title: Investigational Bruton's tyrosine kinase inhibitors for the treatment of rheumatoid arthritis.
abstract: BACKGROUND
  The Tec family of non-receptor tyrosine kinases comprises five members. The cellular expression and function of these kinases has implicated them as potential drug targets for the treatment of both malignant and autoimmune diseases. Most attention has focused on inhibitors of BTK kinase with ibrutinib already approved for the treatment of mantle cell lymphoma and chronic lymphocytic leukaemia. Multiple BTK inhibitors are being developed for both oncology and autoimmune disease indications.
  
  
  METHODS
  BTK inhibitors being evaluated in rheumatoid arthritis are considered. Both inhibitors which have progressed to early clinical development, and those demonstrating activity in rodent models of arthritis are reviewed. These include both reversible and irreversible inhibitors of the kinase, most of which target the cysteine-481 residue of BTK. The selectivity of these inhibitors for Tec family kinases is considered.
  
  
  CONCLUSIONS
  Developing inhibitors of any kinase to treat of rheumatoid arthritis has proved problematic with regard to both efficacy and selectivity. It is anticipated that the more selective BTK inhibitors may prove more useful in treating arthritis, with the use of reversible inhibitors possibly offering a better strategy. Chronic dosing may exacerbate the emergence of drug resistance, with resistant mutations already observed in ibrutinib-treated patients.
authors.affiliation: a Norman Consulting , Burnham Bucks , UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Norman
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000503:physiopathology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000503:physiopathology; D015195:Drug Design; D004351:Drug Resistance; D015507:Drugs, Investigational / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D015507:Drugs, Investigational; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; C089848:Tec protein-tyrosine kinase; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; D000225:Adenine
keywords: Autoimmune disease; B cell; Btk kinase; ibrutinib; rheumatoid arthritis; spebrutinib