title: Kinase Inhibitors in Multitargeted Cancer Therapy.
abstract: The old-fashioned anticancer approaches, aiming at arresting cancer cell proliferation interfering with non-specific targets (e.g. DNA), have been replaced, in the last decades, by more specific target oriented ones. Nonetheless, single-target approaches have not always led to optimal outcomes because, for its complexity, cancer needs to be tackled at various levels by modulation of several targets. Although at present, combinations of individual singletarget drugs represent the most clinically practiced therapeutic approaches, the modulation of multiple proteins by a single drug, in accordance with the polypharmacological strategy, has become more and more appealing. In the perspective of a multi-target approach, the closely related evolutionary members of the tyrosine kinase family are ideal candidates. Indeed, tyrosine kinase activities are not only critical in tumor phenotype maintenance, but also modulate several functions in the tumor microenvironment. Consequently, several multikinase inhibitors were approved in the last decade, and many new molecules are currently in preclinical or clinical development. In the present review we report on the most widely FDA-approved multitargeted drugs, discussing about their mechanism of action and outlining the clinical trials that have brought them to approval.
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche "STEBICEF" - Università di Palermo, Viale delle Scienze - Ed. 17 -90128 Palermo, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Gentile
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche "STEBICEF" - Università di Palermo, Viale delle Scienze - Ed. 17 -90128 Palermo, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Martorana
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche "STEBICEF" - Università di Palermo, Viale delle Scienze - Ed. 17 -90128 Palermo, Italy.
authors.forename: Antonino
authors.initials: A
authors.lastname: Lauria
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche "STEBICEF" - Università di Palermo, Viale delle Scienze - Ed. 17 -90128 Palermo, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Bonsignore
mesh_terms: D000813:Anilides / Q000737:chemistry / Q000627:therapeutic use; D000077547:Crizotinib; D006801:Humans; D000068877:Imatinib Mesylate / Q000737:chemistry / Q000627:therapeutic use; D007093:Imidazoles / Q000737:chemistry / Q000627:therapeutic use; D007211:Indoles / Q000737:chemistry / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009536:Niacinamide / Q000031:analogs & derivatives / Q000737:chemistry / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000737:chemistry / Q000627:therapeutic use; D010880:Piperidines / Q000737:chemistry / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D011720:Pyrazoles / Q000737:chemistry / Q000627:therapeutic use; D011724:Pyridazines / Q000737:chemistry / Q000627:therapeutic use; D011725:Pyridines / Q000737:chemistry / Q000627:therapeutic use; D011758:Pyrroles / Q000737:chemistry / Q000627:therapeutic use; D011799:Quinazolines / Q000737:chemistry / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077157:Sorafenib; D000077210:Sunitinib
chemical_list: D000813:Anilides; D007093:Imidazoles; D007211:Indoles; D010671:Phenylurea Compounds; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011724:Pyridazines; D011725:Pyridines; D011758:Pyrroles; D011799:Quinazolines; C558660:cabozantinib; C559147:regorafenib; D009536:Niacinamide; C545373:ponatinib; D000077547:Crizotinib; D000068877:Imatinib Mesylate; D000077157:Sorafenib; D020794:Receptor Protein-Tyrosine Kinases; D000077210:Sunitinib; C452423:vandetanib
keywords: FDA-approved drugs; Multitargeted drugs; anticancer agents; oncogene addiction; polypharmacology; tumor microenvironment; tyrosine kinase receptors