SARACATINIB DIFUMARATE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C27H32ClN5O5.2C4H4O4
Molecular Weight	774.171
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	2
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

OC(=O)\C=C\C(O)=O.OC(=O)\C=C\C(O)=O.CN1CCN(CCOC2=CC(OC3CCOCC3)=C4C(NC5=C6OCOC6=CC=C5Cl)=NC=NC4=C2)CC1

InChI

InChIKey=OQXMMAQEMJUIQM-LVEZLNDCSA-N

InChI=1S/C27H32ClN5O5.2C4H4O4/c1-32-6-8-33(9-7-32)10-13-35-19-14-21-24(23(15-19)38-18-4-11-34-12-5-18)27(30-16-29-21)31-25-20(28)2-3-22-26(25)37-17-36-22;2*5-3(6)1-2-4(7)8/h2-3,14-16,18H,4-13,17H2,1H3,(H,29,30,31);2*1-2H,(H,5,6)(H,7,8)/b;2*2-1+

HIDE SMILES / InChI

Description
Sources: http://www.alzforum.org/therapeutics/saracatinib | https://www.ncbi.nlm.nih.gov/pubmed/17064066 | https://www.ncbi.nlm.nih.gov/pubmed/25070546

Saracatinib (AZD0530) is an oral, dual inhibitor of c-Src/Abl kinases initially developed by AstraZeneca for the treatment of cancer. The drug was tested for many neoplasms and reached phase III for ovarian cancer (in combination with paclitaxel), however without demonstrating any significant effect. Sarcatinib is also tested in patients with Alzheimer's Disease (Phase II). Its effect on Alzheimer's Disease patients is explained by inhibition of another kinase, Fyn, which is highly expressed in brain.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Tyrosine-protein kinase SRC 19 Target ID: CHEMBL267 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17064066	Inhibitor 8297	2.7 nM [IC50]
Tyrosine-protein kinase ABL 29 Target ID: CHEMBL1862 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17064066	Inhibitor 8297	30.0 nM [IC50]
Tyrosine-protein kinase FYN 6 Target ID: CHEMBL1841 Sources: http://www.alzforum.org/therapeutics/saracatinib	Inhibitor 8297	8.0 nM [Ki]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Alzheimer’s disease 272 Sources: https://clinicaltrials.gov/ct2/show/NCT02167256	Primary		Phase II 1132	Unknown Approved Use Unknown
Ovarian cancer 157 Sources: https://www.ncbi.nlm.nih.gov/pubmed/25070546	Primary		Phase III 656	Unknown Approved Use Unknown

Doses

Dose	Population	Adverse events
250 mg 1 times / day multiple, oral Highest studied dose Dose: 250 mg, 1 times / day Route: oral Route: multiple Dose: 250 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/20805299 Page: p.4879	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/20805299 Page: p.4879	DLT: Asthenia, Acute renal failure... Dose limiting toxicities: Asthenia (grade 3, 14.3%) Acute renal failure (grade 3, 14.3%) Leukopenia (grade 3, 14.3%) Septic shock (grade 5, 14.3%) Sources: https://pubmed.ncbi.nlm.nih.gov/20805299 Page: p.4879
175 mg 1 times / day multiple, oral MTD Dose: 175 mg, 1 times / day Route: oral Route: multiple Dose: 175 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/20805299 Page: 4879	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/20805299 Page: 4879	Sources: https://pubmed.ncbi.nlm.nih.gov/20805299 Page: 4879
200 mg 1 times / day multiple, oral Studied dose Dose: 200 mg, 1 times / day Route: oral Route: multiple Dose: 200 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/20805299 Page: p.4879	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/20805299 Page: p.4879	DLT: Respiratory failure, Febrile neutropenia... Dose limiting toxicities: Respiratory failure (grade 5, 14.3%) Febrile neutropenia (grade 3, 14.3%) Sources: https://pubmed.ncbi.nlm.nih.gov/20805299 Page: p.4879

AEs

AE	Significance	Dose	Population
Acute renal failure	grade 3, 14.3% DLT	250 mg 1 times / day multiple, oral Highest studied dose Dose: 250 mg, 1 times / day Route: oral Route: multiple Dose: 250 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/20805299 Page: p.4879	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/20805299 Page: p.4879
Asthenia	grade 3, 14.3% DLT	250 mg 1 times / day multiple, oral Highest studied dose Dose: 250 mg, 1 times / day Route: oral Route: multiple Dose: 250 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/20805299 Page: p.4879	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/20805299 Page: p.4879
Leukopenia	grade 3, 14.3% DLT	250 mg 1 times / day multiple, oral Highest studied dose Dose: 250 mg, 1 times / day Route: oral Route: multiple Dose: 250 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/20805299 Page: p.4879	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/20805299 Page: p.4879
Septic shock	grade 5, 14.3% DLT, Disc. AE	250 mg 1 times / day multiple, oral Highest studied dose Dose: 250 mg, 1 times / day Route: oral Route: multiple Dose: 250 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/20805299 Page: p.4879	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/20805299 Page: p.4879
Febrile neutropenia	grade 3, 14.3% DLT	200 mg 1 times / day multiple, oral Studied dose Dose: 200 mg, 1 times / day Route: oral Route: multiple Dose: 200 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/20805299 Page: p.4879	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/20805299 Page: p.4879
Respiratory failure	grade 5, 14.3% DLT, Disc. AE	200 mg 1 times / day multiple, oral Studied dose Dose: 200 mg, 1 times / day Route: oral Route: multiple Dose: 200 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/20805299 Page: p.4879	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/20805299 Page: p.4879

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1587 substrate 1737	substrate 1037	substrate 1217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
OCT1 512 CYP2C8 911 P-gp 1461 MRP1 106 OCT2 647 OCTN1 29 OCT3 150	OCTN2 50 OCT2 355 CYP2A1 2 CYP2A6 543 MATE1 135 CYP2A13 12 CYP2E1 667 OCT3 80 OCT1 327 CYP2B6 664 OCTN1 47 CYP2C19 991 CYP1A2 1054 CYP3A5 395	P-gp 257 ABCG1 2

Drug as perpetrator

Target	Modality	Activity	Metabolite
CYP2C8 965	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/24713129/	likely [IC50 201.8 uM]
MRP1 172	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/22623106/	no
P-gp 1650	inducer 1573 Sources: https://pubmed.ncbi.nlm.nih.gov/22623106/	no
OCTN1 29	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/28455521/	yes [IC50 0.072 uM]
OCT2 648	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/28455521/	yes [IC50 0.9 uM]
CYP3A4 1925	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/24713129/	yes [IC50 46 uM]
OCT3 150	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/28455521/	yes [IC50 50 uM]
OCT1 543	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/28455521/	yes [IC50 57 uM]
CYP3A4 1925	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/27769111/	yes [Inhibition 33 uM]	M1 8
ABCG1 2	inducer 1573 Sources: https://pubmed.ncbi.nlm.nih.gov/31931755/	yes
P-gp 1650	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/22623106/	yes

Drug as victim

Target	Modality	Activity
CYP2A13 12	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/27769111/	likely
CYP2A6 543	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/27769111/	likely
CYP2B6 664	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/27769111/	likely
CYP2C19 991	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/27769111/	likely
CYP2C9 1037	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/27769111/	likely
CYP2E1 667	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/27769111/	likely
MATE1 135	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/28455521/	likely
CYP3A4 1737	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/27769111/	major
CYP1A2 1054	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/27769111/	minor
CYP2A1 2	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/27769111/	minor
CYP2D6 1217	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/27769111/	minor
CYP3A5 395	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/27769111/	unlikely
OCTN2 50	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/28455521/	weak
OCT1 327	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/28455521/	yes
OCT2 355	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/28455521/	yes
OCT3 80	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/28455521/	yes
OCTN1 47	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/28455521/	yes

Sourcing

Vendor/Aggregator	ID	URL
001 Chemical	DY116334	https://www.001chemical.com/chem/search?q=DY116334
1PlusChem LLC	1P003A69	https://www.1pchem.com/search?query=1P003A69
AChemBlock	10283	http://www.achemblock.com/catalogsearch/result/?q=10283
AK Scientific	SYN5342	https://aksci.com/item_detail.php?cat=SYN5342
AK Scientific	X2639	https://aksci.com/item_detail.php?cat=X2639
AK Scientific	Y1467	https://aksci.com/item_detail.php?cat=Y1467
ApexBio Technology	A2133	https://www.apexbt.com/catalogsearch/result/?q=A2133
AstaTech	41081	http://astatechinc.com/CPSResult.php?CRNO=41081
Axon MedChem	1456	https://www.axonmedchem.com/product/1456
BLD Pharm	BD157890	http://www.bldpharm.com/search/Search.html?keyword=BD157890
BOC Sciences	379231-04-6	http://www.bocsci.com/description.asp?cas=379231-04-6
BOC Sciences	893428-72-3	http://www.bocsci.com/description.asp?cas=893428-72-3
BioSynth	Q-201699	https://www.biosynth.com/en/products/life-science/other-biochemicals/products/Q-201699
Capot Chemical	25886	https://www.capotchem.com/search.do?q=25886
Cayman Chemical	11497	http://www.caymanchem.com/app/template/Product.vm/catalog/11497
Chem Scene	CS-0101	http://www.chemscene.com/goproductList/searchProductList?productObj=CS-0101
ChemShuttle	104920	https://www.chemshuttle.com/catalogsearch/result/?q=104920
Combi-Blocks	QJ-1835	http://www.combi-blocks.com/cgi-bin/find.cgi?QJ-1835
Excenen	EX-A1576	http://www.excenen.com/searchresultlist.php?id=EX-A1576
KeyOrganics	AS-16692	http://www.keyorganicsinc.com/bionet/catalogsearch/result?q=AS-16692
Lab Seeker	SC-22885	http://www.labseeker.com/search.php?keywords=SC-22885&category=0
LabSeeker	SC-22885	http://www.labseeker.com/search.php?keywords=SC-22885&category=0
Matrix Scientific	145261	http://www.matrixscientific.com/145261.html
MedChem Express	HY-10234	https://www.medchemexpress.com/search.html?q=HY-10234&ft=&fa=&fp=
MolPort	MolPort-008-155-961	https://www.molport.com/shop/molecule-link/MolPort-008-155-961
MolPort	MolPort-035-706-616	https://www.molport.com/shop/molecule-link/MolPort-035-706-616
Molcore	MC116334	http://www.molcore.com/CatMC116334.html
Molnova	M14308	https://www.molnova.com/en/serch-list.html?keywords=M14308
MuseChem	I003391	https://www.musechem.com/product/I003391.html
Selleck Chemicals	S1006	http://www.selleckchem.com/search.html?searchDTO.searchParam=S1006
ShangHai Biochempartner	BCP000078	http://www.biochempartner.com/search_BCP000078
ShangHai Biochempartner	BCP01733	http://www.biochempartner.com/search_BCP01733
TargetMol	T6078	https://www.targetmol.com/search?keyword=T6078
Tetrahedron	TS73118	http://www.thsci.com/search.do?q=TS73118
Toronto Research Chemicals	B288463	https://www.trc-canada.com/product-detail/?CatNum=B288463
Toronto Research Chemicals	S139350	https://www.trc-canada.com/product-detail/?CatNum=S139350
eMolecules	31593305	https://orderbb.emolecules.com/search/#?query=31593305
eMolecules	36367092	https://orderbb.emolecules.com/search/#?query=36367092
eMolecules	44848336	https://orderbb.emolecules.com/search/#?query=44848336
eNovation Chemicals	D372500	https://www.enovationchem.com/Products.asp?SEARCHTEXT=D372500&searchbtn.x=0&searchbtn.y=0
mcule	MCULE-4219101590	https://mcule.com/MCULE-4219101590/

PubMed

Title	Date	PubMed
Research provides new hope for tamoxifen-resistant breast cancer patients.	2008 Mar	19072510
Improved response by co-targeting EGFR/EGFRvIII and Src family kinases in human cancer cells.	2009 Feb	19235590
Src as a therapeutic target in men with prostate cancer and bone metastases.	2009 Feb	19154462
A novel Src kinase inhibitor reduces tumour formation in a skin carcinogenesis model.	2009 Feb	19060248
The effect of the dual Src/Abl kinase inhibitor AZD0530 on Philadelphia positive leukaemia cell lines.	2009 Feb 13	19216789
Aberrant activation of androgen receptor in a new neuropeptide-autocrine model of androgen-insensitive prostate cancer.	2009 Jan 1	19117998
Inhibition of Src with AZD0530 reveals the Src-Focal Adhesion kinase complex as a novel therapeutic target in papillary and anaplastic thyroid cancer.	2009 Jun	19293266
Quantification of focal adhesion kinase activation loop phosphorylation as a biomarker of Src activity.	2009 Mar	19098120
Novel dual Src/Abl inhibitors for hematologic and solid malignancies.	2010 Aug	20557276
Effects of the Src kinase inhibitor saracatinib (AZD0530) on bone turnover in healthy men: a randomized, double-blind, placebo-controlled, multiple-ascending-dose phase I trial.	2010 Mar	19775203
Impact of the Src inhibitor saracatinib on the metastatic phenotype of a fibrosarcoma (KHT) tumor model.	2010 Nov	21115886
[SRC kinases in tumor therapy].	2010 Oct	20981590

Patents

Sample Use Guides

In Vivo Use Guide

Alzheimer's Disease: patients receive 100-125 mg daily. Ovarian cancer: patients receive 175 mg once daily in combination with paclitaxel (80 mg/m2 weekly for 6 weeks followed by a 2 week break (1 cycle), for 4 cycles initially (32 weeks)).

Route of Administration: Oral

In Vitro Use Guide

Ovarian cancer cell lines (OVCA420, TOV112D, DOV13, A2780, EFO27, SKOV3, PEO1, OV167, Hey, OVCAR8, MCAS, ES2, OVCAR5) were exposed to increasing concentrations of saracatinib (ranging from 0–10 uM).

Name

Type

Language

SARACATINIB DIFUMARATE

Official Name

English

4-QUINAZOLINAMINE, N-(5-CHLORO-1,3-BENZODIOXOL-4-YL)-7-(2-(4-METHYL-1-PIPERAZINYL)ETHOXY)-5-((TETRAHYDRO-2H-PYRAN-4-YL)OXY)-, (2E)-2-BUTENEDIOATE (1:2)

Common Name

English

N-(5-CHLORO-1,3-BENZODIOXOL-4-YL)-7-(2-(4-METHYLPIPERAZIN-1-YL)ETHOXY)-5-(TETRAHYDRO-2H-PYRAN-4-YLOXY)QUINAZOLIN-4-AMINE DI((2E)-BUT-2-ENEDIOATE)

Common Name

English

SARACATINIB FUMARATE

Common Name

English

SARACATINIB FUMARATE [JAN]

Common Name

English

AZD0530 DIFUMARATE

Code

English

Saracatinib difumarate [WHO-DD]

Common Name

English

SARACATINIB DIFUMARATE [USAN]

Common Name

English

AZD-0530 DIFUMARATE

Code

English

Classification Tree Code System Code

NCI_THESAURUS

C129825