| Reference | 1. Clin Lymphoma Myeloma Leuk. 2014 Jun;14(3):223-30. doi: 10.1016/j.clml.2013.11.001. Epub 2013 Nov 14.<br />
A phase I and pharmacodynamic study of AT9283, a small-molecule inhibitor of aurora kinases in patients with relapsed/refractory leukemia or myelofibrosis.<br />
Foran J(1), Ravandi F(2), Wierda W(2), Garcia-Manero G(2), Verstovsek S(2), Kadia T(2), Burger J(2), Yule M(3), Langford G(3), Lyons J(3), Ayrton J(3), Lock V(3), Borthakur G(2), Cortes J(2), Kantarjian H(4).<br />
Author information:<br />
(1)University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL. (2)University of Texas MD Anderson Cancer Center, Houston, TX. (3)Astex Pharmaceuticals Inc, Cambridge, United Kingdom. (4)University of Texas MD Anderson Cancer Center, Houston, TX. Electronic address: [email protected].<br />
BACKGROUND: This study sought to identify the maximum tolerated dose (MTD) of AT9283, an inhibitor of Aurora kinases A and B, in patients with relapsed or refractory leukemias. Other endpoints included pharmacokinetics, safety and tolerability, pharmacodynamics, and preliminary evidence of efficacy.<br />
PATIENTS AND METHODS: AT9283 was administered as a continuous 72-hour infusion every 21 days. Doses were escalated by a standard 3 + 3 design. After the MTD for the 72-hour infusion was identified, infusion duration was increased incrementally to 96 hours and 120 hours. In total, 48 patients received ≥ 1 cycle of AT9283. Median age was 61 years (range, 22-86 years); 56% were men; 75% were diagnosed with AML; and 89% had received ≥ 3 (up to 16) prior lines of therapy. RESULTS: 324 mg/m(2)/72 h AT9283 was determined to be the MTD. Dose-limiting toxicities (DLTs) were myocardial infarction, hypertension, cardiomyopathy, tumor lysis syndrome, pneumonia, and multiorgan failure. Other AT9283-related toxicities (non-DLT) included myelosuppression, predominantly leukopenia and mucositis. Bone marrow blasts decreased ≥ 38% after AT9283 treatment in approximately one-third of patients with relapsed/refractory AML; however, this effect was transient and no objective responses were achieved, despite evidence of Aurora kinase B inhibition. Two patients with accelerated-phase chronic myeloid leukemia showed evidence of benefit, manifested as a cytogenetic response in 1 case; 1 patient completed 6 cycles of treatment. Exposure to AT9283 was generally dose proportional.<br />
CONCLUSION: AT9283 tolerability was strongly dose-dependent, with reversible myelosuppression predominating at lower doses and events such as cardiovascular toxicities manifesting at higher doses. Clinical trials with AT9283 are ongoing in alternative patient populations.<br />
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2. Clin Cancer Res. 2011 May 15;17(10):3259-71. doi: 10.1158/1078-0432.CCR-10-3012. Epub 2011 Mar 23.<br />
Antimyeloma activity of a multitargeted kinase inhibitor, AT9283, via potent Aurora kinase and STAT3 inhibition either alone or in combination with lenalidomide.<br />
Santo L(1), Hideshima T, Cirstea D, Bandi M, Nelson EA, Gorgun G, Rodig S, Vallet S, Pozzi S, Patel K, Unitt C, Squires M, Hu Y, Chauhan D, Mahindra A, Munshi NC, Anderson KC, Raje N.<br />
Author information:<br />
(1)Division of Hematology and Oncology, Massachusetts General Hospital Cancer Center, Jerome Lipper Multiple Myeloma Disease Center, Dana-Farber Cancer Institute, Boston, Massachusetts 02114, USA.<br />
PURPOSE: Aurora kinases, whose expression is linked to genetic instability and cellular proliferation, are being investigated as novel therapeutic targets in multiple myeloma (MM). In this study, we investigated the preclinical activity of a small-molecule multitargeted kinase inhibitor, AT9283, with potent activity against Aurora kinase A, Aurora kinase B, and Janus kinase 2/3. EXPERIMENTAL DESIGN: We evaluated the in vitro antimyeloma activity of AT9283 alone and in combination with lenalidomide and the in vivo efficacy by using a xenograft mouse model of human MM.<br />
RESULTS: Our data showed that AT9283 induced cell-growth inhibition and apoptosis in MM. Studying the apoptosis mechanism of AT9283 in MM, we observed features consistent with both Aurora kinase A and Aurora kinase B inhibition, such as increase of cells with polyploid DNA content, decrease in phospho-histone H3, and decrease in phospho-Aurora A. Importantly, AT9283 also inhibited STAT3 tyrosine phosphorylation in MM cells. Genetic depletion of STAT3, Aurora kinase A, or Aurora kinase B showed growth inhibition of MM cells, suggesting a role of AT9283-induced inhibition of these molecules in the underlying mechanism of MM cell death. In vivo studies showed decreased MM cell growth and prolonged survival in AT9283-treated mice compared with controls. Importantly, combination studies of AT9283 with lenalidomide showed significant synergistic cytotoxicity in MM cells, even in the presence of bone marrow stromal cells. Enhanced cytotoxicity was associated with increased inhibition of phosphorylated STAT3 and phosphorylated extracellular signal-regulated kinase.<br />
CONCLUSIONS: Demonstration of in vitro and in vivo anti-MM activity of AT9283 provides the rationale for the clinical evaluation of AT9283 as monotherapy and in combination therapy for treating patients with MM.<br />
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3. Cell Cycle. 2009 Jun 15;8(12):1921-9. Epub 2009 Jun 15.<br />
Aurora B kinase inhibition in mitosis: strategies for optimising the use of aurora kinase inhibitors such as AT9283.<br />
Curry J(1), Angove H, Fazal L, Lyons J, Reule M, Thompson N, Wallis N.<br />
Author information:<br />
(1)Astex Therapeutics Ltd, Cambridge, UK. [email protected]<br />
Aurora kinases play a key role in regulating mitotic division and are attractive oncology targets. AT9283, a multi-targeted kinase inhibitor with potent activity against Aurora A and B kinases, inhibited growth and survival of multiple solid tumor cell lines and was efficacious in mouse xenograft models. AT9283-treatment resulted in endoreduplication and ablation of serine-10 histone H3 phosphorylation in both cells and tumor samples, confirming that in these models it acts as an Aurora B kinase inhibitor. In vitro studies demonstrated that exposure to AT9283 for one complete cell cycle committed an entire population of p53 checkpoint-compromised cells (HCT116) to multinucleation and death whereas treatment of p53 checkpoint-competent cells (HMEC, A549) for a similar length of time led to a reversible arrest of cells with 4N DNA. Further studies in synchronized cell populations suggested that exposure to AT9283 during mitosis was critical for optimal cytotoxicity. We therefore investigated ways in which these properties might be exploited to optimize the efficacy and therapeutic index of Aurora kinase inhibitors for p53 checkpoint compromised tumors in vivo. Combining Aurora B kinase inhibition with paclitaxel, which arrests cells in mitosis, in a xenograft model resulted in promising efficacy without additional toxicity. These findings have implications for optimizing the efficacy of Aurora kinase inhibitors in clinical practice.<br />
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4. J Med Chem. 2009 Jan 22;52(2):379-88. doi: 10.1021/jm800984v.<br />
Fragment-based discovery of the pyrazol-4-yl urea (AT9283), a multitargeted kinase inhibitor with potent aurora kinase activity.<br />
Howard S(1), Berdini V, Boulstridge JA, Carr MG, Cross DM, Curry J, Devine LA, Early TR, Fazal L, Gill AL, Heathcote M, Maman S, Matthews JE, McMenamin RL, Navarro EF, O'Brien MA, O'Reilly M, Rees DC, Reule M, Tisi D, Williams G, Vinković M, Wyatt PG.<br />
Author information:<br />
(1)Astex Therapeutics Ltd., 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, UK. [email protected]<br />
Here, we describe the identification of a clinical candidate via structure-based optimization of a ligand efficient pyrazole-benzimidazole fragment. Aurora kinases play a key role in the regulation of mitosis and in recent years have become attractive targets for the treatment of cancer. X-ray crystallographic structures were generated using a novel soakable form of Aurora A and were used to drive the optimization toward potent (IC(50) approximately 3 nM) dual Aurora A/Aurora B inhibitors. These compounds inhibited growth and survival of HCT116 cells and produced the polyploid cellular phenotype typically associated with Aurora B kinase inhibition. Optimization of cellular activity and physicochemical properties ultimately led to the identification of compound 16 (AT9283). In addition to Aurora A and Aurora B, compound 16 was also found to inhibit a number of other kinases including JAK2 and Abl (T315I). This compound demonstrated in vivo efficacy in mouse xenograft models and is currently under evaluation in phase I clinical trials.<br />
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