2. Academic Validation
  3. Structure-guided conversion from an anaplastic lymphoma kinase inhibitor into Plasmodium lysyl-tRNA synthetase selective inhibitors

Structure-guided conversion from an anaplastic lymphoma kinase inhibitor into Plasmodium lysyl-tRNA synthetase selective inhibitors

  • Commun Biol. 2024 Jun 18;7(1):742. doi: 10.1038/s42003-024-06455-4.
Jintong Zhou # 1 2,  Mingyu Xia # 2,  Zhenghui Huang 3,  Hang Qiao 2,  Guang Yang 1,  Yunan Qian 3,  Peifeng Li 2,  Zhaolun Zhang 4,  Xinai Gao 4,  Lubin Jiang 3,  Jing Wang 5 6,  Wei Li 7,  Pengfei Fang 8 9
Affiliations

Affiliations

  • 1 School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, 1 Sub-lane Xiangshan, Hangzhou, 310024, China.
  • 2 State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China.
  • 3 Key Laboratory of Molecular Virology and Immunology, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China.
  • 4 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu, 211198, China.
  • 5 School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, 1 Sub-lane Xiangshan, Hangzhou, 310024, China. jwang@sioc.ac.cn.
  • 6 State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China. jwang@sioc.ac.cn.
  • 7 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu, 211198, China. wli@cpu.edu.cn.
  • 8 School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, 1 Sub-lane Xiangshan, Hangzhou, 310024, China. fangpengfei@sioc.ac.cn.
  • 9 State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China. fangpengfei@sioc.ac.cn.
  • # Contributed equally.
PMID: 38890421 DOI: 10.1038/s42003-024-06455-4
Abstract

Aminoacyl-tRNA synthetases (aaRSs) play a central role in the translation of genetic code, serving as attractive drug targets. Within this family, the lysyl-tRNA synthetase (LysRS) constitutes a promising antimalarial target. ASP3026, an anaplastic lymphoma kinase (ALK) inhibitor was recently identified as a novel Plasmodium falciparum LysRS (PfLysRS) inhibitor. Here, based on cocrystal structures and biochemical experiments, we developed a series of ASP3026 analogues to improve the selectivity and potency of LysRS inhibition. The leading compound 36 showed a dissociation constant of 15.9 nM with PfLysRS. The inhibitory efficacy on PfLysRS and parasites has been enhanced. Covalent attachment of L-lysine to compound 36 resulted in compound 36K3, which exhibited further increased inhibitory activity against PfLysRS but significantly decreased activity against ALK. However, its inhibitory activity against parasites did not improve, suggesting potential future optimization directions. This study presents a new example of derivatization of kinase inhibitors repurposed to inhibit aaRS.

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