NAV

SNS-314

This drug entry is a stub and has not been fully annotated. It is scheduled to be annotated soon.

Identification

Generic Name
SNS-314
DrugBank Accession Number
DB06134
Background

SNS-314 is a potent and selective inhibitor of Aurora kinases A, B, and C. Proliferating cells treated with SNS-314 bypass the mitotic spindle checkpoint and fail to undergo cytokinesis, leading to multiple rounds of endoreduplication and eventually cell death. SNS-314 inhibits tumor growth in a variety of preclinical models, and it is now being tested in single agent Phase 1 studies in patients with advanced solid tumours.

Type
Small Molecule
Groups
Investigational
Structure
3D
Similar Structures
Weight
Average: 430.934
Monoisotopic: 430.043728219
Chemical Formula
C18H15ClN6OS2
Synonyms
  • 1-(3-chlorophenyl)-3-{5-[2-(thieno[3,2-d]pyrimidin-4-ylamino)ethyl]-1,3-thiazol-2-yl}urea
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Pharmacology

Indication

Investigated for use/treatment in solid tumors.

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Contraindications & Blackbox Warnings
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Pharmacodynamics

SNS-314 inhibits Aurora kinases A, B, and C. Stopping Aurora kinases halts cellular division at the mitotoic phase of the cell cycle and proliferation in tumor cells that overexpress Aurora kinases.

Mechanism of action

The process of cell division, or mitosis, plays a critical role in the uncontrolled proliferation that is a hallmark of cancer. During mitosis, a cell aligns duplicate copies of its DNA along a mitotic spindle and subdivides itself through a process called cytokinesis, creating two identical daughter cells. This process is often poorly regulated in cancer, leading to rapid proliferation and tissue growth. Aurora kinases (A, B, and C) play important, though differentiated, roles in mitosis. Aurora A controls the formation of the spindle assembly, while Aurora B ensures that the DNA is appropriately aligned and that cytokinesis proceeds successfully. Less is known about Aurora C, though it is thought to serve many of the same functions as Aurora B. Elevated expression of Aurora A has been detected in a high percentage of colon, breast, ovarian, gastric, and pancreatic tumors. Aurora B and C are also expressed at high levels in primary tumors.

Given the central roles of all three Aurora kinases in regulating mitosis and the association between their overexpression and tumorigenesis, they are being evaluated as potential targets in cancer therapy. SNS-314 is a potent inhibitor of all 3 Aurora kinases. Cells treated with SNS-314 make additional copies of their DNA, but are unable to create functional spindle assemblies or replicate. As a result, these cells are unable to progress, and ultimately die by a variety of mechanisms. Since most normal cells are not undergoing mitosis in their normal settings, SNS-314 is expected to affect only highly proliferating tissues, particularly tumor tissues. SNS-314 is being tested in a Phase 1 trial in patients with advanced solid tumor malignancies.

TargetActionsOrganism
UAurora kinase ANot AvailableHumans
UAurora kinase CNot AvailableHumans
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 Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
Not Available

Interactions

Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
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

Products

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Product Ingredients
IngredientUNIICASInChI Key
SNS-314 mesylateKGW32FDY3U1146618-41-8FYCODPVDEFFWSR-UHFFFAOYSA-N

Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as n-phenylureas. These are compounds containing a N-phenylurea moiety, which is structurally characterized by a phenyl group linked to one nitrogen atom of a urea group.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
N-phenylureas
Direct Parent
N-phenylureas
Alternative Parents
Thienopyrimidines / 2,5-disubstituted thiazoles / Aminopyrimidines and derivatives / Secondary alkylarylamines / Chlorobenzenes / Aryl chlorides / Imidolactams / Thiophenes / Heteroaromatic compounds / Ureas
show 6 more
Substituents
2,5-disubstituted 1,3-thiazole / Amine / Aminopyrimidine / Aromatic heteropolycyclic compound / Aryl chloride / Aryl halide / Azacycle / Azole / Carbonic acid derivative / Carbonyl group
show 22 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available
Affected organisms
Not Available

Chemical Identifiers

UNII
802IFJ0Z8X
CAS number
1057249-41-8
InChI Key
FAYAUAZLLLJJGH-UHFFFAOYSA-N
InChI
InChI=1S/C18H15ClN6OS2/c19-11-2-1-3-12(8-11)24-17(26)25-18-21-9-13(28-18)4-6-20-16-15-14(5-7-27-15)22-10-23-16/h1-3,5,7-10H,4,6H2,(H,20,22,23)(H2,21,24,25,26)
IUPAC Name
1-(3-chlorophenyl)-3-{5-[2-({thieno[3,2-d]pyrimidin-4-yl}amino)ethyl]-1,3-thiazol-2-yl}urea
SMILES
ClC1=CC=CC(NC(=O)NC2=NC=C(CCNC3=C4SC=CC4=NC=N3)S2)=C1

References

General References
Not Available
ChemSpider
23331599
BindingDB
26326
ChEBI
94720
ChEMBL
CHEMBL482767
ZINC
ZINC000040393428
PDBe Ligand
AK2
PDB Entries
3d15

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
PhaseStatusPurposeConditionsCount
1CompletedTreatmentAdvanced Solid Tumors1

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 Solubility0.00971 mg/mLALOGPS
logP3.75ALOGPS
logP4.62Chemaxon
logS-4.6ALOGPS
pKa (Strongest Acidic)7.38Chemaxon
pKa (Strongest Basic)3.86Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count5Chemaxon
Hydrogen Donor Count3Chemaxon
Polar Surface Area91.83 Å2Chemaxon
Rotatable Bond Count6Chemaxon
Refractivity114.94 m3·mol-1Chemaxon
Polarizability42.37 Å3Chemaxon
Number of Rings4Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9605
Blood Brain Barrier+0.97
Caco-2 permeable-0.6407
P-glycoprotein substrateNon-substrate0.561
P-glycoprotein inhibitor INon-inhibitor0.6294
P-glycoprotein inhibitor IIInhibitor0.6467
Renal organic cation transporterNon-inhibitor0.5491
CYP450 2C9 substrateNon-substrate0.6533
CYP450 2D6 substrateNon-substrate0.7814
CYP450 3A4 substrateNon-substrate0.5468
CYP450 1A2 substrateInhibitor0.9181
CYP450 2C9 inhibitorInhibitor0.8185
CYP450 2D6 inhibitorNon-inhibitor0.6923
CYP450 2C19 inhibitorInhibitor0.8525
CYP450 3A4 inhibitorInhibitor0.7146
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.9599
Ames testNon AMES toxic0.5709
CarcinogenicityNon-carcinogens0.9079
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.5084 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.884
hERG inhibition (predictor II)Non-inhibitor0.621
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-001i-0010900000-f421a59d1688ad8b268d
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-0059-9811700000-2ae93659922267866660
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-004i-0290300000-c638b8e08906bb81d678
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-001i-3792200000-1b7a9b720da6f8d3ec4e
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0udi-1934100000-b9e8e94257eca031252b
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-0f7o-6912000000-c9ddab2ce15a0d247756
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]-192.7411
predicted
DeepCCS 1.0 (2019)
[M+H]+195.0991
predicted
DeepCCS 1.0 (2019)
[M+Na]+201.85313
predicted
DeepCCS 1.0 (2019)

Targets

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Details1. Aurora kinase A
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Protein serine/threonine/tyrosine kinase activity
Specific Function
Mitotic serine/threonine kinases that contributes to the regulation of cell cycle progression. Associates with the centrosome and the spindle microtubules during mitosis and plays a critical role i...
Gene Name
AURKA
Uniprot ID
O14965
Uniprot Name
Aurora kinase A
Molecular Weight
45809.03 Da
Details2. Aurora kinase C
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Protein serine/threonine/tyrosine kinase activity
Specific Function
Serine/threonine-protein kinase component of the chromosomal passenger complex (CPC), a complex that acts as a key regulator of mitosis. The CPC complex has essential functions at the centromere in...
Gene Name
AURKC
Uniprot ID
Q9UQB9
Uniprot Name
Aurora kinase C
Molecular Weight
35590.91 Da
References
  1. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. [Article]

Drug created at November 18, 2007 18:30 / Updated at June 12, 2020 16:52