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Details

Stereochemistry ACHIRAL
Molecular Formula C31H42N6O4
Molecular Weight 562.703
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of TANDUTINIB

SMILES

COC1=CC2=C(N=CN=C2C=C1OCCCN3CCCCC3)N4CCN(CC4)C(=O)NC5=CC=C(OC(C)C)C=C5

InChI

InChIKey=UXXQOJXBIDBUAC-UHFFFAOYSA-N
InChI=1S/C31H42N6O4/c1-23(2)41-25-10-8-24(9-11-25)34-31(38)37-17-15-36(16-18-37)30-26-20-28(39-3)29(21-27(26)32-22-33-30)40-19-7-14-35-12-5-4-6-13-35/h8-11,20-23H,4-7,12-19H2,1-3H3,(H,34,38)

HIDE SMILES / InChI

Molecular Formula C31H42N6O4
Molecular Weight 562.703
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

Description
Curator's Comment: Description was created based on several sources, including https://www.drugbank.ca/drugs/DB05465

Millennium Pharmaceuticals Inc's tandutinib (MLN-518), a piperazinyl derivative of quinazoline, is an orally active inhibitor of FLT3 kinase and family members PDGFR beta and c-Kit. Tandutinib inhibited FLT3 phosphorylation, downstream signaling and malignant growth in vitro and in animal models. The drug exhibited limited activity as a single agent in phase I and II clinical trials in patients with AML and myelodysplastic syndrome, but displayed promising antileukemic activity (90% complete remissions) in a phase I/II trial in patients with newly diagnosed AML when administered in combination with cytarabine and daunorubicin. Phase II clinical trials for tandutinib in patients with Glioblastoma have being discontinued. The use of tandutinib to treat AML has been granted fast-track status by the U.S. Food and Drug Administration. Phase II trials were underway., but later withwrawn.

Approval Year

TargetsConditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
486 ng/mL
600 mg 2 times / day steady-state, oral
dose: 600 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
TANDUTINIB plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
1285 ng/mL
700 mg 2 times / day steady-state, oral
dose: 700 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
TANDUTINIB plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
4659 ng × h/mL
600 mg 2 times / day steady-state, oral
dose: 600 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
TANDUTINIB plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
8193 ng × h/mL
700 mg 2 times / day steady-state, oral
dose: 700 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
TANDUTINIB plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
10.4 h
600 mg 2 times / day steady-state, oral
dose: 600 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
TANDUTINIB plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
13.2 h
700 mg 2 times / day steady-state, oral
dose: 700 mg
route of administration: Oral
experiment type: STEADY-STATE
co-administered:
TANDUTINIB plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
Doses

Doses

DosePopulationAdverse events​
700 mg 2 times / day multiple, oral
Highest studied dose
Dose: 700 mg, 2 times / day
Route: oral
Route: multiple
Dose: 700 mg, 2 times / day
Sources:
unhealthy, ADULT
n = 3
Health Status: unhealthy
Condition: hematologic cancer
Age Group: ADULT
Sex: M+F
Food Status: FASTED
Population Size: 3
Sources:
DLT: Muscular weakness, Diarrhea...
Dose limiting toxicities:
Muscular weakness (grade 3-4, 66.7%)
Diarrhea (grade 3, 33.3%)
Sources:
700 mg 2 times / day multiple, oral
Highest studied dose
Dose: 700 mg, 2 times / day
Route: oral
Route: multiple
Dose: 700 mg, 2 times / day
Sources: Page: p.571
unhealthy, ADULT
n = 3
Health Status: unhealthy
Condition: glioblastoma
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 3
Sources: Page: p.571
DLT: Weakness, Fatigue...
Dose limiting toxicities:
Weakness (grade 3, 33.3%)
Fatigue (grade 3, 33.3%)
Sources: Page: p.571
525 mg 2 times / day multiple, oral
MTD
Dose: 525 mg, 2 times / day
Route: oral
Route: multiple
Dose: 525 mg, 2 times / day
Sources:
unhealthy, ADULT
n = 6
Health Status: unhealthy
Condition: hematologic cancer
Age Group: ADULT
Sex: M+F
Food Status: FASTED
Population Size: 6
Sources:
DLT: Fatigue, Muscular weakness...
Dose limiting toxicities:
Fatigue (grade 3, 16.7%)
Muscular weakness (grade 3, 16.7%)
Sources:
600 mg 2 times / day multiple, oral
MTD
Dose: 600 mg, 2 times / day
Route: oral
Route: multiple
Dose: 600 mg, 2 times / day
Sources: Page: p.571
unhealthy, ADULT
n = 6
Health Status: unhealthy
Condition: glioblastoma
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 6
Sources: Page: p.571
DLT: Blood phosphorus abnormal...
Dose limiting toxicities:
Blood phosphorus abnormal (grade 3, 16.7%)
Sources: Page: p.571
AEs

AEs

AESignificanceDosePopulation
Diarrhea grade 3, 33.3%
DLT
700 mg 2 times / day multiple, oral
Highest studied dose
Dose: 700 mg, 2 times / day
Route: oral
Route: multiple
Dose: 700 mg, 2 times / day
Sources:
unhealthy, ADULT
n = 3
Health Status: unhealthy
Condition: hematologic cancer
Age Group: ADULT
Sex: M+F
Food Status: FASTED
Population Size: 3
Sources:
Muscular weakness grade 3-4, 66.7%
DLT, Disc. AE
700 mg 2 times / day multiple, oral
Highest studied dose
Dose: 700 mg, 2 times / day
Route: oral
Route: multiple
Dose: 700 mg, 2 times / day
Sources:
unhealthy, ADULT
n = 3
Health Status: unhealthy
Condition: hematologic cancer
Age Group: ADULT
Sex: M+F
Food Status: FASTED
Population Size: 3
Sources:
Fatigue grade 3, 33.3%
DLT
700 mg 2 times / day multiple, oral
Highest studied dose
Dose: 700 mg, 2 times / day
Route: oral
Route: multiple
Dose: 700 mg, 2 times / day
Sources: Page: p.571
unhealthy, ADULT
n = 3
Health Status: unhealthy
Condition: glioblastoma
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 3
Sources: Page: p.571
Weakness grade 3, 33.3%
DLT
700 mg 2 times / day multiple, oral
Highest studied dose
Dose: 700 mg, 2 times / day
Route: oral
Route: multiple
Dose: 700 mg, 2 times / day
Sources: Page: p.571
unhealthy, ADULT
n = 3
Health Status: unhealthy
Condition: glioblastoma
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 3
Sources: Page: p.571
Fatigue grade 3, 16.7%
DLT, Disc. AE
525 mg 2 times / day multiple, oral
MTD
Dose: 525 mg, 2 times / day
Route: oral
Route: multiple
Dose: 525 mg, 2 times / day
Sources:
unhealthy, ADULT
n = 6
Health Status: unhealthy
Condition: hematologic cancer
Age Group: ADULT
Sex: M+F
Food Status: FASTED
Population Size: 6
Sources:
Muscular weakness grade 3, 16.7%
DLT, Disc. AE
525 mg 2 times / day multiple, oral
MTD
Dose: 525 mg, 2 times / day
Route: oral
Route: multiple
Dose: 525 mg, 2 times / day
Sources:
unhealthy, ADULT
n = 6
Health Status: unhealthy
Condition: hematologic cancer
Age Group: ADULT
Sex: M+F
Food Status: FASTED
Population Size: 6
Sources:
Blood phosphorus abnormal grade 3, 16.7%
DLT
600 mg 2 times / day multiple, oral
MTD
Dose: 600 mg, 2 times / day
Route: oral
Route: multiple
Dose: 600 mg, 2 times / day
Sources: Page: p.571
unhealthy, ADULT
n = 6
Health Status: unhealthy
Condition: glioblastoma
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 6
Sources: Page: p.571
Sourcing

Sourcing

Vendor/AggregatorIDURL
PubMed

PubMed

TitleDatePubMed
Identification of orally active, potent, and selective 4-piperazinylquinazolines as antagonists of the platelet-derived growth factor receptor tyrosine kinase family.
2002 Aug 15
CT53518, a novel selective FLT3 antagonist for the treatment of acute myelogenous leukemia (AML).
2002 Jun
Sensitivity of oncogenic KIT mutants to the kinase inhibitors MLN518 and PD180970.
2004 Dec 1
Variable sensitivity of FLT3 activation loop mutations to the small molecule tyrosine kinase inhibitor MLN518.
2004 Nov 1
Effects of MLN518, a dual FLT3 and KIT inhibitor, on normal and malignant hematopoiesis.
2004 Nov 1
RNAi-induced down-regulation of FLT3 expression in AML cell lines increases sensitivity to MLN518.
2005 Apr 1
[Possibility of targeting FLT3 kinase for the treatment of leukemia].
2005 Mar
[Current and new therapeutic strategies in acute myeloid leukemia].
2005 Mar
[The present status of, and problems with the development of FLT3 kinase inhibitors].
2006 Apr
Improved synthesis of substituted 6,7-dihydroxy-4-quinazolineamines: tandutinib, erlotinib and gefitinib.
2006 Apr 10
Phase 1 clinical results with tandutinib (MLN518), a novel FLT3 antagonist, in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome: safety, pharmacokinetics, and pharmacodynamics.
2006 Dec 1
FLT3 kinase inhibitors in the management of acute myeloid leukemia.
2007 Dec
[Novel molecularly target therapies for leukemia].
2007 Jan 28
Tandutinib, an oral, small-molecule inhibitor of FLT3 for the treatment of AML and other cancer indications.
2008 Jan
Tandutinib inhibits FMS receptor signalling, and macrophage and osteoclast formation in vitro.
2008 Jul
Can FLT3 inhibitors overcome resistance in AML?
2008 Mar
Detection of FLT3 oncogene mutations in acute myeloid leukemia using conformation sensitive gel electrophoresis.
2008 Nov
Gamma-secretase represents a therapeutic target for the treatment of invasive glioma mediated by the p75 neurotrophin receptor.
2008 Nov 25
Id1 is a common downstream target of oncogenic tyrosine kinases in leukemic cells.
2008 Sep 1
N-(4-Isopropoxyphen-yl)acetamide.
2009 Apr 10
The FLT3 inhibitor tandutinib (formerly MLN518) has sequence-independent synergistic effects with cytarabine and daunorubicin.
2009 Aug 15
ABT-869, a promising multi-targeted tyrosine kinase inhibitor: from bench to bedside.
2009 Jul 30
Patient-derived acute myeloid leukemia (AML) bone marrow cells display distinct intracellular kinase phosphorylation patterns.
2009 May 15
AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML).
2009 Oct 1
Antiangiogenic therapy and mechanisms of tumor resistance in malignant glioma.
2010
P-glycoprotein and breast cancer resistance protein affect disposition of tandutinib, a tyrosine kinase inhibitor.
2010 Dec
The lack of target specificity of small molecule anticancer kinase inhibitors is correlated with their ability to damage myocytes in vitro.
2010 Dec 1
Gateways to clinical trials.
2010 Jan-Feb
FLT3 inhibitors for the treatment of acute myeloid leukemia.
2010 Jun
[FLT3 kinase inhibitors for the treatment of acute leukemia].
2010 Jun
Patents

Sample Use Guides

oral tandutinib 500 mg twice daily on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
Route of Administration: Oral
Tandutinib inhibited IL-3-independent cell growth and FLT3-ITD autophosphorylation with an IC(50) of 10-100 nM.
Substance Class Chemical
Created
by admin
on Fri Dec 15 16:00:53 GMT 2023
Edited
by admin
on Fri Dec 15 16:00:53 GMT 2023
Record UNII
E1IO3ICJ9A
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
TANDUTINIB
INN   USAN   WHO-DD  
USAN   INN  
Official Name English
4-[6-Methoxy-7-[3-(piperidin-1-yl)propoxy]quinazolin-4-yl]-N-[4-(1-methylethoxy)phenyl]piperazine-1-carboxamide
Systematic Name English
Tandutinib [WHO-DD]
Common Name English
CT-53518
Code English
NSC-759851
Code English
MLN-518
Code English
CT53518
Code English
tandutinib [INN]
Common Name English
TANDUTINIB [USAN]
Common Name English
Classification Tree Code System Code
NCI_THESAURUS C129825
Created by admin on Fri Dec 15 16:00:53 GMT 2023 , Edited by admin on Fri Dec 15 16:00:53 GMT 2023
NCI_THESAURUS C1967
Created by admin on Fri Dec 15 16:00:53 GMT 2023 , Edited by admin on Fri Dec 15 16:00:53 GMT 2023
Code System Code Type Description
CHEBI
90237
Created by admin on Fri Dec 15 16:00:53 GMT 2023 , Edited by admin on Fri Dec 15 16:00:53 GMT 2023
PRIMARY
SMS_ID
100000143101
Created by admin on Fri Dec 15 16:00:53 GMT 2023 , Edited by admin on Fri Dec 15 16:00:53 GMT 2023
PRIMARY
MESH
C464670
Created by admin on Fri Dec 15 16:00:53 GMT 2023 , Edited by admin on Fri Dec 15 16:00:53 GMT 2023
PRIMARY
EPA CompTox
DTXSID8048947
Created by admin on Fri Dec 15 16:00:53 GMT 2023 , Edited by admin on Fri Dec 15 16:00:53 GMT 2023
PRIMARY
EVMPD
SUB118670
Created by admin on Fri Dec 15 16:00:53 GMT 2023 , Edited by admin on Fri Dec 15 16:00:53 GMT 2023
PRIMARY
DRUG BANK
DB05465
Created by admin on Fri Dec 15 16:00:53 GMT 2023 , Edited by admin on Fri Dec 15 16:00:53 GMT 2023
PRIMARY
PUBCHEM
3038522
Created by admin on Fri Dec 15 16:00:53 GMT 2023 , Edited by admin on Fri Dec 15 16:00:53 GMT 2023
PRIMARY
USAN
OO-66
Created by admin on Fri Dec 15 16:00:53 GMT 2023 , Edited by admin on Fri Dec 15 16:00:53 GMT 2023
PRIMARY
NCI_THESAURUS
C48404
Created by admin on Fri Dec 15 16:00:53 GMT 2023 , Edited by admin on Fri Dec 15 16:00:53 GMT 2023
PRIMARY
FDA UNII
E1IO3ICJ9A
Created by admin on Fri Dec 15 16:00:53 GMT 2023 , Edited by admin on Fri Dec 15 16:00:53 GMT 2023
PRIMARY
NSC
759851
Created by admin on Fri Dec 15 16:00:53 GMT 2023 , Edited by admin on Fri Dec 15 16:00:53 GMT 2023
PRIMARY
INN
8501
Created by admin on Fri Dec 15 16:00:53 GMT 2023 , Edited by admin on Fri Dec 15 16:00:53 GMT 2023
PRIMARY
CAS
387867-13-2
Created by admin on Fri Dec 15 16:00:53 GMT 2023 , Edited by admin on Fri Dec 15 16:00:53 GMT 2023
PRIMARY
ChEMBL
CHEMBL124660
Created by admin on Fri Dec 15 16:00:53 GMT 2023 , Edited by admin on Fri Dec 15 16:00:53 GMT 2023
PRIMARY
Related Record Type Details
SALT/SOLVATE -> PARENT
TARGET -> INHIBITOR
TARGET -> INHIBITOR
TARGET -> INHIBITOR
Related Record Type Details
ACTIVE MOIETY