BARASERTIB

Details

Stereochemistry	ACHIRAL
Molecular Formula	C26H31FN7O6P
Molecular Weight	587.5398
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

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=GBJVVSCPOBPEIT-UHFFFAOYSA-N

InChI=1S/C26H31FN7O6P/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)

HIDE SMILES / InChI

Molecular Formula	C26H31FN7O6P
Molecular Weight	587.5398
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description
Sources: https://openinnovation.astrazeneca.com/barasertib-azd1152.html
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

Targets

Primary Target	Pharmacology	Condition	Potency
Serine/threonine-protein kinase Aurora-B 28 Target ID: CHEMBL2185 Sources: https://www.ncbi.nlm.nih.gov/pubmed/?term=20420387 \| https://www.ncbi.nlm.nih.gov/pubmed/17495131	Inhibitor 8297		0.37 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Lymphoma 58 Sources: https://clinicaltrials.gov/ct2/show/NCT01354392	Primary		Phase II 1132	Unknown Approved Use Unknown
Acute myeloid leukemia 136 Sources: https://clinicaltrials.gov/ct2/show/NCT00952588	Primary		Phase III 656	Unknown Approved Use Unknown

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: https://pubmed.ncbi.nlm.nih.gov/22661287 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: https://pubmed.ncbi.nlm.nih.gov/22661287 Page: p.375	DLT: Neutropenia... Disc. AE: Proteinuria... Dose limiting toxicities: Neutropenia (grade 4, 20%) AEs leading to discontinuation/dose reduction: Proteinuria (grade 3, 20%) Sources: https://pubmed.ncbi.nlm.nih.gov/22661287 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: https://pubmed.ncbi.nlm.nih.gov/21976672	unhealthy, ADULT n = 6 Health Status: unhealthy Condition: acute myeloid leukemia Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/21976672	DLT: Mucositis oral... Disc. AE: Pseudomonal sepsis, cellulitis... Dose limiting toxicities: Mucositis oral (grade 3-4, 16.7%) AEs leading to discontinuation/dose reduction: Pseudomonal sepsis (16.7%) cellulitis (16.7%) Sources: https://pubmed.ncbi.nlm.nih.gov/21976672
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: https://pubmed.ncbi.nlm.nih.gov/22661287 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: https://pubmed.ncbi.nlm.nih.gov/22661287 Page: p.375	Sources: https://pubmed.ncbi.nlm.nih.gov/22661287 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: https://pubmed.ncbi.nlm.nih.gov/22661287 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: https://pubmed.ncbi.nlm.nih.gov/22661287 Page: p.375	Sources: https://pubmed.ncbi.nlm.nih.gov/22661287 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: https://pubmed.ncbi.nlm.nih.gov/21976672	unhealthy, ADULT n = 6 Health Status: unhealthy Condition: acute myeloid leukemia Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/21976672	DLT: Mucositis oral... Dose limiting toxicities: Mucositis oral (grade 3-4, 33.3%) Sources: https://pubmed.ncbi.nlm.nih.gov/21976672
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: https://pubmed.ncbi.nlm.nih.gov/22661287 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: https://pubmed.ncbi.nlm.nih.gov/22661287 Page: p.375	DLT: Febrile neutropenia, Neutropenia... Dose limiting toxicities: Febrile neutropenia (grade 4, 25%) Neutropenia (grade 4, 25%) Sources: https://pubmed.ncbi.nlm.nih.gov/22661287 Page: p.375

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: https://pubmed.ncbi.nlm.nih.gov/22661287 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: https://pubmed.ncbi.nlm.nih.gov/22661287 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: https://pubmed.ncbi.nlm.nih.gov/22661287 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: https://pubmed.ncbi.nlm.nih.gov/22661287 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: https://pubmed.ncbi.nlm.nih.gov/21976672	unhealthy, ADULT n = 6 Health Status: unhealthy Condition: acute myeloid leukemia Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/21976672
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: https://pubmed.ncbi.nlm.nih.gov/21976672	unhealthy, ADULT n = 6 Health Status: unhealthy Condition: acute myeloid leukemia Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/21976672
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: https://pubmed.ncbi.nlm.nih.gov/21976672	unhealthy, ADULT n = 6 Health Status: unhealthy Condition: acute myeloid leukemia Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/21976672
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: https://pubmed.ncbi.nlm.nih.gov/21976672	unhealthy, ADULT n = 6 Health Status: unhealthy Condition: acute myeloid leukemia Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/21976672
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: https://pubmed.ncbi.nlm.nih.gov/22661287 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: https://pubmed.ncbi.nlm.nih.gov/22661287 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: https://pubmed.ncbi.nlm.nih.gov/22661287 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: https://pubmed.ncbi.nlm.nih.gov/22661287 Page: p.375

Overview

CYP3A4	CYP2C9	CYP2D6	hERG

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
BCRP 699 P-gp 1461	BCRP 561 MRP2 205 P-gp 1537

Drug as perpetrator

Target	Modality	Activity	Metabolite
P-gp 1650	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/21679421/	no	BARASERTIB-hQPA 3
BCRP 773	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/23315030/	yes
BCRP 773	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/23315030/	yes	BARASERTIB-hQPA 3

Drug as victim

Target	Modality	Activity	Metabolite
MRP2 205	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/23315030/	no
MRP2 205	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/23315030/	no	BARASERTIB-hQPA 3
BCRP 561	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/23315030/	yes
BCRP 561	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/23315030/	yes	BARASERTIB-hQPA 3
P-gp 1537	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/23315030/	yes
P-gp 1537	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/23315030/	yes	BARASERTIB-hQPA 3

Sourcing

Vendor/Aggregator	ID	URL
1PlusChem LLC	1P00FCG0	https://www.1pchem.com/search?query=1P00FCG0
AK Scientific	SYN5717	https://aksci.com/item_detail.php?cat=SYN5717
AOBIOUS INC	AOB87338	http://aobious.com/aobious/search?search_query=AOB87338
AbovChem LLC	AC050732	http://www.abovchem.com/pc/en/product_list.aspx?wd=AC050732
ApexBio Technology	A3214	https://www.apexbt.com/catalogsearch/result/?q=A3214
AstaTech	83480	http://astatechinc.com/CPSResult.php?CRNO=83480
BLD Pharm	BD263294	http://www.bldpharm.com/search/Search.html?keyword=BD263294
BOC Sciences	722543-31-9	http://www.bocsci.com/description.asp?cas=722543-31-9
Capot Chemical	16656	https://www.capotchem.com/search.do?q=16656
Cayman Chemical	13647	http://www.caymanchem.com/app/template/Product.vm/catalog/13647
Chem Scene	CS-0978	http://www.chemscene.com/goproductList/searchProductList?productObj=CS-0978
Combi-Blocks	QK-7690	http://www.combi-blocks.com/cgi-bin/find.cgi?QK-7690
Debye Scientific	DB-074538	https://www.debyesci.com/index.php?id=product&ext[cno]=DB-074538
KeyOrganics	AS-17018	http://www.keyorganicsinc.com/bionet/catalogsearch/result?q=AS-17018
MedChem Express	HY-10127	https://www.medchemexpress.com/search.html?q=HY-10127&ft=&fa=&fp=
MolPort	MolPort-016-631-864	https://www.molport.com/shop/molecule-link/MolPort-016-631-864
MolPort	MolPort-044-561-175	https://www.molport.com/shop/molecule-link/MolPort-044-561-175
Molnova	M15764	https://www.molnova.com/en/serch-list.html?keywords=M15764
ShangHai Biochempartner	BCP13793	http://www.biochempartner.com/search_BCP13793
Toronto Research Chemicals	E679550	https://www.trc-canada.com/product-detail/?CatNum=E679550
eMolecules	31229305	https://orderbb.emolecules.com/search/#?query=31229305
eMolecules	49837439	https://orderbb.emolecules.com/search/#?query=49837439
eMolecules	76743560	https://orderbb.emolecules.com/search/#?query=76743560
mcule	MCULE-4303553405	https://mcule.com/MCULE-4303553405/
mcule	MCULE-4958215865	https://mcule.com/MCULE-4958215865/

PubMed

Title	Date	PubMed
Aurora-kinase inhibitors as anticancer agents.	2004 Dec	15573114
Aurora kinases: shining lights on the therapeutic horizon?	2005 Jul 28	16049526
Aurora kinases: new targets for cancer therapy.	2006 Dec 1	17145803
AZD1152, a selective inhibitor of Aurora B kinase, inhibits human tumor xenograft growth by inducing apoptosis.	2007 Jun 15	17575233
Discovery, synthesis, and in vivo activity of a new class of pyrazoloquinazolines as selective inhibitors of aurora B kinase.	2007 May 3	17373783
AZD1152, a novel and selective aurora B kinase inhibitor, induces growth arrest, apoptosis, and sensitization for tubulin depolymerizing agent or topoisomerase II inhibitor in human acute leukemia cells in vitro and in vivo.	2007 Sep 15	17495131
The selective Aurora B kinase inhibitor AZD1152 is a potential new treatment for multiple myeloma.	2008 Feb	18076711
Preclinical evaluation of M30 and M65 ELISAs as biomarkers of drug induced tumor cell death and antitumor activity.	2008 Mar	18347133
Effects of the aurora kinase inhibitors AZD1152-HQPA and ZM447439 on growth arrest and polyploidy in acute myeloid leukemia cell lines and primary blasts.	2008 May	18367484
Enhancement of radiation response in p53-deficient cancer cells by the Aurora-B kinase inhibitor AZD1152.	2008 May 22	18084327
Identification of genes that confer tumor cell resistance to the aurora B kinase inhibitor, AZD1152.	2009 Apr	19188929
Mitotic drivers--inhibitors of the Aurora B Kinase.	2009 Jun	19189202
Pharmacological inhibition of aurora-A but not aurora-B impairs interphase microtubule dynamics.	2009 Jun 1	19395863
The topoisomerase I poison CPT-11 enhances the effect of the aurora B kinase inhibitor AZD1152 both in vitro and in vivo.	2009 Mar 15	19276280
Biochemical characterization of GSK1070916, a potent and selective inhibitor of Aurora B and Aurora C kinases with an extremely long residence time1.	2009 May 13	19284385
AZD1152 rapidly and negatively affects the growth and survival of human acute myeloid leukemia cells in vitro and in vivo.	2009 May 15	19366807
Simultaneous determination of AZD1152 (prodrug) and AZD1152-hydroxyquinazoline pyrazol anilide by reversed phase liquid chromatography.	2009 Nov 1	19744901
The aurora B kinase inhibitor AZD1152 sensitizes cancer cells to fractionated irradiation and induces mitotic catastrophe.	2009 Oct 1	19755861
Aurora kinase inhibitors as anti-cancer therapy.	2010 Apr	20016367
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	20935223
Antineoplastic effects of an Aurora B kinase inhibitor in breast cancer.	2010 Feb 22	20175926
The selective Aurora B kinase inhibitor AZD1152 as a novel treatment for hepatocellular carcinoma.	2010 Jan	19913935
Aurora kinase inhibitor AZD1152 negatively affects the growth and survival of HTLV-1-infected T lymphocytes in vitro.	2010 Oct 1	20091867
Phthalazinone pyrazoles as potent, selective, and orally bioavailable inhibitors of Aurora-A kinase.	2011 Jan 13	21128645
Phase I study of barasertib (AZD1152), a selective inhibitor of Aurora B kinase, in patients with advanced solid tumors.	2013 Apr	22661287

Patents

Sample Use Guides

In Vivo Use Guide

Up to 6 cycles. Each cycle consists of 800 mg. IV infusion over 96 hrs.

Route of Administration: Intravenous

In Vitro Use Guide

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.

Substance Class	Chemical Created by `admin` on `Fri Dec 15 16:47:02 UTC 2023` Edited by `admin` on `Fri Dec 15 16:47:02 UTC 2023`
Record UNII	16XC2U7W8N
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

BARASERTIB

Official Name

English

AZD1152

Code

English

Barasertib [WHO-DD]

Common Name

English

barasertib [INN]

Common Name

English

1H-PYRAZOLE-3-ACETAMIDE, 5-((7-(3-(ETHYL(2-(PHOSPHONOOXY)ETHYL)AMINO)PROPOXY)-4-QUINAZOLINYL)AMINO)-N-(3-FLUOROPHENYL)-

Systematic Name

English

AZD-1152

Code

English

Classification Tree Code System Code

NCI_THESAURUS

C62556