CHR-79888

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C16H22N2O6
Molecular Weight	338.3557
Optical Activity	UNSPECIFIED
Defined Stereocenters	3 / 3
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CC(C)C[C@H]([C@H](O)C(=O)NO)C(=O)N[C@H](C(O)=O)C1=CC=CC=C1

InChI

InChIKey=FIVIXKOBUJPPEI-AGIUHOORSA-N

InChI=1S/C16H22N2O6/c1-9(2)8-11(13(19)15(21)18-24)14(20)17-12(16(22)23)10-6-4-3-5-7-10/h3-7,9,11-13,19,24H,8H2,1-2H3,(H,17,20)(H,18,21)(H,22,23)/t11-,12+,13+/m1/s1

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/26568032
Curator's Comment: The description was created based on several sources, including https://clinicaltrials.gov/ct2/show/NCT01567059 | https://clinicaltrials.gov/ct2/show/NCT02352831 | https://clinicaltrials.gov/ct2/show/NCT00522938 | https://clinicaltrials.gov/ct2/show/NCT00692354 | https://www.ncbi.nlm.nih.gov/pubmed/18701491

Tosedostat is a proprietary orally bioavailable inhibitor of the M1 family of aminopeptidases with potential antineoplastic activity. Tosedostat is converted intracellularly into a poorly membrane-permeable active metabolite (CHR-79888) which inhibits the M1 family of aminopeptidases, particularly puromycin-sensitive aminopeptidase (PuSA), and leukotriene A4 (LTA4) hydrolase; inhibition of these aminopeptidases in tumor cells may result in amino acid deprivation, inhibition of protein synthesis due to a decrease in the intracellular free amino acid pool, an increase in the level of the proapoptotic protein Noxa, and cell death. There are several ongoing Phase 2 cooperative group-sponsored trials and investigator-sponsored trials evaluating the clinical activity of Tosedostat in combination with standard agents in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Aminopeptidase N 3 Target ID: CHEMBL1907 Sources: https://www.ncbi.nlm.nih.gov/pubmed/18701491	Inhibitor 8297	220.0 nM [IC50]
Puromycin-sensitive aminopeptidase 2 Target ID: CHEMBL2264 Sources: https://www.ncbi.nlm.nih.gov/pubmed/18701491	Inhibitor 8297	150.0 nM [IC50]
Leucine aminopeptidase 2 Target ID: CHEMBL3965 Sources: https://www.ncbi.nlm.nih.gov/pubmed/18701491	Inhibitor 8297	100.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Acute myeloid leukemia 136 Sources: https://clinicaltrials.gov/ct2/show/NCT01567059	Primary	Phase II 1132	Unknown Approved Use Unknown
Pancreatic cancer 97 Sources: https://clinicaltrials.gov/ct2/show/NCT02352831	Primary	Phase II 1132	Unknown Approved Use Unknown
Leukemia 87 Sources: https://clinicaltrials.gov/ct2/show/NCT01636609	Primary	Phase II 1132	Unknown Approved Use Unknown
Non-small cell lung cancer 206 Sources: https://clinicaltrials.gov/ct2/show/NCT00522938	Primary	Phase II 1132	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
1400 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20877350	180 mg 1 times / day multiple, oral dose: 180 mg route of administration: Oral experiment type: MULTIPLE co-administered:		TOSEDOSTAT plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FED

AUC

Value	Dose	Co-administered	Analyte	Population
2520 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20877350	180 mg 1 times / day multiple, oral dose: 180 mg route of administration: Oral experiment type: MULTIPLE co-administered:		TOSEDOSTAT plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FED

T_1/2

Value	Dose	Co-administered	Analyte	Population
1.1 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20877350	180 mg 1 times / day multiple, oral dose: 180 mg route of administration: Oral experiment type: MULTIPLE co-administered:		TOSEDOSTAT plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FED

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1587	inhibitor 1767	inhibitor 1852

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
P-gp 1461

Drug as perpetrator

Target	Modality	Activity
CYP2D6 1891	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645840#sid=137276019	no
P-gp 1650	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1346987#sid=137276019	yes [IC50 20.931 uM]
CYP3A4 1925	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645841#sid=137276019	yes [IC50 3.3786 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645842#sid=137276019	yes [IC50 5.3547 uM]

Sourcing

Vendor/Aggregator	ID	URL
1PlusChem LLC	1P006UQE	https://www.1pchem.com/search?query=1P006UQE
AK Scientific	X7552	https://aksci.com/item_detail.php?cat=X7552
AOBIOUS INC	AOB6880	http://aobious.com/aobious/search?search_query=AOB6880
ApexBio Technology	A4355	https://www.apexbt.com/catalogsearch/result/?q=A4355
BLD Pharm	BD682970	http://www.bldpharm.com/search/Search.html?keyword=BD682970
BOC Sciences	238750-77-1	http://www.bocsci.com/description.asp?cas=238750-77-1
Chem Scene	CS-0003570	http://www.chemscene.com/goproductList/searchProductList?productObj=CS-0003570
ChemShuttle	186385	https://www.chemshuttle.com/catalogsearch/result/?q=186385
KeyOrganics	AS-55983	http://www.keyorganicsinc.com/bionet/catalogsearch/result?q=AS-55983
MedChem Express	HY-14807	https://www.medchemexpress.com/search.html?q=HY-14807&ft=&fa=&fp=
MolPort	MolPort-021-804-945	https://www.molport.com/shop/molecule-link/MolPort-021-804-945
Molnova	M13689	https://www.molnova.com/en/serch-list.html?keywords=M13689
TargetMol	T6301	https://www.targetmol.com/search?keyword=T6301
Tocris	3595	https://www.tocris.com/search.php?Type=QuickSearch&Value=3595
Wonderchem	WD05OMT	http://www.wonder-chem.com/search.html?text=WD05OMT
eMolecules	31206120	https://orderbb.emolecules.com/search/#?query=31206120
eMolecules	45954709	https://orderbb.emolecules.com/search/#?query=45954709
mcule	MCULE-1929326577	https://mcule.com/MCULE-1929326577/
mcule	MCULE-7835149784	https://mcule.com/MCULE-7835149784/

PubMed

Title	Date	PubMed
Phase II study of tosedostat with cytarabine or decitabine in newly diagnosed older patients with acute myeloid leukaemia or high-risk MDS.	2016 Jan	26568032

Patents

Sample Use Guides

In Vivo Use Guide

120 mg QD d 1-21 or 180 mg QD d 1-35.

Route of Administration: Oral

In Vitro Use Guide

Lymphoma (U-937, HuT 78) and leukemia (HL-60, KG-1, MEG-01, HNT-34, AML-193, KU812, MV-4-11) cells were seeded in 96-well BD-Falcon plates (Becton Dickinson) at a density of 1 to 5 x 10^3 cells per well in the appropriate serum-containing culture medium and cultured at 37C in a humidified 5% (v/v) CO2 incubator for 24 h. Compounds were diluted in the relevant culture medium and added to the wells for a further 72 h. During the final 4 h of this incubation, cells were pulsed with 0.4 mkCi/well of [3H]thymidine (specific activity, 5 mCi/mmol; Amersham Biosciences), harvested onto GF/C glass fiber filter mats (Perkin-Elmer) using a Tomtec harvester, and counted on a 1450 MicroBeta scintillation counter (Perkin-Elmer) to determine the amount of [3H]thymidine incorporated into cellular DNA.

Name

Type

Language

CHR-79888

Code

English

CHR79888

Code

English

Benzeneacetic acid, α-[[(2R)-2-[(1S)-1-hydroxy-2-(hydroxyamino)-2-oxoethyl]-4-methyl-1-oxopentyl]amino]-, (αS)-

Systematic Name

English

(αS)-α-[[(2R)-2-[(1S)-1-Hydroxy-2-(hydroxyamino)-2-oxoethyl]-4-methyl-1-oxopentyl]amino]benzeneacetic acid

Systematic Name

English

Code System Code Type Description

FDA UNII

HF6P5EF2F6

Created by admin on Sat Dec 16 19:34:02 GMT 2023 , Edited by admin on Sat Dec 16 19:34:02 GMT 2023

PRIMARY

PUBCHEM

44201352

Created by admin on Sat Dec 16 19:34:02 GMT 2023 , Edited by admin on Sat Dec 16 19:34:02 GMT 2023

PRIMARY

CAS

1069128-53-5

Created by admin on Sat Dec 16 19:34:02 GMT 2023 , Edited by admin on Sat Dec 16 19:34:02 GMT 2023

PRIMARY

ACTIVE MOIETY


					HF6P5EF2F6

CHR-79888

PRODRUG (METABOLITE ACTIVE)


					KZK563J2UW

TOSEDOSTAT

Details

SMILES

InChI

Originator

Approval Year

Targets

Conditions

Approved Use

Approved Use

Approved Use

Approved Use

Cmax

AUC

T1/2

Overview

OverviewOther

Drug as perpetrator​

Sourcing

PubMed

Patents

Sample Use Guides

C_max

T_1/2

Drug as perpetrator