Danusertib, an aurora kinase inhibitor

Meulenbeld, Hielke J.; Mathijssen, Ron H.J.; Verweij, Jaap; Wit, Ronald de; Jonge, Maja J. De

doi:10.1517/13543784.2012.652303

Cited by 63 publications

(48 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As reviewed recently (24), an estimated 30 small-molecule inhibitors of Aurora kinases are currently undergoing preclinical and clinical evaluation (25)(26)(27)(28)(29)(30)(31). A number of these compounds are pan-Aurora kinase inhibitors that show inhibitory activity against both AAK and Aurora B kinase (ABK), as well as, in some cases, Aurora C kinase.…”

Section: Introductionmentioning

confidence: 99%

Phase I Pharmacokinetic/Pharmacodynamic Study of MLN8237, an Investigational, Oral, Selective Aurora A Kinase Inhibitor, in Patients with Advanced Solid Tumors

Cervantes

Élez

Roda

et al. 2012

Clinical Cancer Research

131

159

View full text Add to dashboard Cite

Purpose: Aurora A kinase (AAK) is a key regulator of mitosis and a target for anticancer drug development. This phase I study investigated the safety, pharmacokinetics, and pharmacodynamics of MLN8237 (alisertib), an investigational, oral, selective AAK inhibitor, in 59 adults with advanced solid tumors.Experimental Design: Patients received MLN8237 once daily or twice daily for 7, 14, or 21 consecutive days, followed by 14 days recovery, in 21-, 28-, or 35-day cycles. Dose-limiting toxicities (DLT) and the maximum-tolerated dose (MTD) for the 7-and 21-day schedules were determined. Pharmacokinetic parameters were derived from plasma concentration-time profiles. AAK inhibition in skin and tumor biopsies was evaluated and antitumor activity assessed.Results: Neutropenia and stomatitis were the most common DLTs. The MTD for the 7-and 21-day schedules was 50 mg twice daily and 50 mg once daily, respectively. MLN8237 absorption was fast (median time to maximum concentration, 2 hours). Mean terminal half-life was approximately 19 hours. At steady state, pharmacodynamic effects were shown by accumulation of mitotic and apoptotic cells in skin, and exposure-related increases in numbers of mitotic cells with characteristic spindle and chromosomal abnormalities in tumor specimens, supporting AAK inhibition by MLN8237. Stable disease was observed and was durable with repeat treatment cycles, administered over 6 months, in 6 patients, without notable cumulative toxicity.Conclusions: The recommended phase II dose of MLN8237 is 50 mg twice daily on the 7-day schedule, which is being evaluated further in a variety of malignancies, including in a phase III trial in peripheral T-cell lymphoma.

show abstract

Section: Introductionmentioning

confidence: 99%

Phase I Pharmacokinetic/Pharmacodynamic Study of MLN8237, an Investigational, Oral, Selective Aurora A Kinase Inhibitor, in Patients with Advanced Solid Tumors

Cervantes

Élez

Roda

et al. 2012

Clinical Cancer Research

131

159

View full text Add to dashboard Cite

show abstract

“…Despite the positive results, resistance to danusertib treatment emerged during several studies, but its ability in producing molecular complete remissions of tumours was improved using combinations with traditional antineoplastic agents [17].…”

Section: Introductionmentioning

confidence: 99%

Electrochemical and spectrophotometric characterisation of protein kinase inhibitor and anticancer drug danusertib

Popa

Diculescu

2013

Electrochimica Acta

View full text Add to dashboard Cite

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 2 AbstractThe electrochemical oxidation mechanism of the anti-cancer drug and kinases inhibitor danusertib was studied by cyclic, differential pulse, square wave voltammetry and a glassy carbon electrode. Danusertib undergoes oxidation in a cascade mechanism and depending on the pH of the supporting electrolyte several oxidation peaks were observed. The number of electrons and protons involved in each oxidation step as well as the pK a ~ 10.0 were determined. The analytical determination of danusertib was carried out in pH = 7.0 by square wave voltammetry with LOD = 27.4 nM and UV-VIS spectrophotometry with LOD = 0.5 µM. Different electroactive centres of danusertib were identified through comparative studies with similar compounds such as imatinib and piperazine, and an oxidation mechanism of danusertib proposed.

show abstract

“…The most advanced clinical compound is danusertib, a highly effective pan-AKI that inhibits aurora kinases A, B, and C at nanomolar concentrations (9). Off-target effects of danusertib include inhibition of receptor tyrosine kinases such as Abl, Ret, FGFR-1, and TrkA (9,14). Phase II clinical trials for patients with hematologic malignancies and solid tumors are currently being carried out with this inhibitor.…”

Section: Introductionmentioning

confidence: 99%

Targeting Aurora Kinases with Danusertib (PHA-739358) Inhibits Growth of Liver Metastases from Gastroenteropancreatic Neuroendocrine Tumors in an Orthotopic Xenograft Model

Fraedrich

Schrader

Ittrich

et al. 2012

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: Aurora kinases play a crucial role in cell-cycle control. Uncontrolled expression of aurora kinases causes aneuploidy and tumor growth. As conservative treatment options for advanced gastroenteropancreatic neuroendocrine tumors (GEP-NET) are disappointing, aurora kinases may be an interesting target for novel therapeutic strategies.Experimental Design: Human GEP-NETs were tested for aurora kinase expression. The efficacy of the new aurora kinase inhibitor danusertib was evaluated in two human GEP-NET cell lines (BON1 and QGP) in vitro and in vivo.Results: The majority of ten insulinomas and all 33 nonfunctional pancreatic or midgut GEP-NETs expressed aurora A despite a mostly high degree of cell differentiation. Both human GEP-NET cell lines expressed aurora kinase A and B, and high Ser10 phosphorylation of histone H3 revealed increased aurora B activity. Remarkably, danusertib led to cell-cycle arrest and completely inhibited cell proliferation of the GEP-NET cells in vitro. Decreased phosphorylation of histone H3 indicated effective aurora B inhibition. In a subcutaneous murine xenograft model, danusertib significantly reduced tumor growth in vivo compared with controls or mice treated with streptozotocine/5-fluorouracil. As a consequence, decreased levels of tumor marker chromogranin A were found in mouse serum samples. In a newly developed orthotopic model for GEP-NET liver metastases by intrasplenic tumor cell transplantation, dynamic MRI proved significant growth inhibition of BON1-and QGP-derived liver metastases.Conclusions: These results show that danusertib may impose a new therapeutic strategy for aurora kinase expressing metastasized GEP-NETs.

show abstract

Danusertib, an aurora kinase inhibitor

Abstract: Future studies with danusertib should focus on the possibility of combining this agent with other targeted anticancer agents, chemotherapy or radiotherapy. As a single agent, danusertib may show more promise in the treatment of leukemias than in solid tumors.

Cited by 63 publications

References 54 publications

Phase I Pharmacokinetic/Pharmacodynamic Study of MLN8237, an Investigational, Oral, Selective Aurora A Kinase Inhibitor, in Patients with Advanced Solid Tumors

Phase I Pharmacokinetic/Pharmacodynamic Study of MLN8237, an Investigational, Oral, Selective Aurora A Kinase Inhibitor, in Patients with Advanced Solid Tumors

Electrochemical and spectrophotometric characterisation of protein kinase inhibitor and anticancer drug danusertib

Targeting Aurora Kinases with Danusertib (PHA-739358) Inhibits Growth of Liver Metastases from Gastroenteropancreatic Neuroendocrine Tumors in an Orthotopic Xenograft Model

Contact Info

Product

Resources

About