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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 of DANUSERTIB

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
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.

Approval Year

TargetsConditions
Doses

Doses

DosePopulationAdverse 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: 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: 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: 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: 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: 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: 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: 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: Page: p.5, 6, 16
DLT: Febrile neutropenia, Mucositis...
Dose limiting toxicities:
Febrile neutropenia (8.3%)
Mucositis (8.3%)
Sources: 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: 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: 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: 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: Page: p.5096
DLT: Neutropenia, Fatigue...
Dose limiting toxicities:
Neutropenia (grade 4, 14.3%)
Fatigue (grade 3, 14.3%)
Sources: 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: 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: Page: p.5096
DLT: Neutropenia...
Dose limiting toxicities:
Neutropenia (grade 4, 50%)
Sources: 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: 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: 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: 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: 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: Page: p.5, 6, 16
DLT: Neutropenia, Febrile neutropenia...
Dose limiting toxicities:
Neutropenia (14.3%)
Febrile neutropenia (14.3%)
Sources: Page: p.5, 6, 16
AEs

AEs

AESignificanceDosePopulation
Febrile neutropenia 14.3%
DLT
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: 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: Page: p.5, 6, 16
Nausea 14.3%
DLT
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: 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: Page: p.5, 6, 16
Azotemia grade 1-2, 28.6%
Disc. AE
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: 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: Page: p.5, 6, 16
Hypertension grade 1, 12.5%
Disc. AE
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: 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: Page: p.5096, 5097
Fatigue grade 3, 12.5%
DLT
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: 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: Page: p.5096, 5097
Febrile neutropenia grade 3-4, 12.5%
DLT
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: 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: Page: p.5096, 5097
Febrile neutropenia 8.3%
DLT
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: 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: Page: p.5, 6, 16
Mucositis 8.3%
DLT
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: 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: Page: p.5, 6, 16
Fatigue grade 3, 14.3%
DLT, Disc. AE
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: 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: Page: p.5096
Neutropenia grade 4, 14.3%
DLT, Disc. AE
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: 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: Page: p.5096
Neutropenia grade 4, 50%
DLT, Disc. AE
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: 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: Page: p.5096
Febrile neutropenia 33.3%
DLT
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: 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: Page: p.5, 6, 16
Liver function test abnormal grade 3, 16.7%
DLT
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: 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: Page: p.5, 6, 16
Mucositis grade 3, 16.7%
DLT
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: 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: Page: p.5, 6, 16
Febrile neutropenia 14.3%
DLT
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: 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: Page: p.5, 6, 16
Neutropenia 14.3%
DLT
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: 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: Page: p.5, 6, 16
Overview

Overview

CYP3A4CYP2C9CYP2D6hERG

OverviewOther

Other InhibitorOther SubstrateOther Inducer







Drug as perpetrator​Drug as victim

Drug as victim

Sourcing

Sourcing

Vendor/AggregatorIDURL
PubMed

PubMed

TitleDatePubMed
1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazoles: identification of a potent Aurora kinase inhibitor with a favorable antitumor kinase inhibition profile.
2006 Nov 30
Inhibitors of ABL and the ABL-T315I mutation.
2008
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
Phase I pharmacokinetic and pharmacodynamic study of the aurora kinase inhibitor danusertib in patients with advanced or metastatic solid tumors.
2009 Oct 20
Danusertib (formerly PHA-739358)--a novel combined pan-Aurora kinases and third generation Bcr-Abl tyrosine kinase inhibitor.
2010
Identification of Myb-binding protein 1A (MYBBP1A) as a novel substrate for aurora B kinase.
2010 Apr 16
Optimizing combination therapies with existing and future CML drugs.
2010 Aug 23
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
Patents

Sample Use Guides

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
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
  • Download
Name Type Language
DANUSERTIB
INN   WHO-DD  
INN  
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
Created by admin on Sat Dec 16 17:51:50 GMT 2023 , Edited by admin on Sat Dec 16 17:51:50 GMT 2023
NCI_THESAURUS C129825
Created by admin on Sat Dec 16 17:51:50 GMT 2023 , Edited by admin on Sat Dec 16 17:51:50 GMT 2023
Code System Code Type Description
EPA CompTox
DTXSID301002864
Created by admin on Sat Dec 16 17:51:50 GMT 2023 , Edited by admin on Sat Dec 16 17:51:50 GMT 2023
PRIMARY
FDA UNII
M3X659D0FY
Created by admin on Sat Dec 16 17:51:50 GMT 2023 , Edited by admin on Sat Dec 16 17:51:50 GMT 2023
PRIMARY
INN
8993
Created by admin on Sat Dec 16 17:51:50 GMT 2023 , Edited by admin on Sat Dec 16 17:51:50 GMT 2023
PRIMARY
EVMPD
SUB96034
Created by admin on Sat Dec 16 17:51:50 GMT 2023 , Edited by admin on Sat Dec 16 17:51:50 GMT 2023
PRIMARY
DRUG BANK
DB11778
Created by admin on Sat Dec 16 17:51:50 GMT 2023 , Edited by admin on Sat Dec 16 17:51:50 GMT 2023
PRIMARY
SMS_ID
100000141656
Created by admin on Sat Dec 16 17:51:50 GMT 2023 , Edited by admin on Sat Dec 16 17:51:50 GMT 2023
PRIMARY
PUBCHEM
11442891
Created by admin on Sat Dec 16 17:51:50 GMT 2023 , Edited by admin on Sat Dec 16 17:51:50 GMT 2023
PRIMARY
ChEMBL
CHEMBL402548
Created by admin on Sat Dec 16 17:51:50 GMT 2023 , Edited by admin on Sat Dec 16 17:51:50 GMT 2023
PRIMARY
CAS
827318-97-8
Created by admin on Sat Dec 16 17:51:50 GMT 2023 , Edited by admin on Sat Dec 16 17:51:50 GMT 2023
PRIMARY
MESH
C523797
Created by admin on Sat Dec 16 17:51:50 GMT 2023 , Edited by admin on Sat Dec 16 17:51:50 GMT 2023
PRIMARY
NCI_THESAURUS
C61587
Created by admin on Sat Dec 16 17:51:50 GMT 2023 , Edited by admin on Sat Dec 16 17:51:50 GMT 2023
PRIMARY
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