Fragment-based lead discovery of indazole-based compounds as AXL kinase inhibitors
Pearly Shuyi Ng1, Klement Foo1, Sandra Sim1
1Experimental Drug Development Centre, 10 Biopolis Road #05-01 Chromos, 138670, Singapore.
Abstract:
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.
Insights
Researchers developed a novel indazole-based inhibitor targeting AXL receptor tyrosine kinase, a key factor in cancer progression and drug resistance. This new compound shows promise as a starting point for developing more effective cancer therapies.
Area of Science:
- Biochemistry
- Molecular Biology
- Medicinal Chemistry
Background:
- AXL receptor tyrosine kinase is upregulated in various cancers, correlating with poor prognosis and acquired drug resistance.
- Targeting AXL presents a therapeutic strategy to overcome cancer progression and treatment failure.
Purpose of the Study:
- To discover and optimize novel indazole-based inhibitors of AXL.
- To characterize the binding interactions and in vivo properties of the developed inhibitors.
Main Methods:
- Fragment-based lead discovery approach using biochemical screening.
- In-house expanded library of fragments (ELF) screening and optimization.
- Structure-based drug design utilizing docking studies and X-ray crystallography.
Main Results:
- Identification of an indazole fragment hit (11) and its optimization to a potent inhibitor (54).
- Determination of the X-ray crystal structure of an analog (50) complexed with mutated Mer kinase domain, revealing key binding interactions.
- Inhibitor 54 demonstrated good potency, reasonable kinase selectivity, and moderate in vivo exposure.
Conclusions:
- The developed indazole-based AXL inhibitors represent a promising starting point for further optimization.
- The structural insights gained facilitate rational drug design for improved AXL-targeted cancer therapies.
