Tyrosine kinases as new molecular targets in treatment of inflammatory disorders and leukemia.
Many protein tyrosine kinases (PTK), including Janus kinase 3 (JAK3) and Bruton's tyrosine kinase (BTK), have been recently identified as potential drug targets to treat diverse diseases including inflammation and cancer. The wealth of structural information currently available for protein kinase-inhibitor complexes facilitates the structure-based design of novel kinase inhibitors. In this report, we discuss the structural basis of protein kinase inhibitor design and the common binding features of small molecule kinase inhibitors including pyridinyl imidazoles, purines, oxindoles, anilinoquinazolines and isoquinalines. The structural features of targeted kinase proteins and their inhibitor complexes are discussed with respect to their structure-and-activity relationships (SAR). We present a structural comparison of kinase inhibitors with a special emphasis on inhibitors of JAK3 and BTK.
Uckun
Fatih M
FM
Drug Discovery Program, Parker Hughes Institute, 2699 Patton Road, St. Paul, MN 55113, USA. fatih_uckun@ih.org
Mao
Chen
C
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000201:enzymology; D007938:Leukemia / Q000188:drug therapy* / Q000201:enzymology; D008958:Models, Molecular; D015394:Molecular Structure; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*
D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011505:Protein-Tyrosine Kinases