Fragment-based lead discovery of indazole-based compounds as AXL kinase inhibitors.

Cell Line, Tumor Cell Proliferation / drug effects Dose-Response Relationship, Drug Drug Discovery Humans Indazoles / chemical synthesis Models, Molecular Molecular Structure Protein Kinase Inhibitors / chemical synthesis Proto-Oncogene Proteins / antagonists & inhibitors Receptor Protein-Tyrosine Kinases / antagonists & inhibitors Structure-Activity Relationship Axl Receptor Tyrosine Kinase

AXL inhibitor Fragment hit-to-lead Fragment optimization Receptor tyrosine kinase inhibitor TAM family of receptor tyrosine kinase

Journal

Bioorganic & medicinal chemistry

ISSN: 1464-3391

Titre abrégé: Bioorg Med Chem

Pays: England

ID NLM: 9413298

Informations de publication

Date de publication:
01 11 2021

Historique:

received: 16 07 2021

revised: 16 09 2021

accepted: 19 09 2021

pubmed: 3 10 2021

medline: 14 1 2022

entrez: 2 10 2021

Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.bmc.2021.116437 PMID: 34600239

pubmed: 34600239

pii: S0968-0896(21)00445-4

doi: 10.1016/j.bmc.2021.116437

pii:

doi:

Substances chimiques

Indazoles 0

Protein Kinase Inhibitors 0

Proto-Oncogene Proteins 0

Receptor Protein-Tyrosine Kinases EC 2.7.10.1

Axl Receptor Tyrosine Kinase 0

AXL protein, human 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

116437