DANUSERTIB

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C26H30N6O3
Molecular Weight	474.5548
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CO[C@@H](C(=O)N1CC2=C(C1)C(NC(=O)C3=CC=C(C=C3)N4CCN(C)CC4)=NN2)C5=CC=CC=C5

InChI

InChIKey=XKFTZKGMDDZMJI-HSZRJFAPSA-N

InChI=1S/C26H30N6O3/c1-30-12-14-31(15-13-30)20-10-8-19(9-11-20)25(33)27-24-21-16-32(17-22(21)28-29-24)26(34)23(35-2)18-6-4-3-5-7-18/h3-11,23H,12-17H2,1-2H3,(H2,27,28,29,33)/t23-/m1/s1

HIDE SMILES / InChI

Molecular Formula	C26H30N6O3
Molecular Weight	474.5548
Charge	0
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	1 / 1
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/20072840
Curator's Comment: description was created based on several sources, including: https://repository.library.northeastern.edu/files/neu:657/fulltext.pdf | http://adisinsight.springer.com/drugs/800025382 | https://www.ncbi.nlm.nih.gov/pubmed/19770380

Danusertib is a serine/threonine kinase inhibitor of multiple kinases, including aurora-A, B, and C. It also inhibits several cancer related tyrosine kinases as well as Abl, Trk-a, fibroblast growth receptor-1 and Ret. Danusertib is in phase II trials for the treatment of solid tumours, prostate cancer and chronic myeloid leukemia (CML). The most frequently reported side effects were neutropenia, nausea, anorexia, fatigue, and diarrhea.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Serine/threonine-protein kinase Aurora-A 37 Target ID: CHEMBL4722 Sources: https://www.ncbi.nlm.nih.gov/pubmed/?term=26345296 \| https://www.ncbi.nlm.nih.gov/pubmed/18089710	Inhibitor 8297	13.0 nM [IC50]
Serine/threonine-protein kinase Aurora-B 28 Target ID: CHEMBL2185 Sources: https://www.ncbi.nlm.nih.gov/pubmed/?term=26345296 \| https://www.ncbi.nlm.nih.gov/pubmed/18089710	Inhibitor 8297	79.0 nM [IC50]
Serine/threonine-protein kinase Aurora-C 10 Target ID: CHEMBL3935 Sources: https://www.ncbi.nlm.nih.gov/pubmed/?term=26345296 \| https://www.ncbi.nlm.nih.gov/pubmed/18089710	Inhibitor 8297	61.0 nM [IC50]
Fibroblast growth factor receptor 1 45 Target ID: CHEMBL3650 Sources: https://www.ncbi.nlm.nih.gov/pubmed/?term=26345296 \| https://www.ncbi.nlm.nih.gov/pubmed/18089710	Inhibitor 8297	47.0 nM [IC50]
Tyrosine-protein kinase ABL 29 Target ID: CHEMBL2111414 Sources: https://www.ncbi.nlm.nih.gov/pubmed/?term=26345296 \| https://www.ncbi.nlm.nih.gov/pubmed/18089710	Inhibitor 8297	25.0 nM [IC50]
Nerve growth factor receptor Trk-A 15 Target ID: CHEMBL2815 Sources: https://www.ncbi.nlm.nih.gov/pubmed/?term=26345296 \| https://www.ncbi.nlm.nih.gov/pubmed/18089710	Inhibitor 8297	31.0 nM [IC50]
Tyrosine-protein kinase receptor RET 14 Target ID: CHEMBL2041 Sources: https://www.ncbi.nlm.nih.gov/pubmed/?term=26345296 \| https://www.ncbi.nlm.nih.gov/pubmed/18089710	Inhibitor 8297	31.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Prostate cancer 178 Sources: https://www.ncbi.nlm.nih.gov/pubmed/22928785 http://adisinsight.springer.com/drugs/800025382	Primary	Phase II 1132	Unknown Approved Use Unknown
Multiple myeloma 159 Sources: https://clinicaltrials.gov/ct2/show/NCT00872300 http://adisinsight.springer.com/drugs/800025382	Primary	Phase II 1132	Unknown Approved Use Unknown
Chronic myeloid leukemia 25 Sources: https://www.ncbi.nlm.nih.gov/pubmed/25887498 http://en.pharmacodia.com/web/drug/1_1569.html	Primary	Phase II 1132	Unknown Approved Use Unknown

Doses

Dose	Population	Adverse events
1000 mg/m2 1 times / 2 weeks multiple, intravenous Highest studied dose Dose: 1000 mg/m2, 1 times / 2 weeks Route: intravenous Route: multiple Dose: 1000 mg/m2, 1 times / 2 weeks Co-administed with:: Filgrastim(Treatment with G-CSF (5μg/kg/daily) was started 24 h after the end of danusertib infusion and continued for 10 days (from Day 3 to Day 12) ending 48 h before the next infusion.) Sources: https://pubmed.ncbi.nlm.nih.gov/19825950 Page: p.5, 6, 16	unhealthy, ADULT n = 7 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 7 Sources: https://pubmed.ncbi.nlm.nih.gov/19825950 Page: p.5, 6, 16	DLT: Febrile neutropenia, Nausea... Disc. AE: Azotemia... Dose limiting toxicities: Febrile neutropenia (14.3%) Nausea (14.3%) AEs leading to discontinuation/dose reduction: Azotemia (grade 1-2, 28.6%) Sources: https://pubmed.ncbi.nlm.nih.gov/19825950 Page: p.5, 6, 16
330 mg/m2 1 times / week multiple, intravenous MTD Dose: 330 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 330 mg/m2, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/19770380 Page: p.5096, 5097	unhealthy, ADULT n = 8 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 8 Sources: https://pubmed.ncbi.nlm.nih.gov/19770380 Page: p.5096, 5097	DLT: Fatigue, Febrile neutropenia... Disc. AE: Hypertension... Dose limiting toxicities: Fatigue (grade 3, 12.5%) Febrile neutropenia (grade 3-4, 12.5%) AEs leading to discontinuation/dose reduction: Hypertension (grade 1, 12.5%) Sources: https://pubmed.ncbi.nlm.nih.gov/19770380 Page: p.5096, 5097
500 mg/m2 1 times / 2 weeks multiple, intravenous MTD Dose: 500 mg/m2, 1 times / 2 weeks Route: intravenous Route: multiple Dose: 500 mg/m2, 1 times / 2 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/19825950 Page: p.5, 6, 16	unhealthy, ADULT n = 12 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 12 Sources: https://pubmed.ncbi.nlm.nih.gov/19825950 Page: p.5, 6, 16	DLT: Febrile neutropenia, Mucositis... Dose limiting toxicities: Febrile neutropenia (8.3%) Mucositis (8.3%) Sources: https://pubmed.ncbi.nlm.nih.gov/19825950 Page: p.5, 6, 16
750 mg/m2 1 times / 2 weeks multiple, intravenous MTD Dose: 750 mg/m2, 1 times / 2 weeks Route: intravenous Route: multiple Dose: 750 mg/m2, 1 times / 2 weeks Co-administed with:: Filgrastim(Treatment with G-CSF (5μg/kg/daily) was started 24 h after the end of danusertib infusion and continued for 10 days (from Day 3 to Day 12) ending 48 h before the next infusion.) Sources: https://pubmed.ncbi.nlm.nih.gov/19825950 Page: p.5, 6, 16	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/19825950 Page: p.5, 6, 16	Sources: https://pubmed.ncbi.nlm.nih.gov/19825950 Page: p.5, 6, 16
330 mg/m2 1 times / week multiple, intravenous Studied dose Dose: 330 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 330 mg/m2, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/19770380 Page: p.5096	unhealthy, ADULT n = 7 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 7 Sources: https://pubmed.ncbi.nlm.nih.gov/19770380 Page: p.5096	DLT: Neutropenia, Fatigue... Dose limiting toxicities: Neutropenia (grade 4, 14.3%) Fatigue (grade 3, 14.3%) Sources: https://pubmed.ncbi.nlm.nih.gov/19770380 Page: p.5096
400 mg/m2 1 times / week multiple, intravenous Studied dose Dose: 400 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 400 mg/m2, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/19770380 Page: p.5096	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/19770380 Page: p.5096	DLT: Neutropenia... Dose limiting toxicities: Neutropenia (grade 4, 50%) Sources: https://pubmed.ncbi.nlm.nih.gov/19770380 Page: p.5096
580 mg/m2 1 times / 2 weeks multiple, intravenous Studied dose Dose: 580 mg/m2, 1 times / 2 weeks Route: intravenous Route: multiple Dose: 580 mg/m2, 1 times / 2 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/19825950 Page: p.5, 6, 16	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/19825950 Page: p.5, 6, 16	DLT: Mucositis, Liver function test abnormal... Dose limiting toxicities: Mucositis (grade 3, 16.7%) Liver function test abnormal (grade 3, 16.7%) Febrile neutropenia (33.3%) Sources: https://pubmed.ncbi.nlm.nih.gov/19825950 Page: p.5, 6, 16
650 mg/m2 1 times / 2 weeks multiple, intravenous Studied dose Dose: 650 mg/m2, 1 times / 2 weeks Route: intravenous Route: multiple Dose: 650 mg/m2, 1 times / 2 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/19825950 Page: p.5, 6, 16	unhealthy, ADULT n = 7 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 7 Sources: https://pubmed.ncbi.nlm.nih.gov/19825950 Page: p.5, 6, 16	DLT: Neutropenia, Febrile neutropenia... Dose limiting toxicities: Neutropenia (14.3%) Febrile neutropenia (14.3%) Sources: https://pubmed.ncbi.nlm.nih.gov/19825950 Page: p.5, 6, 16

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP 111 P-gp 1461 BCRP 699 MRP4 204	BCRP 561 FMO3 67 P-gp 1537

Drug as perpetrator

Target	Modality	Activity
CYP 147	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/19770380/	no
P-gp 1650	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/19770380/	no
BCRP 773	inhibitor 3277 Sources: https://pub.iapchem.org/ojs/index.php/admet/article/view/322	yes [IC50 7.49 uM]
MRP4 238	inhibitor 3277 Sources: https://pub.iapchem.org/ojs/index.php/admet/article/view/322	yes [IC50 8.7 uM]

Drug as victim

Target	Modality	Activity
FMO3 67	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/20182906/	major
BCRP 561	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/23358255/	yes [Km 57.3 uM]
P-gp 1537	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/20182906/	yes

Sourcing

Vendor/Aggregator	ID	URL
001 Chemical	DY103127	https://www.001chemical.com/chem/search?q=DY103127
1PlusChem LLC	1P003PPD	https://www.1pchem.com/search?query=1P003PPD
AK Scientific	SYN1095	https://aksci.com/item_detail.php?cat=SYN1095
AK Scientific	X7370	https://aksci.com/item_detail.php?cat=X7370
ApexBio Technology	A4116	https://www.apexbt.com/catalogsearch/result/?q=A4116
AstaTech	A11611	http://astatechinc.com/CPSResult.php?CRNO=A11611
BLD Pharm	BD167193	http://www.bldpharm.com/search/Search.html?keyword=BD167193
BOC Sciences	827318-97-8	http://www.bocsci.com/description.asp?cas=827318-97-8
BioSynth	J-502504	https://www.biosynth.com/en/products/life-science/other-biochemicals/products/J-502504
Capot Chemical	16771	https://www.capotchem.com/search.do?q=16771
Cayman Chemical	18387	http://www.caymanchem.com/app/template/Product.vm/catalog/18387
Chem Scene	CS-0152	http://www.chemscene.com/goproductList/searchProductList?productObj=CS-0152
ChemShuttle	104825	https://www.chemshuttle.com/catalogsearch/result/?q=104825
Excenen	EX-A1599	http://www.excenen.com/searchresultlist.php?id=EX-A1599
Exclusive Chemistry	2352	http://www.exchemistry.com/chem-catalog/product-2352.html
KeyOrganics	AS-16243	http://www.keyorganicsinc.com/bionet/catalogsearch/result?q=AS-16243
Lab Seeker	SC-27938	http://www.labseeker.com/search.php?keywords=SC-27938&category=0
LabSeeker	SC-27938	http://www.labseeker.com/search.php?keywords=SC-27938&category=0
Matrix Scientific	120848	http://www.matrixscientific.com/120848.html
MedChem Express	HY-10179	https://www.medchemexpress.com/search.html?q=HY-10179&ft=&fa=&fp=
MolPort	MolPort-009-679-390	https://www.molport.com/shop/molecule-link/MolPort-009-679-390
Molcore	MC103127	http://www.molcore.com/CatMC103127.html
Molnova	M16072	https://www.molnova.com/en/serch-list.html?keywords=M16072
MuseChem	I004992	https://www.musechem.com/product/I004992.html
ShangHai Biochempartner	BCP01750	http://www.biochempartner.com/search_BCP01750
Toronto Research Chemicals	D185070	https://www.trc-canada.com/product-detail/?CatNum=D185070
Toronto Research Chemicals	D462135	https://www.trc-canada.com/product-detail/?CatNum=D462135
Wonderchem	WD045Y8	http://www.wonder-chem.com/search.html?text=WD045Y8
eMolecules	108761839	https://orderbb.emolecules.com/search/#?query=108761839
eMolecules	300421563	https://orderbb.emolecules.com/search/#?query=300421563
eMolecules	31229903	https://orderbb.emolecules.com/search/#?query=31229903
eMolecules	48860153	https://orderbb.emolecules.com/search/#?query=48860153
eMolecules	72977010	https://orderbb.emolecules.com/search/#?query=72977010
eNovation Chemicals	D395247	https://www.enovationchem.com/Products.asp?SEARCHTEXT=D395247&searchbtn.x=0&searchbtn.y=0
mcule	MCULE-1841941964	https://mcule.com/MCULE-1841941964/
mcule	MCULE-4216266063	https://mcule.com/MCULE-4216266063/

PubMed

Title	Date	PubMed
Inhibitors of ABL and the ABL-T315I mutation.	2008	18673174
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.	2009 Nov 1	19825950
Phase I pharmacokinetic and pharmacodynamic study of the aurora kinase inhibitor danusertib in patients with advanced or metastatic solid tumors.	2009 Oct 20	19770380
Danusertib (formerly PHA-739358)--a novel combined pan-Aurora kinases and third generation Bcr-Abl tyrosine kinase inhibitor.	2010	20072840
Identification of Myb-binding protein 1A (MYBBP1A) as a novel substrate for aurora B kinase.	2010 Apr 16	20177074
Optimizing combination therapies with existing and future CML drugs.	2010 Aug 23	20808800
Abcg2 overexpression represents a novel mechanism for acquired resistance to the multi-kinase inhibitor Danusertib in BCR-ABL-positive cells in vitro.	2011 Apr 26	21541334

Patents

Sample Use Guides

In Vivo Use Guide

330 mg/m(2) over 6 h on days 1, 8 and 15 or 500 mg/m(2) over 24 h on days 1 and 15, every 4 weeks.

Route of Administration: Intravenous

In Vitro Use Guide

PHA-739358 strongly inhibited proliferation of all human and murine leukemic and nonleukemic cell lines (BCR-ABL-positive and BCR-ABL-negative) tested, with IC50 values ranging from 0.05 μM to 3.06 μM

Substance Class	Chemical Created by `admin` on `Sat Dec 16 17:51:49 GMT 2023` Edited by `admin` on `Sat Dec 16 17:51:49 GMT 2023`
Record UNII	M3X659D0FY
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

DANUSERTIB

Official Name

English

N-(5-((2R)-2-METHOXY-2-PHENYLACETYL)-1,4,5,6-TETRAHYDROPYRROLO(3,4-C)PYRAZOL-3-YL)-4-(4-METHYLPIPERAZIN-1-YL)BENZAMIDE

Systematic Name

English

PHA-739358

Code

English

Danusertib [WHO-DD]

Common Name

English

danusertib [INN]

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C62556