VARLITINIB

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C22H19ClN6O2S
Molecular Weight	466.943
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

C[C@@H]1COC(NC2=CC=C3N=CN=C(NC4=CC(Cl)=C(OCC5=NC=CS5)C=C4)C3=C2)=N1

InChI

InChIKey=UWXSAYUXVSFDBQ-CYBMUJFWSA-N

InChI=1S/C22H19ClN6O2S/c1-13-10-31-22(27-13)29-14-2-4-18-16(8-14)21(26-12-25-18)28-15-3-5-19(17(23)9-15)30-11-20-24-6-7-32-20/h2-9,12-13H,10-11H2,1H3,(H,27,29)(H,25,26,28)/t13-/m1/s1

HIDE SMILES / InChI

Molecular Formula	C22H19ClN6O2S
Molecular Weight	466.943
Charge	0
Count

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

Description
Sources: http://investor.arraybiopharma.com/phoenix.zhtml?c=123810&p=irol-newsArticle&ID=1584707
Curator's Comment: description was created based on several sources, including http://www.aslanpharma.com/drug/aslan001/

Varlitinib (Alternative Names: ARRY-334543; ARRY-543; ASLAN-001; Varlitinib tosylate) is a small molecule based reversible pan-HER inhibitor of EGFR, HER2 and HER4. In response to the binding of various ligands, these kinases undergo heterodimerisation and homodimerization, resulting in activation of numerous growth factor signaling pathways, by inhibiting the activation of the HER receptors via drug, effects such as shrinkage of the tumor and longer survival can be anticipated. In a large variety of cancers, the overexpression and/or constitutive activation of EGFR and HER2 are often observed and frequently correlate with poor clinical prognosis. Licensed from Array BioPharma with global rights for all indications, varlitinib is being developed as first-in-class drug for cholangiocarcinoma, gastric and colorectal cancer, and as best-in-class drug for breast cancer.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Epidermal growth factor receptor erbB1 58 Target ID: CHEMBL203 Sources: http://www.aslanpharma.com/drug/aslan001/	Inhibitor 8297	36.0 nM [IC50]
Receptor protein-tyrosine kinase erbB-2 35 Target ID: CHEMBL1824 Sources: http://www.aslanpharma.com/drug/aslan001/	Inhibitor 8297	43.0 nM [IC50]
Receptor protein-tyrosine kinase erbB-4 12 Target ID: CHEMBL3009 Sources: http://www.aslanpharma.com/drug/aslan001/	Inhibitor 8297	132.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Cholangiocarcinoma 17 Sources: https://clinicaltrials.gov/ct2/show/NCT02609958	Primary	Phase II 1132	Unknown Approved Use Unknown
Gastric cancer 53 Sources: https://clinicaltrials.gov/ct2/show/NCT01614522	Primary	Phase II 1132	Unknown Approved Use Unknown
Breast cancer 434 Sources: https://clinicaltrials.gov/ct2/show/NCT02396108	Primary	Phase II 1132	Unknown Approved Use Unknown

Doses

Dose	Population	Adverse events
600 mg 2 times / day multiple, oral Highest studied dose Dose: 600 mg, 2 times / day Route: oral Route: multiple Dose: 600 mg, 2 times / day Sources: https://www.researchgate.net/publication/274997361_Abstract_B54_A_phase_1_study_to_assess_the_safety_tolerability_and_pharmacokinetics_of_the_ErbB-family_inhibitor_ARRY-334543_in_patients_with_advanced_solid_tumors	unhealthy, ADULT n = 4 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 4 Sources: https://www.researchgate.net/publication/274997361_Abstract_B54_A_phase_1_study_to_assess_the_safety_tolerability_and_pharmacokinetics_of_the_ErbB-family_inhibitor_ARRY-334543_in_patients_with_advanced_solid_tumors	DLT: Thrombosis, AST increased... Dose limiting toxicities: Thrombosis (grade 3, 25%) AST increased (grade 3, 25%) ALT increased (grade 3, 25%) Anorexia (grade 3, 25%) Sources: https://www.researchgate.net/publication/274997361_Abstract_B54_A_phase_1_study_to_assess_the_safety_tolerability_and_pharmacokinetics_of_the_ErbB-family_inhibitor_ARRY-334543_in_patients_with_advanced_solid_tumors
300 mg 2 times / day multiple, oral MTD Dose: 300 mg, 2 times / day Route: oral Route: multiple Dose: 300 mg, 2 times / day Co-administed with:: 5-fluorouracil leucovorin irinotecan Sources: https://www.annalsofoncology.org/article/S0923-7534(19)58694-X/pdf	unhealthy, ADULT n = 6 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: https://www.annalsofoncology.org/article/S0923-7534(19)58694-X/pdf	DLT: Stomatitis... Dose limiting toxicities: Stomatitis (grade 3) Sources: https://www.annalsofoncology.org/article/S0923-7534(19)58694-X/pdf

AEs

AE	Significance	Dose	Population
ALT increased	grade 3, 25% DLT	600 mg 2 times / day multiple, oral Highest studied dose Dose: 600 mg, 2 times / day Route: oral Route: multiple Dose: 600 mg, 2 times / day Sources: https://www.researchgate.net/publication/274997361_Abstract_B54_A_phase_1_study_to_assess_the_safety_tolerability_and_pharmacokinetics_of_the_ErbB-family_inhibitor_ARRY-334543_in_patients_with_advanced_solid_tumors	unhealthy, ADULT n = 4 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 4 Sources: https://www.researchgate.net/publication/274997361_Abstract_B54_A_phase_1_study_to_assess_the_safety_tolerability_and_pharmacokinetics_of_the_ErbB-family_inhibitor_ARRY-334543_in_patients_with_advanced_solid_tumors
AST increased	grade 3, 25% DLT	600 mg 2 times / day multiple, oral Highest studied dose Dose: 600 mg, 2 times / day Route: oral Route: multiple Dose: 600 mg, 2 times / day Sources: https://www.researchgate.net/publication/274997361_Abstract_B54_A_phase_1_study_to_assess_the_safety_tolerability_and_pharmacokinetics_of_the_ErbB-family_inhibitor_ARRY-334543_in_patients_with_advanced_solid_tumors	unhealthy, ADULT n = 4 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 4 Sources: https://www.researchgate.net/publication/274997361_Abstract_B54_A_phase_1_study_to_assess_the_safety_tolerability_and_pharmacokinetics_of_the_ErbB-family_inhibitor_ARRY-334543_in_patients_with_advanced_solid_tumors
Anorexia	grade 3, 25% DLT	600 mg 2 times / day multiple, oral Highest studied dose Dose: 600 mg, 2 times / day Route: oral Route: multiple Dose: 600 mg, 2 times / day Sources: https://www.researchgate.net/publication/274997361_Abstract_B54_A_phase_1_study_to_assess_the_safety_tolerability_and_pharmacokinetics_of_the_ErbB-family_inhibitor_ARRY-334543_in_patients_with_advanced_solid_tumors	unhealthy, ADULT n = 4 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 4 Sources: https://www.researchgate.net/publication/274997361_Abstract_B54_A_phase_1_study_to_assess_the_safety_tolerability_and_pharmacokinetics_of_the_ErbB-family_inhibitor_ARRY-334543_in_patients_with_advanced_solid_tumors
Thrombosis	grade 3, 25% DLT	600 mg 2 times / day multiple, oral Highest studied dose Dose: 600 mg, 2 times / day Route: oral Route: multiple Dose: 600 mg, 2 times / day Sources: https://www.researchgate.net/publication/274997361_Abstract_B54_A_phase_1_study_to_assess_the_safety_tolerability_and_pharmacokinetics_of_the_ErbB-family_inhibitor_ARRY-334543_in_patients_with_advanced_solid_tumors	unhealthy, ADULT n = 4 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 4 Sources: https://www.researchgate.net/publication/274997361_Abstract_B54_A_phase_1_study_to_assess_the_safety_tolerability_and_pharmacokinetics_of_the_ErbB-family_inhibitor_ARRY-334543_in_patients_with_advanced_solid_tumors
Stomatitis	grade 3 DLT	300 mg 2 times / day multiple, oral MTD Dose: 300 mg, 2 times / day Route: oral Route: multiple Dose: 300 mg, 2 times / day Co-administed with:: 5-fluorouracil leucovorin irinotecan Sources: https://www.annalsofoncology.org/article/S0923-7534(19)58694-X/pdf	unhealthy, ADULT n = 6 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: https://www.annalsofoncology.org/article/S0923-7534(19)58694-X/pdf

Sourcing

Vendor/Aggregator	ID	URL
1PlusChem LLC	1P00G471	https://www.1pchem.com/search?query=1P00G471
AChemBlock	A-630	http://www.achemblock.com/catalogsearch/result/?q=A-630
AK Scientific	SYN1192	https://aksci.com/item_detail.php?cat=SYN1192
AK Scientific	Y0288	https://aksci.com/item_detail.php?cat=Y0288
Angene	AGN-PC-0US1MM	http://www.angenechemical.com/productshow/AGN-PC-0US1MM.html
ApexBio Technology	A8365	https://www.apexbt.com/catalogsearch/result/?q=A8365
AstaTech	40943	http://astatechinc.com/CPSResult.php?CRNO=40943
AstaTech	C16455	http://astatechinc.com/CPSResult.php?CRNO=C16455
BLD Pharm	BD305996	http://www.bldpharm.com/search/Search.html?keyword=BD305996
BOC Sciences	845272-21-1	http://www.bocsci.com/description.asp?cas=845272-21-1
Chem Scene	CS-5222	http://www.chemscene.com/goproductList/searchProductList?productObj=CS-5222
ChemShuttle	109725	https://www.chemshuttle.com/catalogsearch/result/?q=109725
Hairui	VAJB015	http://www.hairuichem.com/en/product/search.do?q=VAJB015
Matrix Scientific	146643	http://www.matrixscientific.com/146643.html
MedChem Express	HY-10530	https://www.medchemexpress.com/search.html?q=HY-10530&ft=&fa=&fp=
MolPort	MolPort-028-720-424	https://www.molport.com/shop/molecule-link/MolPort-028-720-424
MuseChem	I005054	https://www.musechem.com/product/I005054.html
Toronto Research Chemicals	V099100	https://www.trc-canada.com/product-detail/?CatNum=V099100
eMolecules	44696716	https://orderbb.emolecules.com/search/#?query=44696716
eMolecules	44833708	https://orderbb.emolecules.com/search/#?query=44833708
eMolecules	95699350	https://orderbb.emolecules.com/search/#?query=95699350
eNovation Chemicals	D480567	https://www.enovationchem.com/Products.asp?SEARCHTEXT=D480567&searchbtn.x=0&searchbtn.y=0
mcule	MCULE-4359905459	https://mcule.com/MCULE-4359905459/
mcule	MCULE-9549822466	https://mcule.com/MCULE-9549822466/

PubMed

Title	Date	PubMed
ARRY-334543 reverses multidrug resistance by antagonizing the activity of ATP-binding cassette subfamily G member 2.	2014 Aug	24939447

Patents

Sample Use Guides

In Vivo Use Guide

starting dose: 300 mg BID (two times a day); target dose: 400 mg BID; dose modification by investigator allowed between 200 mg BID to 500 mg BID

Route of Administration: Oral

In Vitro Use Guide

Lung cancer cell line NCI-H460 and its ABCG2-overexpressing NCI-H460/MX20, as well as the ABCG2-, ABCB1-, and ABCC10-overexpressing transfected cell lines were used for the reversal study. ARRY-334543 (VARLITINIB) (1.0 μM) significantly reversed ABCG2-mediated multidrug resistance (MDR) by directly inhibiting the drug efflux function of ABCG2, resulting in the elevated intracellular accumulation of chemotherapeutic drugs in the ABCG2-overexpressing cell lines. In addition, in isolated membranes, ARRY-334543 stimulated ATPase activity and inhibited photolabeling of ABCG2 with [(125)I]-iodoarylazidoprazosin in a concentration-dependent manner indicating that this drug directly interacts at the drug-binding pocket of this transporter. ARRY-334543 (1.0 μM) only slightly reversed ABCB1- and partially reversed ABCC10-mediated MDR suggesting that it exhibits high affinity toward ABCG2.

Substance Class	Chemical Created by `admin` on `Fri Dec 15 16:25:34 GMT 2023` Edited by `admin` on `Fri Dec 15 16:25:34 GMT 2023`
Record UNII	846Y8197W1
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

VARLITINIB

Official Name

English

VARLITINIB [USAN]

Common Name

English

ARRY-334543

Code

English

ARRY-543

Code

English

4,6-QUINAZOLINEDIAMINE, N(SUP 4)-(3-CHLORO-4-(2-THIAZOLYLMETHOXY)PHENYL)-N(SUP 6)-((4R)-4,5-DIHYDRO-4-METHYL-2-OXAZOLYL)-

Common Name

English

varlitinib [INN]

Common Name

English

N4-(3-CHLORO-4-(1,3-THIAZOL-2-YLMETHOXY)PHENYL)-N6-((4R)-4-METHYL-4,5-DIHYDRO-1,3-OXAZOL-2-YL)QUINAZOLINE-4,6-DIAMINE

Systematic Name

English

AR-00334543

Code

English

ASLAN-001

Code

English

4,6-QUINAZOLINEDIAMINE, N4-(3-CHLORO-4-(2-THIAZOLYLMETHOXY)PHENYL)-N6-((4R)-4,5-DIHYDRO-4-METHYL-2-OXAZOLYL)-

Systematic Name

English

N(SUP 4)-(3-CHLORO-4-(THIAZOL-2-YLMETHOXY)PHENYL)-N(SUP 6)-((4R)-4-METHYL-4,5-DIHYDROOXAZOL-2- YL)QUINAZOLINE-4,6-DIAMINE

Systematic Name

English

AR00334543

Code

English

ASLAN001

Code

English

Varlitinib [WHO-DD]

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C129825