Activity of the multitargeted kinase inhibitor, AT9283, in imatinib-resistant BCR-ABL–positive leukemic cells

Abstract

IntroductionPhiladelphia (Ph) chromosome results from a reciprocal translocation between chromosomes 9 and 22 and generates the BCR-ABL chimera protein, the cause of chronic myeloid leukemia (CML) and Ph ϩ acute lymphoid leukemia (ALL). The ABL tyrosine kinase inhibitor (TKI), imatinib mesylate, has dramatically changed the first-line therapy of CML. 1 Most patients with newly diagnosed CML with chronic phase, when treated with imatinib, achieve durable responses. However, emergence of refractory disease and relapse have frequently been reported, particularly in patients with CML with advanced-stage disease and patients with Ph ϩ ALL. 2,3 Among several mechanisms of resistance, point mutations within the ABL kinase domain that interfere with imatinib binding are the most critical cause of imatinib resistance. 4,5 To overcome these imatinib resistance mechanisms, 4 secondgeneration ABL TKIs have been developed: dasatinib, 6 nilotinib, 7 bosutinib 8 and bafetinib (formerly INNO-406). 9,10 Despite promising clinical results from these second-generation ABL TKIs for most patients with imatinib-resistant BCR-ABL ϩ leukemia, the mutation of threonine 315 to isoleucine (T315I) confers resistance to all these TKIs. 11,12 Thus, identification of novel agents for the effective treatment of patients with CML with T315I is an important and challenging task. 13 Aurora kinases A and B are a family of serine/threonine kinases involved in many cellular functions. [14][15][16] Inappropriate expression of these enzymes in certain cancers may result in aneuploidy and carcinogenesis. 17 Consequently, the potential therapeutic value of targeting Aurora kinases has become a focus of anticancer therapy. 14 Recently, we identified an Aurora kinase inhibitor, AT9283 (1-cyclopropyl-3[5-morpholin-4yl methyl-1H-benzomidazol-2-yl]-urea) by way of structure-based optimization of a ligand-efficient pyrazole-benzimidazole fragment. X-ray crystallographic structures were generated with the use of a novel soakable form of Aurora A and were used to drive the optimization toward potent (half-maximal inhibition constant [IC 50 ] Ͻ 3nM) dual Aurora A/B inhibitor. AT9283 that also potently inhibits several kinases, including Janus kinase-2 (JAK2) and JAK3 (1.2 and 1.1nM, respectively), c-ABL (110nM), and ABL/T315I (4nM), is currently under evaluation in phase 1 clinical trials for metastatic solid tumors and hematologic malignancies. 18,19 Here, we report the putative mechanism by which AT9283 binds to BCR-ABL/T315I and its activity against imatinib-resistant BCR-ABL ϩ leukemic cells, including those with the T315I mutation. Methods Reagent and cell linesAT9283 was synthesized by Astex Therapeutics Ltd ( Figure 1A). 18 Human CML cell lines (K562, MEG-01, BV173, KU812, MYL, KT-1, and The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC sectio...

New Drugs for Chronic Myelogenous Leukemia

“…In cell-based assays, AT9283 inhibited proliferation of BaF3 cells transduced with wild-type BCR-ABL1 (IC50 = 13 nM) and mutated BCR-ABL1, including T315I (IC50 = 11 nM), Y253F (IC50 = 16 nM), and E255K (IC50 = 13 nM) [28]. AT9283 does not form hydrogen bonds with residue T315 and does not bind within the pocket behind this residue [28]. Thus, AT9283 does not suffer from steric hindrance imposed by the T315I mutation.…”

Clinical Experience with Aurora Kinase Inhibitors: A Review

“…A variety of other cancer-related protein kinases is also inhibited by AT9283, including Abl kinase, JAK2, JAK3, Ret, and GSK3 beta. The inhibitory potential of AT9283 against the T315I Abl mutant makes this compound an attractive option for the treatment of imatinib-resistant patients with CML [79]. Clinical studies with this compound are ongoing, and preliminary results of a phase I study in patients with refractory leukemia were presented at ASCO 2008.…”

Synthesis of n-acetylglucosaminides dimers

“…Для покращен-ня селективності останніх було введено основну функціональну групу та замінено феніламідний залишок на циклопропілсечовину, що призвело до утворення сполуки-лідера АТ9283 (рис. 12), яка знаходиться на стадії клінічних досліджень як по-тенційний ЛЗ для фармакотерапії метастазуючих пухлин та гемобластозів [59]. Слід відмітити, що дослідження кристалічної структури комплексу АТ9283 із Aurora A кіназою виявило ідентичне зв'язування АТ9283 та почат-кового фрагменту 5 (рис.…”