolysaccharide, respectively. This study suggested that combination of deep conditional transformer neural network SyntaLinker and transfer learning could be a powerful tool for scaffold hopping in drug discovery.

Keywords

Generative modelling; Structure-activity relationship; SyntaLinker; TBK1 inhibitor; pyrrolo[2,3-d]pyrimidine.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-152237
    99.63%, TBK1 Inhibitor
    IKK