TOZASERTIB

Details

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

SHOW SMILES / InChI

Structure Search

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	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/19684075
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

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Serine/threonine-protein kinase Aurora-B 28 Target ID: CHEMBL2185 Sources: https://www.ncbi.nlm.nih.gov/pubmed/14981513 \| https://www.ncbi.nlm.nih.gov/pubmed/17850214	Inhibitor 8297	0.04 µM [IC50]
Serine/threonine-protein kinase Aurora-C 10 Target ID: CHEMBL3935 Sources: https://www.ncbi.nlm.nih.gov/pubmed/14981513 \| https://www.ncbi.nlm.nih.gov/pubmed/17850214	Inhibitor 8297	0.07 µM [IC50]
Tyrosine-protein kinase SRC 19 Target ID: CHEMBL3655 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17850214	Inhibitor 8297	0.34 µM [IC50]
Serine/threonine-protein kinase Aurora-A 37 Target ID: CHEMBL4722 Sources: https://www.ncbi.nlm.nih.gov/pubmed/14981513 \| https://www.ncbi.nlm.nih.gov/pubmed/16451062	Inhibitor 8297	0.6 nM [Ki]
Tyrosine-protein kinase receptor FLT3 43 Target ID: CHEMBL1974 Sources: https://www.ncbi.nlm.nih.gov/pubmed/16451062	Inhibitor 8297	30.0 nM [Ki]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Non-small cell lung cancer 206 Sources: https://clinicaltrials.gov/ct2/show/NCT00290550	Primary		Phase II 1132	Unknown Approved Use Unknown
Leukemia 87 Sources: https://clinicaltrials.gov/ct2/show/NCT00405054	Primary		Phase II 1132	Unknown Approved Use Unknown

C_max

Value	Dose	Analyte	Population
7.635 μM EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20386909	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20386909	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20386909	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20386909	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20386909	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20386909	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

Value	Dose	Analyte	Population
167.4 μM × h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20386909	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20386909	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20386909	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20386909	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20386909	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20386909	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

T_1/2

Value	Dose	Analyte	Population
6.6 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20386909	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20386909	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20386909	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20386909	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20386909	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 EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20386909	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

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737	substrate 1037	substrate 1217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
	CYP2E1 667 CYP2C8 693 CYP3A5 395 P-gp 1537 CYP1A2 1054 BCRP 561 CYP2A6 543 CYP2B6 664 FMO3 67 CYP2C19 991

Drug as victim

Target	Modality	Activity
CYP2D6 1217	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/17537870/	minor
CYP1A2 1054	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/17537870/	no
CYP2A6 543	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/17537870/	no
CYP2B6 664	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/17537870/	no
CYP2C19 991	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/17537870/	no
CYP2C9 1037	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/17537870/	no
CYP2E1 667	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/17537870/	no
CYP3A5 395	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/17537870/	no
BCRP 561	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/26415506/	yes
CYP2C8 693	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/17537870/	yes
CYP3A4 1737	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/17537870/	yes
FMO3 67	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/17537870/	yes
P-gp 1537	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/26415506/	yes

Sourcing

Vendor/Aggregator	ID	URL
1PlusChem LLC	1P0037KK	https://www.1pchem.com/search?query=1P0037KK
A2B Chem	AB48980	http://a2bchem.com/prod/AB48980
AChemBlock	M15323	http://www.achemblock.com/catalogsearch/result/?q=M15323
AK Scientific	W9901	https://aksci.com/item_detail.php?cat=W9901
AOBIOUS INC	AOB87770	http://aobious.com/aobious/search?search_query=AOB87770
Ambeed	A153482	http://www.ambeed.com/search/Search.html?keyword=A153482
ApexBio Technology	A4111	https://www.apexbt.com/catalogsearch/result/?q=A4111
AstaTech	41089	http://astatechinc.com/CPSResult.php?CRNO=41089
Axon MedChem	1540	https://www.axonmedchem.com/product/1540
BLD Pharm	BD161453	http://www.bldpharm.com/search/Search.html?keyword=BD161453
BOC Sciences	639089-54-6	http://www.bocsci.com/description.asp?cas=639089-54-6
Capot Chemical	22451	https://www.capotchem.com/search.do?q=22451
Cayman Chemical	13600	http://www.caymanchem.com/app/template/Product.vm/catalog/13600
Chem Scene	CS-0007	http://www.chemscene.com/goproductList/searchProductList?productObj=CS-0007
Enamine	EN300-396166	https://www.enaminestore.com/catalog/EN300-396166
Excenen	EX-A2179	http://www.excenen.com/searchresultlist.php?id=EX-A2179
Exclusive Chemistry	2365	http://www.exchemistry.com/chem-catalog/product-2365.html
KeyOrganics	AS-18632	http://www.keyorganicsinc.com/bionet/catalogsearch/result?q=AS-18632
MedChem Express	HY-10161	https://www.medchemexpress.com/search.html?q=HY-10161&ft=&fa=&fp=
MolPort	MolPort-009-199-504	https://www.molport.com/shop/molecule-link/MolPort-009-199-504
MolPort	MolPort-016-631-877	https://www.molport.com/shop/molecule-link/MolPort-016-631-877
Molnova	M15426	https://www.molnova.com/en/serch-list.html?keywords=M15426
MuseChem	I004416	https://www.musechem.com/product/I004416.html
PI Chemicals	PI-42616	http://www.pipharm.com/catalog_products/PI-42616.html
Selleck Chemicals	S1048	http://www.selleckchem.com/search.html?searchDTO.searchParam=S1048
ShangHai Biochempartner	BCP000153	http://www.biochempartner.com/search_BCP000153
ShangHai Biochempartner	BCP01859	http://www.biochempartner.com/search_BCP01859
Tetrahedron	TS32736	http://www.thsci.com/search.do?q=TS32736
Toronto Research Chemicals	T700000	https://www.trc-canada.com/product-detail/?CatNum=T700000
eMolecules	31507548	https://orderbb.emolecules.com/search/#?query=31507548
eMolecules	36370217	https://orderbb.emolecules.com/search/#?query=36370217
eNovation Chemicals	D518798	https://www.enovationchem.com/Products.asp?SEARCHTEXT=D518798&searchbtn.x=0&searchbtn.y=0
mcule	MCULE-3820870579	https://mcule.com/MCULE-3820870579/

PubMed

Title	Date	PubMed
		252160235
VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo.	2004 Mar	14981513
Hepatic metabolism of MK-0457, a potent aurora kinase inhibitor: interspecies comparison and role of human cytochrome P450 and flavin-containing monooxygenase.	2007 Sep	17537870
Inhibitors of ABL and the ABL-T315I mutation.	2008	18673174
Cotreatment with vorinostat enhances activity of MK-0457 (VX-680) against acute and chronic myelogenous leukemia cells.	2008 Oct 1	18829489
Targeting aurora kinase with MK-0457 inhibits ovarian cancer growth.	2008 Sep 1	18765535
Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry.	2010 Nov 24	21095574
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	21417343
Comprehensive analysis of kinase inhibitor selectivity.	2011 Oct 30	22037378
Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity.	2011 Oct 30	22037377
A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery.	2013 Apr 15	23398362

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 `Sat Dec 16 17:31:45 UTC 2023` Edited by `admin` on `Sat Dec 16 17:31:45 UTC 2023`
Record UNII	234335M86K
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

TOZASERTIB

Official Name

English

VX-680

Code

English

tozasertib [INN]

Common Name

English

TOZASERTIB [USAN]

Common Name

English

Tozasertib [WHO-DD]

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