2. Academic Validation
  3. Discovery of novel potent migrastatic Thiazolo[5,4-b]pyridines targeting Lysyl-tRNA synthetase (KRS) for treatment of Cancer metastasis

Discovery of novel potent migrastatic Thiazolo[5,4-b]pyridines targeting Lysyl-tRNA synthetase (KRS) for treatment of Cancer metastasis

  • Eur J Med Chem. 2021 Jun 5:218:113405. doi: 10.1016/j.ejmech.2021.113405.
Seungbeom Lee 1,  Nam Hoon Kwon 2,  Bokyung Seo 3,  Jin Young Lee 3,  Hye Young Cho 4,  Kyeojin Kim 3,  Hyun Su Kim 5,  Kiwon Jung 5,  Young Ho Jeon 4,  Sunghoon Kim 6,  Young-Ger Suh 7
Affiliations

Affiliations

  • 1 College of Pharmacy, CHA University, Gyeonggi-do, 11160, Republic of Korea; College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea.
  • 2 Medicinal Bioconvergence Research Center, Institute for Artificial Intelligence and Biomedical Research, College of Pharmacy and College of Medicine, Gangnam Severance Hospital, Yonsei University, Incheon, South Korea, 21983.
  • 3 College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea.
  • 4 College of Pharmacy, Korea University, 2511 Sejong-ro, Sejong, 339-700, Republic of Korea.
  • 5 College of Pharmacy, CHA University, Gyeonggi-do, 11160, Republic of Korea.
  • 6 Medicinal Bioconvergence Research Center, Institute for Artificial Intelligence and Biomedical Research, College of Pharmacy and College of Medicine, Gangnam Severance Hospital, Yonsei University, Incheon, South Korea, 21983. Electronic address: sunghoonkim@yonsei.ac.kr.
  • 7 College of Pharmacy, CHA University, Gyeonggi-do, 11160, Republic of Korea; College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea. Electronic address: ygsuh@snu.ac.kr.
PMID: 33831781 DOI: 10.1016/j.ejmech.2021.113405
Abstract

Recently, non-canonical roles of Lysyl-tRNA Synthetase (KRS), which is associated with cell migration and Cancer metastasis, have been reported. Therefore, KRS has emerged as a promising target for the treatment of cell migration-related diseases, especially Cancer metastasis, although the satisfying chemical inhibitors targeting KRS have not yet been identified. Here, we report the discovery of novel, mechanistically unique, and potent cell migration inhibitors targeting KRS, including the chemical and biological studies on the most effective N,N-dialkylthiazolo [5,4-b]pyridin-2-amine (SL-1910). SL-1910 exhibited highly potent migration inhibition (EC50 = 81 nM against the mutant KRS-overexpressed MDA-MB-231 cells) and was superior to the previously reported KRS inhibitor (migration inhibitory EC50 = 8.5 μM against H226 cells). The KRS protein binding study via fluorescence-based binding titration and KRS protein 2D-NMR mapping study, in vitro concentration-dependent cell migration inhibition, and in vivo anti-metastatic activity of SL-1910, which consists of a new scaffold, have been reported in this study. In addition, in vitro absorption, distribution, metabolism, and excretion studies and mouse pharmacokinetics experiments for SL-1910 were conducted.

Keywords

Cell migration; Core scaffold hopping; Identification of binding pocket and residues; In vivo metastasis assay; Lysyl-tRNA synthetase; Migrastatics.

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