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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 of VARLITINIB

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
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.

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
36.0 nM [IC50]
43.0 nM [IC50]
132.0 nM [IC50]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
Doses

Doses

DosePopulationAdverse events​
600 mg 2 times / day multiple, oral
Highest studied dose
unhealthy, ADULT
n = 4
DLT: Thrombosis, AST increased...
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:
unhealthy, ADULT
n = 6
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 6
Sources:
DLT: Stomatitis...
Dose limiting toxicities:
Stomatitis (grade 3)
Sources:
AEs

AEs

AESignificanceDosePopulation
ALT increased grade 3, 25%
DLT
600 mg 2 times / day multiple, oral
Highest studied dose
unhealthy, ADULT
n = 4
AST increased grade 3, 25%
DLT
600 mg 2 times / day multiple, oral
Highest studied dose
unhealthy, ADULT
n = 4
Anorexia grade 3, 25%
DLT
600 mg 2 times / day multiple, oral
Highest studied dose
unhealthy, ADULT
n = 4
Thrombosis grade 3, 25%
DLT
600 mg 2 times / day multiple, oral
Highest studied dose
unhealthy, ADULT
n = 4
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:
unhealthy, ADULT
n = 6
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 6
Sources:
Sourcing

Sourcing

Vendor/AggregatorIDURL
PubMed

PubMed

TitleDatePubMed
Patents

Sample Use Guides

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
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
  • Download
Name Type Language
VARLITINIB
INN   USAN   WHO-DD  
USAN   INN  
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
Created by admin on Fri Dec 15 16:25:34 GMT 2023 , Edited by admin on Fri Dec 15 16:25:34 GMT 2023
FDA ORPHAN DRUG 524216
Created by admin on Fri Dec 15 16:25:34 GMT 2023 , Edited by admin on Fri Dec 15 16:25:34 GMT 2023
NCI_THESAURUS C2167
Created by admin on Fri Dec 15 16:25:34 GMT 2023 , Edited by admin on Fri Dec 15 16:25:34 GMT 2023
FDA ORPHAN DRUG 485915
Created by admin on Fri Dec 15 16:25:34 GMT 2023 , Edited by admin on Fri Dec 15 16:25:34 GMT 2023
Code System Code Type Description
DRUG BANK
DB05944
Created by admin on Fri Dec 15 16:25:34 GMT 2023 , Edited by admin on Fri Dec 15 16:25:34 GMT 2023
PRIMARY
EPA CompTox
DTXSID501025597
Created by admin on Fri Dec 15 16:25:34 GMT 2023 , Edited by admin on Fri Dec 15 16:25:34 GMT 2023
PRIMARY
USAN
UU-43
Created by admin on Fri Dec 15 16:25:34 GMT 2023 , Edited by admin on Fri Dec 15 16:25:34 GMT 2023
PRIMARY
FDA UNII
846Y8197W1
Created by admin on Fri Dec 15 16:25:34 GMT 2023 , Edited by admin on Fri Dec 15 16:25:34 GMT 2023
PRIMARY
SMS_ID
100000174734
Created by admin on Fri Dec 15 16:25:34 GMT 2023 , Edited by admin on Fri Dec 15 16:25:34 GMT 2023
PRIMARY
INN
9187
Created by admin on Fri Dec 15 16:25:34 GMT 2023 , Edited by admin on Fri Dec 15 16:25:34 GMT 2023
PRIMARY
NCI_THESAURUS
C62530
Created by admin on Fri Dec 15 16:25:34 GMT 2023 , Edited by admin on Fri Dec 15 16:25:34 GMT 2023
PRIMARY
CAS
845272-21-1
Created by admin on Fri Dec 15 16:25:34 GMT 2023 , Edited by admin on Fri Dec 15 16:25:34 GMT 2023
PRIMARY
ChEMBL
CHEMBL2103842
Created by admin on Fri Dec 15 16:25:34 GMT 2023 , Edited by admin on Fri Dec 15 16:25:34 GMT 2023
PRIMARY
PUBCHEM
42642648
Created by admin on Fri Dec 15 16:25:34 GMT 2023 , Edited by admin on Fri Dec 15 16:25:34 GMT 2023
PRIMARY
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