Details
Stereochemistry | ACHIRAL |
Molecular Formula | C26H31FN7O6P.2ClH |
Molecular Weight | 660.462 |
Optical Activity | NONE |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
Cl.Cl.CCN(CCCOC1=CC2=C(C=C1)C(NC3=CC(CC(=O)NC4=CC=CC(F)=C4)=NN3)=NC=N2)CCOP(O)(O)=O
InChI
InChIKey=PEVRMFUIHQMEHQ-UHFFFAOYSA-N
InChI=1S/C26H31FN7O6P.2ClH/c1-2-34(10-12-40-41(36,37)38)9-4-11-39-21-7-8-22-23(16-21)28-17-29-26(22)31-24-14-20(32-33-24)15-25(35)30-19-6-3-5-18(27)13-19;;/h3,5-8,13-14,16-17H,2,4,9-12,15H2,1H3,(H,30,35)(H2,36,37,38)(H2,28,29,31,32,33);2*1H
DescriptionCurator's Comment: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/27496133
http://adisinsight.springer.com/drugs/800024339
Curator's Comment: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/27496133
http://adisinsight.springer.com/drugs/800024339
Barasertib (AZD1152) is a dihydrogen phosphate prodrug of a pyrazoloquinazoline Aurora kinase inhibitor [AZD1152–hydroxyquinazoline pyrazol anilide (HQPA)] and is converted rapidly to the active AZD1152-HQPA in plasma. AstraZeneca was developing the aurora kinase inhibitor, barasertib (AZD 1152) as a therapeutic for cancer. AZD1152-HQPA is a highly potent and selective inhibitor of Aurora B (Ki, 0.36nmol/L) compared with Aurora A (Ki, 1,369nmol/L) and has a high specificity versus a panel of 50 other kinases. Consistent with inhibition of Aurora B kinase, addition of AZD1152-HQPA to tumour cells in vitro induces chromosome misalignment, prevents cell division, and consequently reduces cell viability and induces apoptosis. Barasertib (AZD1152) potently inhibited the growth of human colon, lung, and haematologic tumour xenografts (mean tumour growth inhibition range, 55% to ≥100%; P < 0.05) in immunodeficient mice. Detailed pharmacodynamic analysis in colorectal SW620 tumour-bearing athymic rats treated i.v. with Barasertib (AZD1152) revealed a temporal sequence of phenotypic events in tumours: transient suppression of histone H3 phosphorylation followed by accumulation of 4N DNA in cells (2.4-fold higher compared with controls) and then an increased proportion of polyploid cells (>4N DNA, 2.3-fold higher compared with controls). Histologic analysis showed aberrant cell division that was concurrent with an increase in apoptosis in AZD1152-treated tumours. Bone marrow analyses revealed transient myelosuppression with the drug that was fully reversible following cessation of Barasertib (AZD1152) treatment. Barasertib (AZD1152) was in phase III for the treatment of Acute myeloid leukaemia, but later these studies were discontinued.
Originator
Approval Year
Doses
Dose | Population | Adverse events |
---|---|---|
300 mg 1 times / day multiple, intravenous (total) Highest studied dose Dose: 300 mg, 1 times / day Route: intravenous Route: multiple Dose: 300 mg, 1 times / day Sources: Page: p.375 |
unhealthy, ADULT n = 5 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 5 Sources: Page: p.375 |
DLT: Neutropenia... Disc. AE: Proteinuria... Dose limiting toxicities: Neutropenia (grade 4, 20%) AEs leading todiscontinuation/dose reduction: Proteinuria (grade 3, 20%) Sources: Page: p.375 |
1200 mg 1 times / day multiple, intravenous (total) MTD Dose: 1200 mg, 1 times / day Route: intravenous Route: multiple Dose: 1200 mg, 1 times / day Sources: |
unhealthy, ADULT n = 6 Health Status: unhealthy Condition: acute myeloid leukemia Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: |
DLT: Mucositis oral... Disc. AE: Pseudomonal sepsis, cellulitis... Dose limiting toxicities: Mucositis oral (grade 3-4, 16.7%) AEs leading todiscontinuation/dose reduction: Pseudomonal sepsis (16.7%) Sources: cellulitis (16.7%) |
150 mg 1 times / day multiple, intravenous (total) MTD Dose: 150 mg, 1 times / day Route: intravenous Route: multiple Dose: 150 mg, 1 times / day Sources: Page: p.375 |
unhealthy, ADULT n = 20 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 20 Sources: Page: p.375 |
|
220 mg 1 times / day multiple, intravenous (total) MTD Dose: 220 mg, 1 times / day Route: intravenous Route: multiple Dose: 220 mg, 1 times / day Sources: Page: p.375 |
unhealthy, ADULT n = 6 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: Page: p.375 |
|
1600 mg 1 times / day multiple, intravenous (total) Studied dose Dose: 1600 mg, 1 times / day Route: intravenous Route: multiple Dose: 1600 mg, 1 times / day Sources: |
unhealthy, ADULT n = 6 Health Status: unhealthy Condition: acute myeloid leukemia Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: |
DLT: Mucositis oral... Dose limiting toxicities: Mucositis oral (grade 3-4, 33.3%) Sources: |
225 mg 1 times / day multiple, intravenous (total) Studied dose Dose: 225 mg, 1 times / day Route: intravenous Route: multiple Dose: 225 mg, 1 times / day Sources: Page: p.375 |
unhealthy, ADULT n = 4 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 4 Sources: Page: p.375 |
DLT: Febrile neutropenia, Neutropenia... Dose limiting toxicities: Febrile neutropenia (grade 4, 25%) Sources: Page: p.375Neutropenia (grade 4, 25%) |
AEs
AE | Significance | Dose | Population |
---|---|---|---|
Proteinuria | grade 3, 20% Disc. AE |
300 mg 1 times / day multiple, intravenous (total) Highest studied dose Dose: 300 mg, 1 times / day Route: intravenous Route: multiple Dose: 300 mg, 1 times / day Sources: Page: p.375 |
unhealthy, ADULT n = 5 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 5 Sources: Page: p.375 |
Neutropenia | grade 4, 20% DLT |
300 mg 1 times / day multiple, intravenous (total) Highest studied dose Dose: 300 mg, 1 times / day Route: intravenous Route: multiple Dose: 300 mg, 1 times / day Sources: Page: p.375 |
unhealthy, ADULT n = 5 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 5 Sources: Page: p.375 |
Pseudomonal sepsis | 16.7% Disc. AE |
1200 mg 1 times / day multiple, intravenous (total) MTD Dose: 1200 mg, 1 times / day Route: intravenous Route: multiple Dose: 1200 mg, 1 times / day Sources: |
unhealthy, ADULT n = 6 Health Status: unhealthy Condition: acute myeloid leukemia Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: |
cellulitis | 16.7% Disc. AE |
1200 mg 1 times / day multiple, intravenous (total) MTD Dose: 1200 mg, 1 times / day Route: intravenous Route: multiple Dose: 1200 mg, 1 times / day Sources: |
unhealthy, ADULT n = 6 Health Status: unhealthy Condition: acute myeloid leukemia Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: |
Mucositis oral | grade 3-4, 16.7% DLT |
1200 mg 1 times / day multiple, intravenous (total) MTD Dose: 1200 mg, 1 times / day Route: intravenous Route: multiple Dose: 1200 mg, 1 times / day Sources: |
unhealthy, ADULT n = 6 Health Status: unhealthy Condition: acute myeloid leukemia Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: |
Mucositis oral | grade 3-4, 33.3% DLT, Disc. AE |
1600 mg 1 times / day multiple, intravenous (total) Studied dose Dose: 1600 mg, 1 times / day Route: intravenous Route: multiple Dose: 1600 mg, 1 times / day Sources: |
unhealthy, ADULT n = 6 Health Status: unhealthy Condition: acute myeloid leukemia Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: |
Febrile neutropenia | grade 4, 25% DLT |
225 mg 1 times / day multiple, intravenous (total) Studied dose Dose: 225 mg, 1 times / day Route: intravenous Route: multiple Dose: 225 mg, 1 times / day Sources: Page: p.375 |
unhealthy, ADULT n = 4 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 4 Sources: Page: p.375 |
Neutropenia | grade 4, 25% DLT |
225 mg 1 times / day multiple, intravenous (total) Studied dose Dose: 225 mg, 1 times / day Route: intravenous Route: multiple Dose: 225 mg, 1 times / day Sources: Page: p.375 |
unhealthy, ADULT n = 4 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 4 Sources: Page: p.375 |
PubMed
Title | Date | PubMed |
---|---|---|
Preclinical evaluation of M30 and M65 ELISAs as biomarkers of drug induced tumor cell death and antitumor activity. | 2008 Mar |
|
Enhancement of radiation response in p53-deficient cancer cells by the Aurora-B kinase inhibitor AZD1152. | 2008 May 22 |
|
Mitotic drivers--inhibitors of the Aurora B Kinase. | 2009 Jun |
|
Pharmacological inhibition of aurora-A but not aurora-B impairs interphase microtubule dynamics. | 2009 Jun 1 |
|
Simultaneous determination of AZD1152 (prodrug) and AZD1152-hydroxyquinazoline pyrazol anilide by reversed phase liquid chromatography. | 2009 Nov 1 |
|
Preclinical evaluation of AMG 900, a novel potent and highly selective pan-aurora kinase inhibitor with activity in taxane-resistant tumor cell lines. | 2010 Dec 1 |
|
Antineoplastic effects of an Aurora B kinase inhibitor in breast cancer. | 2010 Feb 22 |
|
Aurora kinase inhibitor AZD1152 negatively affects the growth and survival of HTLV-1-infected T lymphocytes in vitro. | 2010 Oct 1 |
|
Phthalazinone pyrazoles as potent, selective, and orally bioavailable inhibitors of Aurora-A kinase. | 2011 Jan 13 |
|
Phase I study of barasertib (AZD1152), a selective inhibitor of Aurora B kinase, in patients with advanced solid tumors. | 2013 Apr |
Sample Use Guides
In Vivo Use Guide
Sources: https://clinicaltrials.gov/ct2/show/NCT01354392
Up to 6 cycles. Each cycle consists of 800 mg. IV infusion over 96 hrs.
Route of Administration:
Intravenous
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/17495131
Barasertib inhibited the proliferation of AML lines (HL-60, NB4, MOLM13), ALL line (PALL-2), biphenotypic leukemia (MV4-11), acute eosinophilic leukemia (EOL-1), and the blast crisis of chronic myeloid leukemia K562 cells with an IC50 ranging from 3 nM to 40 nM, as measured by thymidine uptake on day 2 of culture.
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722543-50-2
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H3T2NXF7ZK
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16221572
Created by
admin on Sat Dec 16 11:05:12 GMT 2023 , Edited by admin on Sat Dec 16 11:05:12 GMT 2023
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ACTIVE MOIETY
SUBSTANCE RECORD