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Varlitinib

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Identification

Generic Name
Varlitinib
DrugBank Accession Number
DB05944
Background

Varlitinib is an oral, selective, reversible, small molecule tyrosine kinase inhibitor of both ErbB-2 (Her-2/neu) and EGFR. Over-expression of ErbB-2 and EGFR receptors in tumors is predictive of poor prognosis in cancer patients. Varlitinib has shown significant anti-tumor activity in preclinical models of human breast, lung, and epidermal carcinoma tumors.

Type
Small Molecule
Groups
Investigational
Structure
3D
Similar Structures
Weight
Average: 466.94
Monoisotopic: 466.0978727
Chemical Formula
C22H19ClN6O2S
Synonyms
  • Varlitinib
External IDs
  • AR-00334543
  • AR00334543
  • ARRY-334543
  • ARRY-543
  • ASLAN-001
  • ASLAN001
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Pharmacology

Indication

Investigated for use/treatment in cancer/tumors (unspecified).

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Contraindications & Blackbox Warnings
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Pharmacodynamics

Not Available

Mechanism of action

Varlitinib is an orally active, reversible, enzymatic and cellular inhibitor, with nanomolar potency, of the key growth factor receptor tyrosine kinases ErbB-2 and EGFR. The compound possesses improved physiochemical properties relative to compounds directed at these targets currently in clinical development, and provides superior exposure and equivalent or greater efficacy in animal models of human cancer. Currently, there is no single drug on the market that selectively inhibits both ErbB-2 and EGFR. Varlitinib, which concurrently inhibits the molecular targets of the drugs Herceptin(R) (ErbB-2) and Erbitux(R) (EGFR), may provide enhanced efficacy in the treatment of cancer patients.

TargetActionsOrganism
AEpidermal growth factor receptor
modulator
Humans
AReceptor tyrosine-protein kinase erbB-2
modulator
Humans
Absorption

Not Available

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism
Not Available
Route of elimination

Not Available

Half-life

Not Available

Clearance

Not Available

Adverse Effects
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Toxicity

Not Available

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available
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Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Not Available
Food Interactions
Not Available

Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as quinazolinamines. These are heterocyclic aromatic compounds containing a quianazoline moiety substituted by one or more amine groups.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Diazanaphthalenes
Sub Class
Benzodiazines
Direct Parent
Quinazolinamines
Alternative Parents
Phenoxy compounds / Phenol ethers / Aniline and substituted anilines / Alkyl aryl ethers / Aminopyrimidines and derivatives / Chlorobenzenes / Aryl chlorides / Imidolactams / Heteroaromatic compounds / Thiazoles
show 8 more
Substituents
Alkyl aryl ether / Amine / Aminopyrimidine / Aniline or substituted anilines / Aromatic heteropolycyclic compound / Aryl chloride / Aryl halide / Azacycle / Azole / Benzenoid
show 23 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available
Affected organisms
Not Available

Chemical Identifiers

UNII
846Y8197W1
CAS number
845272-21-1
InChI Key
UWXSAYUXVSFDBQ-CYBMUJFWSA-N
InChI
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
IUPAC Name
N4-{3-chloro-4-[(1,3-thiazol-2-yl)methoxy]phenyl}-N6-[(4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-yl]quinazoline-4,6-diamine
SMILES
C[C@@H]1COC(NC2=CC=C3N=CN=C(NC4=CC=C(OCC5=NC=CS5)C(Cl)=C4)C3=C2)=N1

References

General References
Not Available
PubChem Compound
42642648
PubChem Substance
347827751
ChemSpider
25027380
BindingDB
50205268
ChEMBL
CHEMBL2103842
ZINC
ZINC000013980035

Clinical Trials

Clinical Trials
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PhaseStatusPurposeConditionsCountStart DateWhy Stopped100+ additional columns
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2CompletedBasic ScienceGastric Cancer / Neoplasm of Stomach / Neoplasm, Gastric1somestatusstop reasonjust information to hide
2CompletedTreatmentBile Duct Cancer1somestatusstop reasonjust information to hide
2CompletedTreatmentCholangiocarcinoma1somestatusstop reasonjust information to hide
2CompletedTreatmentMetastatic Breast Cancer1somestatusstop reasonjust information to hide
2WithdrawnTreatmentAdvanced or Metastatic Biliary Tract Cancer (BTC)1somestatusstop reasonjust information to hide

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0047 mg/mLALOGPS
logP4.46ALOGPS
logP4.67Chemaxon
logS-5ALOGPS
pKa (Strongest Acidic)17.09Chemaxon
pKa (Strongest Basic)4.64Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count8Chemaxon
Hydrogen Donor Count2Chemaxon
Polar Surface Area93.55 Å2Chemaxon
Rotatable Bond Count6Chemaxon
Refractivity124.18 m3·mol-1Chemaxon
Polarizability48.53 Å3Chemaxon
Number of Rings5Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-014i-1000900000-8feb0defbd0bbdb0b30f
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-014i-3101900000-9a6057080f5917453e37
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0159-0004900000-d20d3451136922af4d7b
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-014i-3016900000-6bc93235ef4745359fd3
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-00or-4036900000-9edf0b7f84ce200b1576
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-001i-9034200000-ea6a71115d3d26a30699
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-210.06883
predicted
DeepCCS 1.0 (2019)
[M+H]+212.42683
predicted
DeepCCS 1.0 (2019)
[M+Na]+218.51999
predicted
DeepCCS 1.0 (2019)

Targets

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Details1. Epidermal growth factor receptor
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Modulator
General Function
Receptor tyrosine kinase binding ligands of the EGF family and activating several signaling cascades to convert extracellular cues into appropriate cellular responses (PubMed:10805725, PubMed:27153536, PubMed:2790960, PubMed:35538033). Known ligands include EGF, TGFA/TGF-alpha, AREG, epigen/EPGN, BTC/betacellulin, epiregulin/EREG and HBEGF/heparin-binding EGF (PubMed:12297049, PubMed:15611079, PubMed:17909029, PubMed:20837704, PubMed:27153536, PubMed:2790960, PubMed:7679104, PubMed:8144591, PubMed:9419975). Ligand binding triggers receptor homo- and/or heterodimerization and autophosphorylation on key cytoplasmic residues. The phosphorylated receptor recruits adapter proteins like GRB2 which in turn activates complex downstream signaling cascades. Activates at least 4 major downstream signaling cascades including the RAS-RAF-MEK-ERK, PI3 kinase-AKT, PLCgamma-PKC and STATs modules (PubMed:27153536). May also activate the NF-kappa-B signaling cascade (PubMed:11116146). Also directly phosphorylates other proteins like RGS16, activating its GTPase activity and probably coupling the EGF receptor signaling to the G protein-coupled receptor signaling (PubMed:11602604). Also phosphorylates MUC1 and increases its interaction with SRC and CTNNB1/beta-catenin (PubMed:11483589). Positively regulates cell migration via interaction with CCDC88A/GIV which retains EGFR at the cell membrane following ligand stimulation, promoting EGFR signaling which triggers cell migration (PubMed:20462955). Plays a role in enhancing learning and memory performance (By similarity). Plays a role in mammalian pain signaling (long-lasting hypersensitivity) (By similarity)
Specific Function
actin filament binding
Gene Name
EGFR
Uniprot ID
P00533
Uniprot Name
Epidermal growth factor receptor
Molecular Weight
134276.185 Da
References
  1. Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]
Details2. Receptor tyrosine-protein kinase erbB-2
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Modulator
General Function
Protein tyrosine kinase that is part of several cell surface receptor complexes, but that apparently needs a coreceptor for ligand binding. Essential component of a neuregulin-receptor complex, although neuregulins do not interact with it alone. GP30 is a potential ligand for this receptor. Regulates outgrowth and stabilization of peripheral microtubules (MTs). Upon ERBB2 activation, the MEMO1-RHOA-DIAPH1 signaling pathway elicits the phosphorylation and thus the inhibition of GSK3B at cell membrane. This prevents the phosphorylation of APC and CLASP2, allowing its association with the cell membrane. In turn, membrane-bound APC allows the localization of MACF1 to the cell membrane, which is required for microtubule capture and stabilization
Specific Function
ATP binding
Gene Name
ERBB2
Uniprot ID
P04626
Uniprot Name
Receptor tyrosine-protein kinase erbB-2
Molecular Weight
137909.27 Da
References
  1. Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]

Drug created at November 18, 2007 18:28 / Updated at August 26, 2024 19:23