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Details

Stereochemistry ACHIRAL
Molecular Formula C23H28N8OS
Molecular Weight 464.586
Optical Activity UNSPECIFIED
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of TOZASERTIB

SMILES

CN1CCN(CC1)C2=NC(SC3=CC=C(NC(=O)C4CC4)C=C3)=NC(NC5=NNC(C)=C5)=C2

InChI

InChIKey=GCIKSSRWRFVXBI-UHFFFAOYSA-N
InChI=1S/C23H28N8OS/c1-15-13-20(29-28-15)25-19-14-21(31-11-9-30(2)10-12-31)27-23(26-19)33-18-7-5-17(6-8-18)24-22(32)16-3-4-16/h5-8,13-14,16H,3-4,9-12H2,1-2H3,(H,24,32)(H2,25,26,27,28,29)

HIDE SMILES / InChI

Molecular Formula C23H28N8OS
Molecular Weight 464.586
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

Description

Tozasertib, originally developed as VX-680 by Vertex (Cambridge, MA) and later renamed MK-0457 by Merck (Whitehouse Station, NY), was the first aurora kinase inhibitor to be tested in clinical trials. The drug, a pyrimidine derivative, has affinity for all aurora family members at nanomolar concentrations with inhibitory constant values (Ki(app)) of 0.6, 18, and 4.6 nM for aurora A, aurora B, and aurora C, respectively. Preclinical studies confirmed that tozasertib inhibited both aurora A and aurora B kinase activity, and activity has been reported against prostate, thyroid, ovarian, and oral squamous cancer cell lines. Upon treatment with tozasertib, cells accumulate with a 4N DNA content due to a failure of cytokinesis. This ultimately leads to apoptosis, preferentially in cells with a compromised p53 function. Tozasertib is an anticancer chemotherapeutic pan-aurora kinase (AurK) inhibitor that also inhibits FMS-like tyrosine kinase 3 (FLT3) and Abl. Tozasertib is currently in clinical trials as a potential treatment for acute lymphoblastic leukemia (ALL). In cellular models of cancer, tozasertib activates caspase-3 and PARP and decreases expression of HDAC, increasing apoptosis and inhibiting cell growth. In other cellular models, tozasertib inhibits cell proliferation and metastasis by blocking downstream ERK signaling and downregulating cdc25c and cyclin B. This compound also decreases tumor growth in an in vivo model of prostate cancer.

CNS Activity

Originator

Approval Year

PubMed

PubMed

TitleDatePubMed
VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo.
2004 Mar
Hepatic metabolism of MK-0457, a potent aurora kinase inhibitor: interspecies comparison and role of human cytochrome P450 and flavin-containing monooxygenase.
2007 Sep
Inhibitors of ABL and the ABL-T315I mutation.
2008
Cotreatment with vorinostat enhances activity of MK-0457 (VX-680) against acute and chronic myelogenous leukemia cells.
2008 Oct 1
Targeting aurora kinase with MK-0457 inhibits ovarian cancer growth.
2008 Sep 1
Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry.
2010 Nov 24
Crystal structures of ABL-related gene (ABL2) in complex with imatinib, tozasertib (VX-680), and a type I inhibitor of the triazole carbothioamide class.
2011 Apr 14
Phthalazinone pyrazoles as potent, selective, and orally bioavailable inhibitors of Aurora-A kinase.
2011 Jan 13
Comprehensive analysis of kinase inhibitor selectivity.
2011 Oct 30
Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity.
2011 Oct 30
A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery.
2013 Apr 15
Patents

Sample Use Guides

In Vivo Use Guide
IV infusion at 10 mg/m2/hour; 5-day continuous infusion every 21 days
Route of Administration: Intravenous
In Vitro Use Guide
The treatment of K562, KCL22 and CML CD34⁺ cells with Tozasertib of 20-100 nmol/L for 3 days could obviously inhibit the cell proliferation in a concentration-dependent manner.
Substance Class Chemical
Created
by admin
on Mon Oct 21 23:14:05 UTC 2019
Edited
by admin
on Mon Oct 21 23:14:05 UTC 2019
Record UNII
234335M86K
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
TOZASERTIB
INN   USAN   WHO-DD  
USAN   INN  
Official Name English
VX-680
Code English
TOZASERTIB [WHO-DD]
Common Name English
TOZASERTIB [INN]
Common Name English
TOZASERTIB [USAN]
Common Name English
N-(4-((4-(4-METHYLPIPERAZIN-1-YL)-6-((5-METHYL-1H-PYRAZOL-3-YL)AMINO)PYRIMIDIN-2-YL)SULFANYL)PHENYL)CYCLOPROPANECARBOXAMIDE
Systematic Name English
CYCLOPROPANECARBOXAMIDE, N-(4-((4-(4-METHYL-1-PIPERAZINYL)-6-((5-METHYL-1H-PYRAZOL-3-YL)AMINO)-2-PYRIMIDINYL)THIO)PHENYL)-
Systematic Name English
Classification Tree Code System Code
NCI_THESAURUS C62556
Created by admin on Mon Oct 21 23:14:05 UTC 2019 , Edited by admin on Mon Oct 21 23:14:05 UTC 2019
Code System Code Type Description
EVMPD
SUB130344
Created by admin on Mon Oct 21 23:14:05 UTC 2019 , Edited by admin on Mon Oct 21 23:14:05 UTC 2019
PRIMARY
ChEMBL
CHEMBL572878
Created by admin on Mon Oct 21 23:14:05 UTC 2019 , Edited by admin on Mon Oct 21 23:14:05 UTC 2019
PRIMARY
PUBCHEM
5494449
Created by admin on Mon Oct 21 23:14:05 UTC 2019 , Edited by admin on Mon Oct 21 23:14:05 UTC 2019
PRIMARY
INN
9007
Created by admin on Mon Oct 21 23:14:05 UTC 2019 , Edited by admin on Mon Oct 21 23:14:05 UTC 2019
PRIMARY
EPA CompTox
639089-54-6
Created by admin on Mon Oct 21 23:14:05 UTC 2019 , Edited by admin on Mon Oct 21 23:14:05 UTC 2019
PRIMARY
CAS
639089-54-6
Created by admin on Mon Oct 21 23:14:05 UTC 2019 , Edited by admin on Mon Oct 21 23:14:05 UTC 2019
PRIMARY
NCI_THESAURUS
C98053
Created by admin on Mon Oct 21 23:14:05 UTC 2019 , Edited by admin on Mon Oct 21 23:14:05 UTC 2019
PRIMARY
Related Record Type Details
TARGET->WEAK INHIBITOR
TRANSPORTER -> SUBSTRATE
SALT/SOLVATE -> PARENT
Related Record Type Details
ACTIVE MOIETY