TANDUTINIB

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 Search

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
Sources: https://www.ncbi.nlm.nih.gov/pubmed/18175263
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.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Tyrosine-protein kinase receptor FLT3 43 Target ID: CHEMBL1974 Sources: https://www.drugbank.ca/drugs/DB05465	Antagonist 2778	0.22 µM [IC50]
Platelet-derived growth factor receptor beta 56 Target ID: CHEMBL1913 Sources: https://www.ncbi.nlm.nih.gov/pubmed/12124172	Antagonist 2778	0.2 µM [IC50]
Stem cell growth factor receptor 53 Target ID: CHEMBL1936 Sources: https://www.ncbi.nlm.nih.gov/pubmed/12124172	Antagonist 2778	0.17 µM [IC50]
Macrophage colony stimulating factor receptor 24 Target ID: CHEMBL1844 Sources: https://www.ncbi.nlm.nih.gov/pubmed/12124172	Antagonist 2778	3.43 µM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Glioblastoma 65 Sources: https://clinicaltrials.gov/ct2/show/NCT00667394	Primary	Phase II 1132	Unknown Approved Use Unknown
Acute myelogenous leukemia 19 Sources: https://clinicaltrials.gov/ct2/show/NCT00274248	Primary	Withdrawn	Unknown Approved Use Unknown
Kidney cancer 10 Sources: https://clinicaltrials.gov/ct2/show/NCT00408902	Primary	Phase II 1132	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
486 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27663390	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27663390	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

Value	Dose	Co-administered	Analyte	Population
4659 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27663390	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27663390	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

T_1/2

Value	Dose	Co-administered	Analyte	Population
10.4 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27663390	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27663390	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

Dose	Population	Adverse 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: https://pubmed.ncbi.nlm.nih.gov/16902153	unhealthy, ADULT n = 3 Health Status: unhealthy Condition: hematologic cancer Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/16902153	DLT: Muscular weakness, Diarrhea... Dose limiting toxicities: Muscular weakness (grade 3-4, 66.7%) Diarrhea (grade 3, 33.3%) Sources: https://pubmed.ncbi.nlm.nih.gov/16902153
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: https://pubmed.ncbi.nlm.nih.gov/27663390 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: https://pubmed.ncbi.nlm.nih.gov/27663390 Page: p.571	DLT: Weakness, Fatigue... Dose limiting toxicities: Weakness (grade 3, 33.3%) Fatigue (grade 3, 33.3%) Sources: https://pubmed.ncbi.nlm.nih.gov/27663390 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: https://pubmed.ncbi.nlm.nih.gov/16902153	unhealthy, ADULT n = 6 Health Status: unhealthy Condition: hematologic cancer Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/16902153	DLT: Fatigue, Muscular weakness... Dose limiting toxicities: Fatigue (grade 3, 16.7%) Muscular weakness (grade 3, 16.7%) Sources: https://pubmed.ncbi.nlm.nih.gov/16902153
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: https://pubmed.ncbi.nlm.nih.gov/27663390 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: https://pubmed.ncbi.nlm.nih.gov/27663390 Page: p.571	DLT: Blood phosphorus abnormal... Dose limiting toxicities: Blood phosphorus abnormal (grade 3, 16.7%) Sources: https://pubmed.ncbi.nlm.nih.gov/27663390 Page: p.571

AEs

AE	Significance	Dose	Population
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: https://pubmed.ncbi.nlm.nih.gov/16902153	unhealthy, ADULT n = 3 Health Status: unhealthy Condition: hematologic cancer Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/16902153
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: https://pubmed.ncbi.nlm.nih.gov/16902153	unhealthy, ADULT n = 3 Health Status: unhealthy Condition: hematologic cancer Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/16902153
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: https://pubmed.ncbi.nlm.nih.gov/27663390 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: https://pubmed.ncbi.nlm.nih.gov/27663390 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: https://pubmed.ncbi.nlm.nih.gov/27663390 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: https://pubmed.ncbi.nlm.nih.gov/27663390 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: https://pubmed.ncbi.nlm.nih.gov/16902153	unhealthy, ADULT n = 6 Health Status: unhealthy Condition: hematologic cancer Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/16902153
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: https://pubmed.ncbi.nlm.nih.gov/16902153	unhealthy, ADULT n = 6 Health Status: unhealthy Condition: hematologic cancer Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/16902153
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: https://pubmed.ncbi.nlm.nih.gov/27663390 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: https://pubmed.ncbi.nlm.nih.gov/27663390 Page: p.571

Sourcing

Vendor/Aggregator	ID	URL
001 Chemical	DY106920	https://www.001chemical.com/chem/search?q=DY106920
1PlusChem LLC	1P0078KQ	https://www.1pchem.com/search?query=1P0078KQ
A2B Chem	AD36906	http://a2bchem.com/prod/AD36906
AOBIOUS INC	AOB5045	http://aobious.com/aobious/search?search_query=AOB5045
ApexBio Technology	B1526	https://www.apexbt.com/catalogsearch/result/?q=B1526
ApexBio Technology	B7853	https://www.apexbt.com/catalogsearch/result/?q=B7853
AstaTech	41110	http://astatechinc.com/CPSResult.php?CRNO=41110
Axon MedChem	1415	https://www.axonmedchem.com/product/1415
BLD Pharm	BD152374	http://www.bldpharm.com/search/Search.html?keyword=BD152374
BOC Sciences	387867-13-2	http://www.bocsci.com/description.asp?cas=387867-13-2
Capot Chemical	25875	https://www.capotchem.com/search.do?q=25875
Cayman Chemical	12098	http://www.caymanchem.com/app/template/Product.vm/catalog/12098
Chem Scene	CS-0098521	http://www.chemscene.com/goproductList/searchProductList?productObj=CS-0098521
Chem Scene	CS-0128	http://www.chemscene.com/goproductList/searchProductList?productObj=CS-0128
ChemShuttle	109823	https://www.chemshuttle.com/catalogsearch/result/?q=109823
Excenen	EX-A1637	http://www.excenen.com/searchresultlist.php?id=EX-A1637
Exclusive Chemistry	2262	http://www.exchemistry.com/chem-catalog/product-2262.html
Hairui	HR135978	http://www.hairuichem.com/en/product/search.do?q=HR135978
KeyOrganics	ES-0051	http://www.keyorganicsinc.com/bionet/catalogsearch/result?q=ES-0051
Lab Seeker	SC-23292	http://www.labseeker.com/search.php?keywords=SC-23292&category=0
LabSeeker	SC-23292	http://www.labseeker.com/search.php?keywords=SC-23292&category=0
Matrix Scientific	132329	http://www.matrixscientific.com/132329.html
MedChem Express	HY-10202	https://www.medchemexpress.com/search.html?q=HY-10202A&ft=&fa=&fp=
MedChem Express	HY-10202A	https://www.medchemexpress.com/search.html?q=HY-10202A&ft=&fa=&fp=
MolPort	MolPort-006-170-097	https://www.molport.com/shop/molecule-link/MolPort-006-170-097
MolPort	MolPort-046-925-804	https://www.molport.com/shop/molecule-link/MolPort-046-925-804
Molcore	MC106920	http://www.molcore.com/CatMC106920.html
Molnova	M14334	https://www.molnova.com/en/serch-list.html?keywords=M14334
MuseChem	I003421	https://www.musechem.com/product/I003421.html
Ryan Scientific	Desalkylterbuthylazine	https://ryansci.com/products?q=Desalkylterbuthylazine&list_q=&search_type=exact
Selleck Chemicals	S1043	http://www.selleckchem.com/search.html?searchDTO.searchParam=S1043
ShangHai Biochempartner	BCP000047	http://www.biochempartner.com/search_BCP000047
ShangHai Biochempartner	BCP01370	http://www.biochempartner.com/search_BCP01370
TargetMol	T1667	https://www.targetmol.com/search?keyword=T1667
Tetrahedron	TS39421	http://www.thsci.com/search.do?q=TS39421
Toronto Research Chemicals	T006550	https://www.trc-canada.com/product-detail/?CatNum=T006550
eMolecules	10713991	https://orderbb.emolecules.com/search/#?query=10713991
eNovation Chemicals	D395232	https://www.enovationchem.com/Products.asp?SEARCHTEXT=D395232&searchbtn.x=0&searchbtn.y=0
mcule	MCULE-2424855079	https://mcule.com/MCULE-2424855079/

PubMed

Title	Date	PubMed
		252160125
Identification of orally active, potent, and selective 4-piperazinylquinazolines as antagonists of the platelet-derived growth factor receptor tyrosine kinase family.	2002 Aug 15	12166950
CT53518, a novel selective FLT3 antagonist for the treatment of acute myelogenous leukemia (AML).	2002 Jun	12124172
Sensitivity of oncogenic KIT mutants to the kinase inhibitors MLN518 and PD180970.	2004 Dec 1	15304388
Effects of MLN518, a dual FLT3 and KIT inhibitor, on normal and malignant hematopoiesis.	2004 Nov 1	15242881
[Possibility of targeting FLT3 kinase for the treatment of leukemia].	2005 Mar	16447713
FLT3 kinase inhibitors in the management of acute myeloid leukemia.	2007 Dec	18282363
Tandutinib, an oral, small-molecule inhibitor of FLT3 for the treatment of AML and other cancer indications.	2008 Jan	18175263
Can FLT3 inhibitors overcome resistance in AML?	2008 Mar	18342808
Gamma-secretase represents a therapeutic target for the treatment of invasive glioma mediated by the p75 neurotrophin receptor.	2008 Nov 25	19067488
Id1 is a common downstream target of oncogenic tyrosine kinases in leukemic cells.	2008 Sep 1	18559972
N-(4-Isopropoxyphen-yl)acetamide.	2009 Apr 10	21583839
The FLT3 inhibitor tandutinib (formerly MLN518) has sequence-independent synergistic effects with cytarabine and daunorubicin.	2009 Aug 15	19625780
Patient-derived acute myeloid leukemia (AML) bone marrow cells display distinct intracellular kinase phosphorylation patterns.	2009 May 15	21188123
AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML).	2009 Oct 1	19654408
Antiangiogenic therapy and mechanisms of tumor resistance in malignant glioma.	2010	20414333
P-glycoprotein and breast cancer resistance protein affect disposition of tandutinib, a tyrosine kinase inhibitor.	2010 Dec	20670210
The lack of target specificity of small molecule anticancer kinase inhibitors is correlated with their ability to damage myocytes in vitro.	2010 Dec 1	20832415
Gateways to clinical trials.	2010 Jan-Feb	20383346
FLT3 inhibitors for the treatment of acute myeloid leukemia.	2010 Jun	20733555
[FLT3 kinase inhibitors for the treatment of acute leukemia].	2010 Jun	20622483

Patents

Sample Use Guides

In Vivo Use Guide

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

In Vitro Use Guide

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 UTC 2023` Edited by `admin` on `Fri Dec 15 16:00:53 UTC 2023`
Record UNII	E1IO3ICJ9A
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

TANDUTINIB

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