Fragment-based lead discovery of indazole-based compounds as AXL kinase inhibitors
| Autor: | Susmitha Vuddagiri, Doris Hui Ying Tee, Sandra Sim, Alvin W. Hung, Gang Wang, Thomas H. Keller, Li Hong Tan, Zhiyuan Ke, Anders Poulsen, Nithya Baburajendran, Boping Liu, Vishal Pendharkar, Pearly Shuyi Ng, Jeffrey Hill, Jothi Anantharajan, Joma Joy, May Ann Lee, Zekui Perlyn Kwek, Kanda Sangthongpitag, Sifang Wang, Vithya Manoharan, Klement Foo, Chuhui Huang, Nur Huda Binte Ahmad |
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| Rok vydání: | 2021 |
| Předmět: |
Models
Molecular Indazoles Clinical Biochemistry Fragment-based lead discovery Pharmaceutical Science Biochemistry Receptor tyrosine kinase chemistry.chemical_compound Structure-Activity Relationship In vivo Cell Line Tumor Proto-Oncogene Proteins Drug Discovery Humans Molecular Biology Protein Kinase Inhibitors Cell Proliferation Indazole biology Dose-Response Relationship Drug Molecular Structure Chemistry Kinase Organic Chemistry Receptor Protein-Tyrosine Kinases Axl Receptor Tyrosine Kinase Protein kinase domain Docking (molecular) biology.protein Molecular Medicine TYRO3 |
| Zdroj: | Bioorganicmedicinal chemistry. 49 |
| ISSN: | 1464-3391 |
| Popis: | AXL is a member of the TAM (TYRO3, AXL, MER) subfamily of receptor tyrosine kinases. It is upregulated in a variety of cancers and its overexpression is associated with poor disease prognosis and acquired drug resistance. Utilizing a fragment-based lead discovery approach, a new indazole-based AXL inhibitor was obtained. The indazole fragment hit 11, identified through a high concentration biochemical screen, was expeditiously improved to fragment 24 by screening our in-house expanded library of fragments (ELF) collection. Subsequent fragment optimization guided by docking studies provided potent inhibitor 54 with moderate exposure levels in mice. X-ray crystal structure of analog 50 complexed with the I650M mutated kinase domain of Mer revealed the key binding interactions for the scaffold. The good potency coupled with reasonable kinase selectivity, moderate in vivo exposure levels, and availability of structural information for the series makes it a suitable starting point for further optimization efforts. |
| Databáze: | OpenAIRE |
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