RÉSUMÉ
AXL is a receptor tyrosine kinase that plays a key role in tumor growth and proliferation. The scientific community has validated AXL as therapeutic target in the treatment of cancers for several years now, and several AXL inhibitors have been developed but none of them are approved. In this context, we started to design new kinase inhibitors targeting AXL from the 7-azaindole scaffold well known to interact with the ATP binding site of the kinase. Focused screening and chemical diversification around 7-azaindole scaffold were developed, based on modeling studies and medicinal chemistry rational, leading to the discovery of a new family of hits with potent inhibitory activity against AXL.
Sujet(s)
Indoles/composition chimique , Inhibiteurs de protéines kinases/composition chimique , Inhibiteurs de protéines kinases/pharmacologie , Protéines proto-oncogènes/antagonistes et inhibiteurs , Récepteurs à activité tyrosine kinase/antagonistes et inhibiteurs , Adénosine triphosphate/composition chimique , Adénosine triphosphate/métabolisme , Sites de fixation , Évaluation préclinique de médicament , Activation enzymatique/effets des médicaments et des substances chimiques , Humains , Concentration inhibitrice 50 , Simulation de docking moléculaire , Liaison aux protéines , Structure tertiaire des protéines , Protéines proto-oncogènes/métabolisme , Récepteurs à activité tyrosine kinase/métabolisme , Axl Receptor Tyrosine KinaseRÉSUMÉ
Receptor tyrosine kinases (RTK) are transmembrane receptors that regulate signal transduction in cells. As a member of the TAM (Tyro-3, Axl, Mer) RTK subfamily, Axl regulates key processes such as cell growth, migration, aggregation, and apoptosis through several pathways. Its overexpression/overactivation has been underlined in several conditions, especially cancers, and in both chemotherapy and targeted therapy sensitivity loss. In this review, we propose to highlight the therapeutic implication of Axl, starting with the pathways it regulates, validating its interest as a therapeutic target, and defining the tools available to develop strategies for its inhibition. We especially focus on small molecule inhibitors, their structure, inhibition profile, and development stages.