Imatinib and its successors--how modern chemistry has changed drug development.
Since protein kinases are frequently mutated or otherwise deregulated in human malignancies, they serve as a target for differentiating between tumor cells and normal tissues. Imatinib mesylat (IM), an inhibitor of the BCR-ABL tyrosine kinase was introduced in 2001 and has revolutionized the treatment of patients with chronic myeloid leukemia (CML). Since 2005 a second generation of tyrosine kinase inhibitors is to follow in Imatinib's footsteps: The development of these new small molecules was promoted by the identification of potential target kinases within the cellular signaling apparatus. Modern biochemical tools provide relevant amounts of these target kinases necessary for high throughput screening (HTS) campaigns and for elucidation of their 3-D structure by crystallography. Supported by computational chemistry the resulting data have enabled rational drug design. In this review low molecular weight inhibitors used for the CML treatment are summarized, pointing out their chemical similarities and differences.
Müller
Bernhard A
BA
Department of Chemistry, Division of Organic Chemistry, University of Natural Resources and Applied Life Sciences, Vienna, Muthgasse 18, Vienna, Austria. bernhard.mueller@boku.ac.at
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000266:history / Q000627:therapeutic use; D064127:Aurora Kinases; D001549:Benzamides; D000069439:Dasatinib; D055808:Drug Discovery / Q000266:history / Q000379:methods*; D049673:History, 20th Century; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology; D010879:Piperazines / Q000737:chemistry* / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000737:chemistry* / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000627:therapeutic use
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; C498826:nilotinib; C506918:bafetinib; D000069439:Dasatinib