title: Type III or allosteric kinase inhibitors for the treatment of non-small cell lung cancer.
abstract: BACKGROUND
  In recent times, there has been much interest in the development of pharmacological kinase inhibitors that treat NSCLC. Furthermore, treatment options have been guided by the development of a wide panel of synthetic small molecule kinase inhibitors. Most of the molecules developed belong to the type I class of inhibitors that target the ATP-binding site in its active conformation. The high sequence similarity in the ATP-binding site among members of the kinase families often results in low selectivity and additional toxicities. Also, second mutations in the ATP-binding site, such as threonine to methionine at position 790, have been described as a mechanism of resistance to ATP-competitive kinase inhibitors. For these reasons, alternative drug development approaches targeting sites other than the ATP cleft are being pursued. The class III or allosteric inhibitors, which bind outside the ATP-binding site, have been shown to negatively modulate kinase activity.
  
  
  METHODS
  In this review, the authors discuss the most well-characterised allosteric inhibitors that have reached clinical development in NSCLC.
  
  
  CONCLUSIONS
  Great progress has made in developing inhibitors with entirely new modes of action. That being said, it is important to highlight that despite their apparent simplicity, biochemical assays will remain at the core of drug discovery activities to better explore these new opportunities.
authors.affiliation: Second University of Naples, Medical Oncology, Department of Experimental and Internal Medicine "F. Magrassi e A. Lanzara" , Via S. Pansini 5, 80131 Napoli , Italia +39 081 5666745 ; +39 081 5666732 ; florianamorgillo@yahoo.com.
authors.forename: Morena
authors.initials: M
authors.lastname: Fasano
authors.forename: Carminia Maria
authors.initials: CM
authors.lastname: Della Corte
authors.forename: Raffaele
authors.initials: R
authors.lastname: Califano
authors.forename: Annalisa
authors.initials: A
authors.lastname: Capuano
authors.forename: Teresa
authors.initials: T
authors.lastname: Troiani
authors.forename: Erika
authors.initials: E
authors.lastname: Martinelli
authors.forename: Fortunato
authors.initials: F
authors.lastname: Ciardiello
authors.forename: Floriana
authors.initials: F
authors.lastname: Morgillo
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000494:Allosteric Regulation / Q000502:physiology*; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism*; D002986:Clinical Trials as Topic; D004311:Double-Blind Method; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic
chemical_list: D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate
keywords: AKT; MAPK kinase; non-small cell lung cancer; type III tyrosine kinase inhibitor