TNP-470

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C19H28ClNO6
Molecular Weight	401.882
Optical Activity	UNSPECIFIED
Defined Stereocenters	6 / 6
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

[H][C@@]1([C@H](OC)[C@@H](CC[C@]12CO2)OC(=O)NC(=O)CCl)[C@@]3(C)O[C@@H]3CC=C(C)C

InChI

InChIKey=MSHZHSPISPJWHW-PVDLLORBSA-N

InChI=1S/C19H28ClNO6/c1-11(2)5-6-13-18(3,27-13)16-15(24-4)12(7-8-19(16)10-25-19)26-17(23)21-14(22)9-20/h5,12-13,15-16H,6-10H2,1-4H3,(H,21,22,23)/t12-,13-,15-,16-,18+,19+/m1/s1

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/11060750
Curator's Comment: The description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/23634668 | https://clinicaltrials.gov/ct2/show/NCT00000763 | https://clinicaltrials.gov/ct2/show/NCT00038701 | https://www.ncbi.nlm.nih.gov/pubmed/18587385

TNP-470 (AGM-1470, (3R,4S,5S,6R)-5-methoxy-4- [(2R,3R)-2-methyl-3-(3-methyl-2-butenyl) -oxiranyl]-1-oxaspiro[2,5]oct-6-yl(chloroacetyl) carbamate) is an anti-angiogenic, semisynthetic analogue of fumagillin, a known antibiotic secreted by the fungus Aspergillus fumigatus fresenius, which is under clinical development for the treatment of cancer by Takeda Chemical Industries Ltd. in Japan and TAP Pharmaceuticals, Inc. in the United States. TNP-470 binds to and irreversibly inactivates methionine aminopeptidase-2 (MetAP2), resulting in endothelial cell cycle arrest late in the G1 phase and inhibition of tumor angiogenesis. This agent may also induce the p53 pathway, thereby stimulating the production of cyclin-dependent kinase inhibitor p21 and inhibiting angiogenesis. In early clinical reports, TNP-470 is tolerated up to 177 mg/m(2) with neurotoxic effects (fatigue, vertigo, ataxia, and loss of concentration) being the principal dose-limiting toxicity (DLT). TNP-470 is being evaluated in Phase I-II trials in the US in patients with Kaposi’s sarcoma, cervical cancer, breast cancer, brain cancer, prostate cancer and renal cell carcinoma.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Methionine aminopeptidase 2 4 Target ID: CHEMBL3922 Sources: https://www.ncbi.nlm.nih.gov/pubmed/16970390	Inhibitor 8297		1.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Pancreatic cancer 97 Sources: https://clinicaltrials.gov/ct2/show/NCT00038701	Primary	Phase II 1132	Unknown Approved Use Unknown
Kaposi’s sarcoma 13 Sources: https://clinicaltrials.gov/ct2/show/NCT00000763	Primary	Phase I 428	Unknown Approved Use Unknown
Renal cell carcinoma 31 Sources: https://www.ncbi.nlm.nih.gov/pubmed/11060750	Primary	Phase II 1132	Unknown Approved Use Unknown
Prostate cancer 178 Sources: https://www.ncbi.nlm.nih.gov/pubmed/11060750	Primary	Not Provided 504	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
498 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/10473076	177 mg/m² 1 times / week multiple, intravenous dose: 177 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:		TNP-470 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
490 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/10473076	235 mg/m² 1 times / week multiple, intravenous dose: 235 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:		TNP-470 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
1239 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/10473076	177 mg/m² 1 times / week multiple, intravenous dose: 177 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:		TNP-470 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
1459 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/10473076	235 mg/m² 1 times / week multiple, intravenous dose: 235 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:		TNP-470 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
3 min EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/10473076	177 mg/m² 1 times / week multiple, intravenous dose: 177 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:		TNP-470 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
2 min EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/10473076	235 mg/m² 1 times / week multiple, intravenous dose: 235 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:		TNP-470 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

Doses

Dose	Population	Adverse events
235 mg/m2 1 times / week multiple, intravenous Highest studied dose Dose: 235 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 235 mg/m2, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/10473076 Page: p.1991	unhealthy, ADULT n = 6 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/10473076 Page: p.1991	DLT: ataxia, Cerebellar disorder NOS... Disc. AE: Vertigo, Short-term memory loss... Dose limiting toxicities: ataxia (grade 3, 33.3%) Cerebellar disorder NOS (33.3%) AEs leading to discontinuation/dose reduction: Vertigo (grade 1, 16.7%) Short-term memory loss (grade 1-2, 16.7%) confusion (grade 1-2, 16.7%) Incoordination (grade 1, 16.7%) Sources: https://pubmed.ncbi.nlm.nih.gov/10473076 Page: p.1991
177 mg/m2 1 times / week multiple, intravenous MTD Dose: 177 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 177 mg/m2, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/10473076 Page: p.1991	unhealthy, ADULT n = 12 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 12 Sources: https://pubmed.ncbi.nlm.nih.gov/10473076 Page: p.1991	Sources: https://pubmed.ncbi.nlm.nih.gov/10473076 Page: p.1991

AEs

AE	Significance	Dose	Population
Cerebellar disorder NOS	33.3% DLT, Disc. AE	235 mg/m2 1 times / week multiple, intravenous Highest studied dose Dose: 235 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 235 mg/m2, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/10473076 Page: p.1991	unhealthy, ADULT n = 6 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/10473076 Page: p.1991
Incoordination	grade 1, 16.7% Disc. AE	235 mg/m2 1 times / week multiple, intravenous Highest studied dose Dose: 235 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 235 mg/m2, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/10473076 Page: p.1991	unhealthy, ADULT n = 6 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/10473076 Page: p.1991
Vertigo	grade 1, 16.7% Disc. AE	235 mg/m2 1 times / week multiple, intravenous Highest studied dose Dose: 235 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 235 mg/m2, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/10473076 Page: p.1991	unhealthy, ADULT n = 6 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/10473076 Page: p.1991
Short-term memory loss	grade 1-2, 16.7% Disc. AE	235 mg/m2 1 times / week multiple, intravenous Highest studied dose Dose: 235 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 235 mg/m2, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/10473076 Page: p.1991	unhealthy, ADULT n = 6 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/10473076 Page: p.1991
confusion	grade 1-2, 16.7% Disc. AE	235 mg/m2 1 times / week multiple, intravenous Highest studied dose Dose: 235 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 235 mg/m2, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/10473076 Page: p.1991	unhealthy, ADULT n = 6 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/10473076 Page: p.1991
ataxia	grade 3, 33.3% DLT, Disc. AE	235 mg/m2 1 times / week multiple, intravenous Highest studied dose Dose: 235 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 235 mg/m2, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/10473076 Page: p.1991	unhealthy, ADULT n = 6 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/10473076 Page: p.1991

Sourcing

Vendor/Aggregator	ID	URL
1PlusChem LLC	1P000ZIT	https://www.1pchem.com/search?query=1P000ZIT
AOBIOUS INC	AOB5062	http://aobious.com/aobious/search?search_query=AOB5062
Alfa Chemistry	ACM129298915	http://www.alfa-chemistry.com/search.aspx?q=ACM129298915
BOC Sciences	129298-91-5	http://www.bocsci.com/description.asp?cas=129298-91-5
Cayman Chemical	16449	http://www.caymanchem.com/app/template/Product.vm/catalog/16449
Chem Scene	CS-8106	http://www.chemscene.com/goproductList/searchProductList?productObj=CS-8106
Matrix Scientific	152579	http://www.matrixscientific.com/152579.html
MedChem Express	HY-101932	https://www.medchemexpress.com/search.html?q=HY-101932&ft=&fa=&fp=
MolPort	MolPort-044-561-343	https://www.molport.com/shop/molecule-link/MolPort-044-561-343
Molnova	M11185	https://www.molnova.com/en/serch-list.html?keywords=M11185
MuseChem	I011402	https://www.musechem.com/product/I011402.html
eMolecules	29937026	https://orderbb.emolecules.com/search/#?query=29937026
eMolecules	36500512	https://orderbb.emolecules.com/search/#?query=36500512
eNovation Chemicals	D500347	https://www.enovationchem.com/Products.asp?SEARCHTEXT=D500347&searchbtn.x=0&searchbtn.y=0

PubMed

Title	Date	PubMed
Synthetic analogues of fumagillin that inhibit angiogenesis and suppress tumour growth.	1990 Dec 6	1701033
Effects of albendazole, fumagillin, and TNP-470 on microsporidial replication in vitro.	1997 Jul	9210681
Roxithromycin inhibits constitutive activation of nuclear factor {kappa}B by diminishing oxidative stress in a rat model of hepatocellular carcinoma.	2005 Aug 1	16061884
Fumagillin suppresses HIV-1 infection of macrophages through the inhibition of Vpr activity.	2006 May 15	16631749

Patents

Sample Use Guides

In Vivo Use Guide

60 mg/m(2) infused over 1h three times per week

Route of Administration: Intravenous

In Vitro Use Guide

KB cells were seeded on a 10-cm plastic dish (Falcon,; Becton Dickinson Labware, Lincoln Park, NJ) at 1 x 10^6 cells/well in complete medium. After 24-, 48- and 72 hour-treatments with anti-IL-8 antibody and/or TNP470 (0, 1, 10, 100, 100 ng/ml), KB cell proliferation was determined by cell counting after washing with cold phosphate-buffered saline (PBS), trypsinizing and staining with trypan saline. In the in vitro study, the combination treatment of TNP470 and anti-IL-8 antibody significantly reduced the proliferation of KB cells.

Name

Type

Language

TNP-470

Common Name

English

NSC-642492

Code

English

TNP-470 [MI]

Common Name

English

O-(CHLOROACETYLCARBAMOYL)FUMAGILLOL

Common Name

English

CARBAMIC ACID, N-(2-CHLOROACETYL)-, (3R,4S,5S,6R)-5-METHOXY-4-((2R,3R)-2-METHYL-3-(3-METHYL-2-BUTEN-1-YL)-2-OXIRANYL)-1-OXASPIRO(2.5)OCT-6-YL ESTER

Systematic Name

English

O-CHLOROACETYLCARBAMOYLFUMAGILLOL

Common Name

English

AGM-1470

Code

English

Classification Tree Code System Code

NCI_THESAURUS

C783