Allosteric targeting of receptor tyrosine kinases.
The drug discovery landscape has been transformed over the past decade by the discovery of allosteric modulators of all major mammalian receptor superfamilies. Allosteric ligands are a rich potential source of drugs and drug targets with clear therapeutic advantages. G protein-coupled receptors, ligand-gated ion channels and intracellular nuclear hormone receptors have all been targeted by allosteric modulators. More recently, a receptor tyrosine kinase (RTK) has been targeted by an extracellular small-molecule allosteric modulator. Allosteric mechanisms of structurally distinct molecules that target the various receptor families are more alike than originally anticipated and include selectivity, orthosteric probe dependence and pathway-biased signaling.
1] The Switch Laboratory, Department of Cellular and Molecular Medicine, University of Leuven, Leuven, Belgium. [2] The Switch Laboratory, Flanders Institute for Biotechnology (VIB), Leuven, Belgium.
Frederik
F
De Smet
Drug Discovery Biology and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, Victoria, Australia.
Arthur
A
Christopoulos
1] Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, Department of Oncology, University of Leuven, Leuven, Belgium. [2] Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven, Belgium.
Peter
P
Carmeliet
D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D055808:Drug Discovery; D006801:Humans; D058446:Ligand-Gated Ion Channels / Q000235:genetics / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000494:pharmacology
D058446:Ligand-Gated Ion Channels; D018160:Receptors, Cytoplasmic and Nuclear; D043562:Receptors, G-Protein-Coupled; D054852:Small Molecule Libraries; D020794:Receptor Protein-Tyrosine Kinases