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Investigational New Drugs Oct 2011Danusertib is a serine/threonine kinase inhibitor of multiple kinases, including aurora-A, B, and C. This explorative study aims to identify possible relationships...
OBJECTIVES
Danusertib is a serine/threonine kinase inhibitor of multiple kinases, including aurora-A, B, and C. This explorative study aims to identify possible relationships between single nucleotide polymorphisms in genes coding for drug metabolizing enzymes and transporter proteins and clearance of danusertib, to clarify the interpatient variability in exposure. In addition, this study explores the relationship between target receptor polymorphisms and toxicity of danusertib.
METHODS
For associations with clearance, 48 cancer patients treated in a phase I study were analyzed for ABCB1, ABCG2 and FMO3 polymorphisms. Association analyses between neutropenia and drug target receptors, including KDR, RET, FLT3, FLT4, AURKB and AURKA, were performed in 30 patients treated at recommended phase II dose-levels in three danusertib phase I or phase II trials.
RESULTS
No relationships between danusertib clearance and drug metabolizing enzymes and transporter protein polymorphisms were found. Only, for the one patient with FMO3 18281AA polymorphism, a significantly higher clearance was noticed, compared to patients carrying at least 1 wild type allele. No effect of target receptor genotypes or haplotypes on neutropenia was observed.
CONCLUSIONS
As we did not find any major correlations between pharmacogenetic variability in the studied enzymes and transporters and pharmacokinetics nor toxicity, it is unlikely that danusertib is highly susceptible for pharmacogenetic variation. Therefore, no dosing alterations of danusertib are expected in the future, based on the polymorphisms studied. However, the relationship between FMO3 polymorphisms and clearance of danusertib warrants further research, as we could study only a small group of patients.
Topics: Adult; Aged; Analysis of Variance; Antineoplastic Agents; Aurora Kinase A; Aurora Kinase B; Aurora Kinases; Benzamides; Female; Haplotypes; Humans; Male; Middle Aged; Neoplasm Grading; Pharmacogenetics; Polymorphism, Genetic; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Pyrazoles; Young Adult
PubMed: 20182906
DOI: 10.1007/s10637-010-9405-7 -
The Journal of Biological Chemistry Apr 2010Aurora kinases are mitotic enzymes involved in centrosome maturation and separation, spindle assembly and stability, and chromosome condensation, segregation, and...
Aurora kinases are mitotic enzymes involved in centrosome maturation and separation, spindle assembly and stability, and chromosome condensation, segregation, and cytokinesis and represent well known targets for cancer therapy because their deregulation has been linked to tumorigenesis. The availability of suitable markers is of crucial importance to investigate the functions of Auroras and monitor kinase inhibition in in vivo models and in clinical trials. Extending the knowledge on Aurora substrates could help to better understand their biology and could be a source for clinical biomarkers. Using biochemical, mass spectrometric, and cellular approaches, we identified MYBBP1A as a novel Aurora B substrate and serine 1303 as the major phosphorylation site. MYBBP1A is phosphorylated in nocodazole-arrested cells and is dephosphorylated upon Aurora B silencing or by treatment with Danusertib, a small molecule inhibitor of Aurora kinases. Furthermore, we show that MYBBP1A depletion by RNA interference causes mitotic progression delay and spindle assembly defects. MYBBP1A has until now been described as a nucleolar protein, mainly involved in transcriptional regulation. The results presented herein show MYBBP1A as a novel Aurora B kinase substrate and reveal a not yet recognized link of this nucleolar protein to mitosis.
Topics: Amino Acid Sequence; Aurora Kinase B; Aurora Kinases; Binding Sites; Cell Line; DNA-Binding Proteins; HeLa Cells; Humans; Nuclear Proteins; Nucleocytoplasmic Transport Proteins; Phosphorylation; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; RNA Interference; RNA-Binding Proteins; Recombinant Proteins; Serine; Substrate Specificity; Transcription Factors
PubMed: 20177074
DOI: 10.1074/jbc.M109.068312 -
Recent Results in Cancer Research.... 2010The Aurora kinases belong to a family of highly conserved serine/threonine protein kinases. They play an essential role as key mitotic regulators, controlling entry into... (Review)
Review
The Aurora kinases belong to a family of highly conserved serine/threonine protein kinases. They play an essential role as key mitotic regulators, controlling entry into mitosis, centrosome function, chromosome assembly, and segregation. As many other regulators of mitosis, Aurora kinases are frequently found to be aberrantly overexpressed in cancer cells. Therefore, these proteins have become an attractive target for the development of new anticancer therapies. In fact, several small-molecule inhibitors of Aurora kinases have already been developed and some of them have shown promising clinical efficacy in a number of human tumors in Phase I and II clinical trials. Among those, one of the most advanced clinical compound currently is Danusertib (formerly PHA-739358), which exhibits inhibitory activity against all known Aurora kinases as well as other cancer-relevant kinases such as the Bcr-Abl tyrosine kinase, including its multidrug-resistant T315I mutant. This mutation is responsible for up to 25% of all clinically observed resistances in CML patients undergoing Imatinib therapy. However, this particular mutation is predicted to play an even more important clinical role in the future, since in addition to Imatinib, it also confers resistance to second-generation Bcr-Abl inhibitors such as Nilotinib, Dasatinib, and Bosutinib. Therefore, combined Aurora and Bcr-Abl inhibition (the latter including high-grade resistance conferring mutations) with compounds such as Danusertib represents a promising new strategy for treatment of Bcr-Abl positive leukemias, especially those in second and third line of treatment.
Topics: Animals; Aurora Kinases; Benzamides; Clinical Trials as Topic; Humans; Neoplasms; Protein Serine-Threonine Kinases; Pyrazoles
PubMed: 20072840
DOI: 10.1007/978-3-642-01222-8_14 -
Anti-cancer Drugs Apr 2010Aurora kinases are serine and threonine kinases that function as key regulators of the mitosis process. There are three distinct human aurora kinases known as Aurora A,... (Review)
Review
Aurora kinases are serine and threonine kinases that function as key regulators of the mitosis process. There are three distinct human aurora kinases known as Aurora A, Aurora B, and Aurora C. Aurora A and Aurora B are overexpressed in a number of human cancers including non-small cell lung cancer, glioblastomas, and upper gastrointestinal adenocarcinomas. Given their association with tumorigenesis, both Aurora A and Aurora B have been targeted for cancer therapy. Currently, a number of selective and nonselective aurora kinase inhibitors are being tested in preclinical and clinical settings as anti-tumor agents. We review the biology of human aurora kinases, followed by an overview of inhibitors undergoing current clinical investigations.
Topics: Antineoplastic Agents; Aurora Kinase B; Aurora Kinase C; Aurora Kinases; Benzamides; Benzimidazoles; Cyclohexanecarboxylic Acids; Drug Screening Assays, Antitumor; Enzyme Activation; Humans; Neoplasms; Organophosphates; Phenylurea Compounds; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Pyrazoles; Quinazolines; Thiazoles; Urea
PubMed: 20016367
DOI: 10.1097/CAD.0b013e3283350dd1 -
Leukemia & Lymphoma Nov 2009Chronic myeloid leukemia is defined by the acquired genetic mutation, t(9;22), which leads to the fusion-protein BCR-ABL. Prior to the development of imatinib mesylate... (Review)
Review
Chronic myeloid leukemia is defined by the acquired genetic mutation, t(9;22), which leads to the fusion-protein BCR-ABL. Prior to the development of imatinib mesylate (Gleevec), treatment was limited and provided only limited survival benefit. Imatinib has dramatically changed the course of the disease and has led to the significantly prolonged survival in the majority of patients. However, there is growing concern for resistance to imatinib and to subsequent second generation tyrosine kinase inhibitors (dasatinib and nilotinib) due to the T315I mutation. With no currently approved effective treatment for TKI-resistant CML with the T315I mutation, molecularly-based, targeted drug development has focused on several strategies to overcome resistance. In this review, we describe agents which overcome the T315I mutation, as well as native BCR-ABL, via several mechanisms, including increased degradation of BCR-ABL, optimization of direct inhibition of the BCR-ABL kinase, inhibition of BCR-ABL-mediated cell growth via interruption of the BCR-ABL-mediated transcription, protein synthesis or post-translational modification, all of which lead to decreased proliferation and malignant cell death.
Topics: Benzamides; Drug Resistance, Neoplasm; Fusion Proteins, bcr-abl; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Models, Biological; Piperazines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Signal Transduction
PubMed: 19883308
DOI: 10.3109/10428190903267559 -
Clinical Cancer Research : An Official... Nov 2009This study was conducted to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of the i.v. pan-aurora kinase inhibitor PHA-739358, danusertib, in...
A phase I dose-escalation study of danusertib (PHA-739358) administered as a 24-hour infusion with and without granulocyte colony-stimulating factor in a 14-day cycle in patients with advanced solid tumors.
PURPOSE
This study was conducted to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of the i.v. pan-aurora kinase inhibitor PHA-739358, danusertib, in patients with advanced solid tumors.
EXPERIMENTAL DESIGN
In part 1, patients received escalating doses of danusertib (24-hour infusion every 14 days) without filgrastim (granulocyte colony-stimulating factor, G-CSF). Febrile neutropenia was the dose-limiting toxicity without G-CSF. Further dose escalation was done in part 2 with G-CSF. Blood samples were collected for danusertib pharmacokinetics and pharmacodynamics. Skin biopsies were collected to assess histone H3 phosphorylation (pH3).
RESULTS
Fifty-six patients were treated, 40 in part 1 and 16 in part 2. Febrile neutropenia was the dose-limiting toxicity in part 1 without G-CSF. Most other adverse events were grade 1 to 2, occurring at doses >or=360 mg/m(2) with similar incidence in parts 1 and 2. The maximum tolerated dose without G-CSF is 500 mg/m(2). The recommended phase 2 dose in part 2 with G-CSF is 750 mg/m(2). Danusertib showed dose-proportional pharmacokinetics in parts 1 and 2 with a median half-life of 18 to 26 hours. pH3 modulation in skin biopsies was observed at >or=500 mg/m(2). One patient with refractory small cell lung cancer (1,000 mg/m(2) with G-CSF) had an objective response lasting 23 weeks. One patient with refractory ovarian cancer had 27% tumor regression and 30% CA125 decline.
CONCLUSIONS
Danusertib was well tolerated with target inhibition in skin at >or=500 mg/m(2). Preliminary evidence of antitumor activity, including a partial response and several occurrences of prolonged stable disease, was seen across a variety of advanced refractory cancers. Phase II studies are ongoing.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Aurora Kinases; Benzamides; Drug Administration Schedule; Enzyme Inhibitors; Female; Granulocyte Colony-Stimulating Factor; Humans; Infusions, Intravenous; Male; Middle Aged; Neoplasms; Neutropenia; Protein Serine-Threonine Kinases; Pyrazoles; Recombinant Proteins
PubMed: 19825950
DOI: 10.1158/1078-0432.CCR-09-1445 -
Journal of Clinical Oncology : Official... Oct 2009Danusertib (PHA-739358) is a small-molecule pan-aurora kinase inhibitor. This phase I dose escalation study was conducted to evaluate safety and tolerability of...
PURPOSE
Danusertib (PHA-739358) is a small-molecule pan-aurora kinase inhibitor. This phase I dose escalation study was conducted to evaluate safety and tolerability of danusertib with additional pharmacokinetic, biomarker, and efficacy assessments.
PATIENTS AND METHODS
Patients with solid tumors refractory to standard therapies or with no standard therapy available were enrolled. Danusertib was administered intravenously on days 1, 8, and 15 every 28 days in 6-hour or 3-hour infusion schedules (ie, 6-hour IVS or 3-hour IVS). Dose levels from 45 mg/m(2) in the 6-hour IVS, and from 250 mg/m(2) in the 3-hour IVS, were studied.
RESULTS
Fifty patients were treated. For the 6-hour IVS, the most frequently reported adverse effects were neutropenia (55%), nausea (25%), anorexia (23%), fatigue (20%), and diarrhea (18%). In the 3-hour IVS, fatigue (70%), neutropenia (60%), diarrhea (50%), and nausea (30%) were seen. Nonhematologic toxicity was mild to moderate. Neutropenia was dose limiting. The maximum-tolerated dose was 330 mg/m(2) for the 6-hour IVS and was not identified for the 3-hour IVS. The systemic exposure to danusertib increased linearly with dose. The infusion rate did not appear to remarkably influence the pharmacokinetics of danusertib. Biomarker analysis showed inhibition of histone H3 phosphorylation, indicative of aurora B inhibition, at doses of 190 mg/m(2) or greater. Stable disease was observed in 23.7% of evaluable patients, and disease stabilization occurred in 6 or more months in five patients.
CONCLUSION
Dose-limiting toxicity of danusertib is neutropenia, which was short lasting and generally uncomplicated; danusertib administration had limited nonhematologic toxicity. The recommended dose of danusertib for phase II studies is 330 mg/m(2) infused over 6 hours on days 1, 8, and 15 every 28 days.
Topics: Adult; Aged; Aurora Kinase B; Aurora Kinases; Benzamides; Dose-Response Relationship, Drug; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Pyrazoles; Young Adult
PubMed: 19770380
DOI: 10.1200/JCO.2008.21.6655 -
Neoplasia (New York, N.Y.) Sep 2009Patients with advanced stages of hepatocellular carcinoma (HCC) face a poor prognosis. Although encouraging clinical results have been obtained with multikinase...
Patients with advanced stages of hepatocellular carcinoma (HCC) face a poor prognosis. Although encouraging clinical results have been obtained with multikinase inhibitor sorafenib, the development of improved therapeutic strategies for HCC remains an urgent goal. Aurora kinases are key regulators of the cell cycle, and their uncontrolled expression promotes aneuploidy and tumor development. In tissue microarray analyses, we detected aurora-A kinase expression in all of the examined 93 human HCC samples, whereas aurora-B kinase expression levels significantly correlated with the proliferation index of HCCs. In addition, two human HCC cell lines (Huh-7 and HepG2) were tested positive for aurora-A and -B and revealed Ser10 phosphorylation of histone H3, indicating an increased aurora-B kinase activity. The antiproliferative features of a novel aurora kinase inhibitor, PHA-739358, currently under investigation in phase 2 clinical trials for other solid tumors, were examined in vitro and in vivo. At concentrations exceeding 50 nM, PHA-739358 completely suppressed tumor cell proliferation in cell culture experiments and strongly decreased histone H3 phosphorylation. Cell cycle inhibition and endoreduplication were observed at 50 nM, whereas higher concentrations led to a complete G(2)/M-phase arrest. In vivo, administration of PHA-739358 resulted in significant tumor growth inhibition at a well-tolerated dose. In combination with sorafenib, additive effects were observed. Remarkably, when tumors restarted to grow under sorafenib monotherapy, subsequent treatment with PHA-739358 induced tumor shrinkage by up to 81%. Thus, targeting aurora kinases with PHA-739358 is a promising therapeutic strategy administered alone or in combination with sorafenib for patients with advanced stages of HCC.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Aurora Kinase A; Aurora Kinase B; Aurora Kinases; Benzamides; Benzenesulfonates; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; G2 Phase; Humans; Immunoenzyme Techniques; In Vitro Techniques; Liver Neoplasms; Mice; Mice, Inbred NOD; Mice, SCID; Niacinamide; Phenylurea Compounds; Phosphorylation; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Pyrazoles; Pyridines; Receptors, Vascular Endothelial Growth Factor; Sorafenib; Tissue Array Analysis; Xenograft Model Antitumor Assays
PubMed: 19724687
DOI: 10.1593/neo.09664 -
Blood Apr 2008The emergence of resistance to imatinib (IM) mediated by mutations in the BCR-ABL domain has become a major challenge in the treatment of chronic myeloid leukemia (CML)....
Simultaneous targeting of Aurora kinases and Bcr-Abl kinase by the small molecule inhibitor PHA-739358 is effective against imatinib-resistant BCR-ABL mutations including T315I.
The emergence of resistance to imatinib (IM) mediated by mutations in the BCR-ABL domain has become a major challenge in the treatment of chronic myeloid leukemia (CML). Here, we report on studies performed with a novel small molecule inhibitor, PHA-739358, which selectively targets Bcr-Abl and Aurora kinases A to C. PHA-739358 exhibits strong antiproliferative and proapoptotic activity against a broad panel of human BCR-ABL-positive and -negative cell lines and against murine BaF3 cells ectopically expressing wild-type (wt) or IM-resistant BCR-ABL mutants, including T315I. Pharmacologic synergism of IM and PHA-739358 was observed in leukemia cell lines with subtotal resistance to IM. Treatment with PHA-739358 significantly decreased phosphorylation of histone H3, a marker of Aurora B activity and of CrkL, a downstream target of Bcr-Abl, suggesting that PHA-739358 acts via combined inhibition of Bcr-Abl and Aurora kinases. Moreover, strong antiproliferative effects of PHA-739358 were observed in CD34(+) cells derived from untreated CML patients and from IM-resistant individuals in chronic phase or blast crisis, including those harboring the T315I mutation. Thus, PHA-739358 represents a promising new strategy for treatment of IM-resistant BCR-ABL-positive leukemias, including those harboring the T315I mutation. Clinical trials investigating this compound in IM-resistant CML have recently been initiated.
Topics: Adaptor Proteins, Signal Transducing; Animals; Antigens, CD34; Apoptosis; Aurora Kinase B; Aurora Kinases; Benzamides; Cell Line, Tumor; Cell Proliferation; DNA, Neoplasm; Drug Resistance, Neoplasm; Drug Synergism; Fusion Proteins, bcr-abl; G2 Phase; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Mice; Mitosis; Mutant Proteins; Mutation; Nuclear Proteins; Phosphorylation; Piperazines; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines
PubMed: 18268096
DOI: 10.1182/blood-2007-09-113175 -
Molecular Cancer Therapeutics Dec 2007PHA-739358 is a small-molecule 3-aminopyrazole derivative with strong activity against Aurora kinases and cross-reactivities with some receptor tyrosine kinases relevant...
PHA-739358 is a small-molecule 3-aminopyrazole derivative with strong activity against Aurora kinases and cross-reactivities with some receptor tyrosine kinases relevant for cancer. PHA-739358 inhibits all Aurora kinase family members and shows a dominant Aurora B kinase inhibition-related cellular phenotype and mechanism of action in cells in vitro and in vivo. p53 status-dependent endoreduplication is observed upon treatment of cells with PHA-739358, and phosphorylation of histone H3 in Ser(10) is inhibited. The compound has significant antitumor activity in different xenografts and spontaneous and transgenic animal tumor models and shows a favorable pharmacokinetic and safety profile. In vivo target modulation is observed as assessed by the inhibition of the phosphorylation of histone H3, which has been validated preclinically as a candidate biomarker for the clinical phase. Pharmacokinetics/pharmacodynamics modeling was used to define drug potency and to support the prediction of active clinical doses and schedules. We conclude that PHA-739358, which is currently tested in clinical trials, has great therapeutic potential in anticancer therapy in a wide range of cancers.
Topics: Animals; Aurora Kinase B; Aurora Kinases; Benzamides; Cell Line, Tumor; Cell Proliferation; Female; Humans; Immunohistochemistry; Male; Mice; Mice, Nude; Neoplasms; Phosphorylation; Protein Serine-Threonine Kinases; Pyrazoles; Rats; Rats, Sprague-Dawley
PubMed: 18089710
DOI: 10.1158/1535-7163.MCT-07-0444