U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

Details

Stereochemistry ABSOLUTE
Molecular Formula C23H28N8OS.C3H6O3
Molecular Weight 554.664
Optical Activity UNSPECIFIED
Defined Stereocenters 1 / 1
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of TOZASERTIB LACTATE

SMILES

C[C@H](O)C(O)=O.CN1CCN(CC1)C2=NC(SC3=CC=C(NC(=O)C4CC4)C=C3)=NC(NC5=NNC(C)=C5)=C2

InChI

InChIKey=MHFUWOIXNMZFIW-WNQIDUERSA-N
InChI=1S/C23H28N8OS.C3H6O3/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;1-2(4)3(5)6/h5-8,13-14,16H,3-4,9-12H2,1-2H3,(H,24,32)(H2,25,26,27,28,29);2,4H,1H3,(H,5,6)/t;2-/m.0/s1

HIDE SMILES / InChI

Molecular Formula C3H6O3
Molecular Weight 90.0779
Charge 0
Count
Stereochemistry ABSOLUTE
Additional Stereochemistry No
Defined Stereocenters 1 / 1
E/Z Centers 0
Optical Activity UNSPECIFIED

Molecular Formula C23H28N8OS
Molecular Weight 464.586
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

Description
Curator's Comment: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/14981513

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

Curator's Comment: Dasatinib crosses the blood-brain barrier

Approval Year

Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
7.635 μM
96 mg/m²/h 1 times / 3 weeks multiple, intravenous
dose: 96 mg/m²/h
route of administration: Intravenous
experiment type: MULTIPLE
co-administered:
TOZASERTIB LACTATE plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
0.911 μM
16 mg/m²/h 1 times / 3 weeks multiple, intravenous
dose: 16 mg/m²/h
route of administration: Intravenous
experiment type: MULTIPLE
co-administered:
TOZASERTIB LACTATE plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: UNKNOWN
food status: UNKNOWN
2.17 μM
32 mg/m²/h 1 times / 3 weeks multiple, intravenous
dose: 32 mg/m²/h
route of administration: Intravenous
experiment type: MULTIPLE
co-administered:
TOZASERTIB LACTATE plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: UNKNOWN
food status: UNKNOWN
0.274 μM
8 mg/m²/h 1 times / 3 weeks multiple, intravenous
dose: 8 mg/m²/h
route of administration: Intravenous
experiment type: MULTIPLE
co-administered:
TOZASERTIB LACTATE plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: UNKNOWN
food status: UNKNOWN
2.666 μM
45 mg/m²/h 1 times / 3 weeks multiple, intravenous
dose: 45 mg/m²/h
route of administration: Intravenous
experiment type: MULTIPLE
co-administered:
TOZASERTIB LACTATE plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
4.015 μM
64 mg/m²/h 1 times / 3 weeks multiple, intravenous
dose: 64 mg/m²/h
route of administration: Intravenous
experiment type: MULTIPLE
co-administered:
TOZASERTIB LACTATE plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
167.4 μM × h
96 mg/m²/h 1 times / 3 weeks multiple, intravenous
dose: 96 mg/m²/h
route of administration: Intravenous
experiment type: MULTIPLE
co-administered:
TOZASERTIB LACTATE plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
18.8 μM × h
16 mg/m²/h 1 times / 3 weeks multiple, intravenous
dose: 16 mg/m²/h
route of administration: Intravenous
experiment type: MULTIPLE
co-administered:
TOZASERTIB LACTATE plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: UNKNOWN
food status: UNKNOWN
47.2 μM × h
32 mg/m²/h 1 times / 3 weeks multiple, intravenous
dose: 32 mg/m²/h
route of administration: Intravenous
experiment type: MULTIPLE
co-administered:
TOZASERTIB LACTATE plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: UNKNOWN
food status: UNKNOWN
6.4 μM × h
8 mg/m²/h 1 times / 3 weeks multiple, intravenous
dose: 8 mg/m²/h
route of administration: Intravenous
experiment type: MULTIPLE
co-administered:
TOZASERTIB LACTATE plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: UNKNOWN
food status: UNKNOWN
62.9 μM × h
45 mg/m²/h 1 times / 3 weeks multiple, intravenous
dose: 45 mg/m²/h
route of administration: Intravenous
experiment type: MULTIPLE
co-administered:
TOZASERTIB LACTATE plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
90.3 μM × h
64 mg/m²/h 1 times / 3 weeks multiple, intravenous
dose: 64 mg/m²/h
route of administration: Intravenous
experiment type: MULTIPLE
co-administered:
TOZASERTIB LACTATE plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
6.6 h
96 mg/m²/h 1 times / 3 weeks multiple, intravenous
dose: 96 mg/m²/h
route of administration: Intravenous
experiment type: MULTIPLE
co-administered:
TOZASERTIB LACTATE plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
8.5 h
16 mg/m²/h 1 times / 3 weeks multiple, intravenous
dose: 16 mg/m²/h
route of administration: Intravenous
experiment type: MULTIPLE
co-administered:
TOZASERTIB LACTATE plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: UNKNOWN
food status: UNKNOWN
10.2 h
32 mg/m²/h 1 times / 3 weeks multiple, intravenous
dose: 32 mg/m²/h
route of administration: Intravenous
experiment type: MULTIPLE
co-administered:
TOZASERTIB LACTATE plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: UNKNOWN
food status: UNKNOWN
9.3 h
8 mg/m²/h 1 times / 3 weeks multiple, intravenous
dose: 8 mg/m²/h
route of administration: Intravenous
experiment type: MULTIPLE
co-administered:
TOZASERTIB LACTATE plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: UNKNOWN
food status: UNKNOWN
10.2 h
45 mg/m²/h 1 times / 3 weeks multiple, intravenous
dose: 45 mg/m²/h
route of administration: Intravenous
experiment type: MULTIPLE
co-administered:
TOZASERTIB LACTATE plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
8 h
64 mg/m²/h 1 times / 3 weeks multiple, intravenous
dose: 64 mg/m²/h
route of administration: Intravenous
experiment type: MULTIPLE
co-administered:
TOZASERTIB LACTATE plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
Sourcing

Sourcing

Vendor/AggregatorIDURL
PubMed

PubMed

TitleDatePubMed
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
Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity.
2011 Oct 30
Patents

Sample Use Guides

IV infusion at 10 mg/m2/hour; 5-day continuous infusion every 21 days
Route of Administration: Intravenous
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 Wed Jul 05 23:55:26 UTC 2023
Edited
by admin
on Wed Jul 05 23:55:26 UTC 2023
Record UNII
CN8EF9N084
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
TOZASERTIB LACTATE
USAN   WHO-DD  
USAN  
Official Name English
N-(4-((4-(4-METHYLPIPERAZIN-1-YL)-6-((5-METHYL-1H-PYRAZOL-3-YL)AMINO)PYRIMIDIN-2- YL)SULFANYL)PHENYL)CYCLOPROPANECARBOXAMIDE (2S)-2-HYDROXYPROPANOATE
Systematic Name English
VX-680 LACTATE
Code English
TOZASERTIB LACTATE [USAN]
Common Name English
PROPANOIC ACID, 2-HYDROXY-, (2S)-, COMPD. WITH N-(4-((4-(4-METHYL-1-PIPERAZINYL)-6-((5- METHYL-1H-PYRAZOL-3-YL)AMINO)-2-PYRIMIDINYL)THIO)PHENYL)CYCLOPROPANECARBOXAMIDE
Common Name English
MK-0457
Code English
MK0457
Code English
Tozasertib lactate [WHO-DD]
Common Name English
Classification Tree Code System Code
NCI_THESAURUS C62556
Created by admin on Wed Jul 05 23:55:26 UTC 2023 , Edited by admin on Wed Jul 05 23:55:26 UTC 2023
NCI_THESAURUS C129825
Created by admin on Wed Jul 05 23:55:26 UTC 2023 , Edited by admin on Wed Jul 05 23:55:26 UTC 2023
Code System Code Type Description
EPA CompTox
DTXSID201009081
Created by admin on Wed Jul 05 23:55:26 UTC 2023 , Edited by admin on Wed Jul 05 23:55:26 UTC 2023
PRIMARY
FDA UNII
CN8EF9N084
Created by admin on Wed Jul 05 23:55:26 UTC 2023 , Edited by admin on Wed Jul 05 23:55:26 UTC 2023
PRIMARY
ChEMBL
CHEMBL572878
Created by admin on Wed Jul 05 23:55:26 UTC 2023 , Edited by admin on Wed Jul 05 23:55:26 UTC 2023
PRIMARY
NCI_THESAURUS
C61319
Created by admin on Wed Jul 05 23:55:26 UTC 2023 , Edited by admin on Wed Jul 05 23:55:26 UTC 2023
PRIMARY
PUBCHEM
44153236
Created by admin on Wed Jul 05 23:55:26 UTC 2023 , Edited by admin on Wed Jul 05 23:55:26 UTC 2023
PRIMARY
USAN
TT-17
Created by admin on Wed Jul 05 23:55:26 UTC 2023 , Edited by admin on Wed Jul 05 23:55:26 UTC 2023
PRIMARY
WIKIPEDIA
VX-680
Created by admin on Wed Jul 05 23:55:26 UTC 2023 , Edited by admin on Wed Jul 05 23:55:26 UTC 2023
PRIMARY
SMS_ID
300000044510
Created by admin on Wed Jul 05 23:55:26 UTC 2023 , Edited by admin on Wed Jul 05 23:55:26 UTC 2023
PRIMARY
CAS
899827-04-4
Created by admin on Wed Jul 05 23:55:26 UTC 2023 , Edited by admin on Wed Jul 05 23:55:26 UTC 2023
NON-SPECIFIC STOICHIOMETRY
Related Record Type Details
PARENT -> SALT/SOLVATE
PARENT -> SALT/SOLVATE
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ACTIVE MOIETY