[Innovation of clinical trials for anti-cancer drugs in Japan--proposals from academia with special reference to the development of novel Bcr-Abl/Lyn tyrosine kinase inhibitor INNO-406 (NS-187) for imatinib-resistant chronic myelogenous leukemia].
Imatinib mesylate (Gleevec) has dramatically changed the strategy of chronic myeloid leukemia (CML) therapy. However, resistance is often reported in advanced-stage CML patients. Several novel tyrosine kinase inhibitors which have been developed to override imatinib resistance mechanism due to point mutations within the Abl kinase domain. Quite recently we successfully developed the novel Bcr-Abl/Lyn dual inhibitor INNO-406 (NS-187) which shows unique profile to overcome this resistance. Inhibitors of Abl tyrosine kinase are divided into two groups, ATP-competitive and non-competitive inhibitors. ATP-competitive inhibitors are further fall into two subclasses, the Src/Abl inhibitors and 2-phenylaminopyrimidin-based compounds. Dasatinib (BMS-354825, Sprycel) is classified as Src/Ablinhibitors while nilotinib (AMN 107) and INNO-406 (NS-187) belong to the latter. Among them, clinical studies on dasatinib and AMN 107 had started earlier than the others and favorable results are accumulating. We have performed basic and preclinical studies of INNO-406 (NS-187) in Japan, and then its clinical trials have been commenced firstly in the United States from July, 2006. The ultimate goal of clinical development is to bring the novel therapeutics with regulatory safety and efficacy to the clinical settings as soon as possible. Considerations important for the innovation of clinical trials for anti-cancer drugs in Japan are discussed.
Maekawa
Taira
T
Department of Transfusion Medicine & Cell Therapy, Kyoto University Hospital.
D000970:Antineoplastic Agents; D001549:Benzamides; D002986:Clinical Trials as Topic; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000473:pathology*; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000737:chemistry; D011505:Protein-Tyrosine Kinases / Q000737:chemistry; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology; D013844:Thiazoles / Q000737:chemistry
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C498826:nilotinib; C506918:bafetinib; D000069439:Dasatinib