title: Crystal Structures of Neurotrophin Receptors Kinase Domain.
abstract: Neurotrophins and their receptors (Trk) play key roles in the development of the nervous system and in cell survival. Trk receptors are therefore attractive pharmacological targets for brain disorders as well as for cancers. While the druggability of the extracellular domain of the receptors, that specifically binds neurotrophins, is yet to be proven, the intracellular kinase domains are attractive targets for small-molecule binding. The recent crystal structures of the three isoforms of the Trk family, TrkA, TrkB, and TrkC have been described in their apo forms and in complex with potent and selective pan-Trk inhibitors. The description of the kinase domain of each of the isoforms will be discussed in their apo forms or bound to potent inhibitors of interest in cancer therapy. Nononcology indications and selectivity issues will also be discussed.
authors.affiliation: Sanofi, Vitry-sur-Seine, France. Electronic address: thomas.bertrand@sanofi.com.
authors.forename: T
authors.initials: T
authors.lastname: Bertrand
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001051:Apoenzymes / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D020134:Catalytic Domain; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D008562:Membrane Glycoproteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D008968:Molecular Conformation; D009414:Nerve Growth Factors / Q000737:chemistry / Q000378:metabolism; D010649:Phenylalanine / Q000737:chemistry; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D020917:Receptor, trkA / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D020813:Receptor, trkB / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D020812:Receptor, trkC / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D040681:Structural Homology, Protein
chemical_list: D000970:Antineoplastic Agents; D001051:Apoenzymes; D007527:Isoenzymes; D008024:Ligands; D008562:Membrane Glycoproteins; C000611485:NTRK1 protein, human; D009414:Nerve Growth Factors; D047428:Protein Kinase Inhibitors; D010649:Phenylalanine; D000255:Adenosine Triphosphate; D020917:Receptor, trkA; D020813:Receptor, trkB; D020812:Receptor, trkC; C000591259:tropomyosin-related kinase-B, human
keywords: Drug design; Inhibitors; Kinase; Pharmacology; Selectivity; Structure