title: AT-9283, a small-molecule multi-targeted kinase inhibitor for the potential treatment of cancer.
abstract: AT-9283 has been identified and developed by Astex Therapeutics via structure-based optimization of a ligand-efficient pyrazole-benzimidazole fragment. AT-9283 inhibits several important kinases, including the Aurora kinase A, Aurora kinase B, Janus kinase (Jak)2, Jak3 and Abl kinase. Studies using multiple solid tumor and leukemia cell lines have demonstrated the ability of AT-9283 to inhibit growth and survival of tumor cells, and the direct inhibition of these kinases has been demonstrated in cell-based systems. The in vivo antitumor activity of AT-9283 has also been demonstrated in human tumor xenograft models. Based on these preclinical studies, several clinical trials have been conducted in patients with hematological malignancies, such as leukemias, myelodysplastic syndrome, myeloproliferative disease, chronic myeloid leukemia, lymphomas and multiple myeloma, and also in patients with solid tumors. Although phase II clinical trials have not been completed, AT-9283 demonstrated good safety and efficacy in phase I clinical trials. Thus, AT-9283 has potential as a therapeutic agent in several patient populations through its different inhibitory activities.
authors.affiliation: Saga University, Division of Hematology, Respiratory Medicine and Oncology, Faculty of Medicine, Department of Internal Medicine, Saga University, 5-1-1 Nabeshima, Saga, Japan. shkimu@cc.saga-u.ac.jp
authors.forename: Shinya
authors.initials: S
authors.lastname: Kimura
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D017277:Drug Approval; D004353:Drug Evaluation, Preclinical; D019337:Hematologic Neoplasms / Q000188:drug therapy; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D014508:Urea / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C535237:1-cyclopropyl-3-(3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl)urea; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D047428:Protein Kinase Inhibitors; D014508:Urea; D017346:Protein Serine-Threonine Kinases