EPRENETAPOPT

Details

Stereochemistry	RACEMIC
Molecular Formula	C10H17NO3
Molecular Weight	199.2469
Optical Activity	( + / - )
Defined Stereocenters	0 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

COCC1(CO)N2CCC(CC2)C1=O

InChI

InChIKey=BGBNULCRKBVAKL-UHFFFAOYSA-N

InChI=1S/C10H17NO3/c1-14-7-10(6-12)9(13)8-2-4-11(10)5-3-8/h8,12H,2-7H2,1H3

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/26870698 | https://www.ncbi.nlm.nih.gov/pubmed/15735745 | https://www.ncbi.nlm.nih.gov/pubmed/19411067 | https://www.ncbi.nlm.nih.gov/pubmed/24157875 | https://www.ncbi.nlm.nih.gov/pubmed/20818419 | https://www.aprea.com/pipeline/apr-246/

APR-246 is a methylated form of PRIMA-1, 2-hydroxymethyl-2-methoxymethyl-aza-bicyclo[2.2.2]octan-3-one (PRIMA-1MET). APR-246, is a prodrug that is converted to the Michael acceptor methylene quinuclidinone (MQ) that binds covalently to cysteines in p53, leading to refolding and restoration of wild type p53 function. MQ also targets the cellular redox balance by inhibiting thioredoxin reductase (TrxR1) and depleting glutathione. APR-246 can rescue mutant forms of the p53 family members p63 and p73 that share high sequence homology with p53. APR-246 has demonstrated compelling pre-clinical antitumor activity in a wide variety of solid and hematological (blood) tumors, including ovarian cancer, small cell lung cancer, esophageal cancer and acute myeloid leukemia (AML), among others. Furthermore, strong synergy has been seen with both traditional anticancer agents, such as chemotherapy, as well as newer mechanism-based anticancer drugs. A Phase I clinical study has been completed, demonstrating a favorable safety profile and both biological and clinical responses in hematological tumors with mutations in the p53 gene. A Phase Ib clinical study in combination with full dose chemotherapy (carboplatin and pegylated liposomal doxorubicin) has also been completed, demonstrating a favorable safety profile in patients with high-grade serous ovarian cancer (HGSOC). APR-246 is currently in a Phase II clinical trial in patients with HGSOC, and additional Phase Ib clinical studies of APR-246 in other cancer indications are planned.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
apoptotic process 48 Target ID: GO:0006915 Sources: https://www.ncbi.nlm.nih.gov/pubmed/15735745 \| https://www.ncbi.nlm.nih.gov/pubmed/18663359 \| https://www.ncbi.nlm.nih.gov/pubmed/19946333	Activator 1430
Cellular tumor antigen p53 20 Target ID: CHEMBL4164 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19411067 \| https://www.ncbi.nlm.nih.gov/pubmed/26870698	Activator 1430
Thioredoxin reductase 1, cytoplasmic 3 Target ID: CHEMBL6035 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24157875 \| https://www.ncbi.nlm.nih.gov/pubmed/26870698	Inhibitor 8297
Tumor protein 63 1 Target ID: Q9H3D4\|\|\|Q6VFJ1\|\|\|Q9H3D2\|\|\|Q9UBV9 Gene ID: 8626.0 Gene Symbol: TP63 Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/20818419	Activator 1430
Tumor protein p73 1 Target ID: O15350\|\|\|Q5TBV6 Gene ID: 7161.0 Gene Symbol: TP73 Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/20818419	Activator 1430

Conditions

Condition	Modality	Highest Phase	Product
Ovarian cancer 157 Sources: https://adisinsight.springer.com/drugs/800030245	Primary	Phase II 1132	Unknown Approved Use Unknown
Oesophageal cancer 1 Sources: https://adisinsight.springer.com/drugs/800030245	Primary	Phase II 1132	Unknown Approved Use Unknown
Myeloid neoplasms 1 Sources: https://adisinsight.springer.com/drugs/800030245	Primary	Phase II 1132	Unknown Approved Use Unknown

C_max

Value	Dose	Analyte	Population
57.1 mg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22965953	60 mg/kg single, intravenous dose: 60 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:	APR-246 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
55.4 mg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22965953	60 mg/kg 1 times / day multiple, intravenous dose: 60 mg/kg route of administration: Intravenous experiment type: MULTIPLE co-administered:	APR-246 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
82.6 mg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22965953	90 mg/kg single, intravenous dose: 90 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:	APR-246 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Analyte	Population
347 mg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22965953	60 mg/kg single, intravenous dose: 60 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:	APR-246 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
356 mg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22965953	60 mg/kg 1 times / day multiple, intravenous dose: 60 mg/kg route of administration: Intravenous experiment type: MULTIPLE co-administered:	APR-246 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
584 mg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22965953	90 mg/kg single, intravenous dose: 90 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:	APR-246 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

T_1/2

Value	Dose	Analyte	Population
3.56 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22965953	60 mg/kg single, intravenous dose: 60 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:	APR-246 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
3.71 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22965953	60 mg/kg 1 times / day multiple, intravenous dose: 60 mg/kg route of administration: Intravenous experiment type: MULTIPLE co-administered:	APR-246 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
4.71 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22965953	90 mg/kg single, intravenous dose: 90 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:	APR-246 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1587	inhibitor 1767	inhibitor 1852

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
	P-gp 1537

Drug as perpetrator

Target	Modality	Activity
CYP3A4 1925	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645841#sid=174007096	inconclusive [IC50 37.9083 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645842#sid=174007096	no
CYP2D6 1891	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645840#sid=174007096	no

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
P-gp 1537	substrate 3367 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1346987#sid=174007096	no

Sourcing

Vendor/Aggregator	ID	URL
001 Chemical	DY455017	https://www.001chemical.com/chem/5291-32-7
AA Blocks	AA0037MI	https://www.aablocks.com/goods/Goods/detail?id=AA0037MI
Aaron Chemicals	AR0038EA	http://www.aaronchem.com/5291-32-7
AbMole Bioscience	M9623	http://www.abmole.com/products/apr-246.html
Allbio Pharm Co., Ltd	AF12813	http://www.allbiopharm.com/product/n/AF12813
Ambeed	A631504	https://www.ambeed.com/products/5291-32-7.html
Angel Pharmatech	AG-12951	http://www.angelpharmatech.com/5291-32-7 .html
ApexBio Technology	A4484	http://www.apexbt.com/prima-1met.html
Aurora Fine Chemicals LLC	A18.034.169	http://online.aurorafinechemicals.com/info?ID=A18.034.169
Aurora Fine Chemicals LLC	K16.647.130	http://online.aurorafinechemicals.com/info?ID=K16.647.130
AvaChem Scientific	6699	https://www.avachem.com/productSearch.asp?6699
BLD Pharm	BD492382	http://www.bldpharm.com/products/5291-32-7.html
BOC Sciences	5291-32-7	https://www.bocsci.com/apr-246-cas-5291-32-7-item-84-272309.html
BioChemPartner	BCP20294	http://www.biochempartner.com/5291-32-7-BCP20294
BioCrick	BCC2414	http://www.biocrick.com/PRIMA-1MET-BCC2414.html
CSNpharm	CSN17044	https://www.csnpharm.com/products/apr-246.html
Chem Scene	CS-7614	http://www.chemscene.com/5291-32-7.html
ChemShuttle	186520	https://www.chemshuttle.com/catalogsearch/result/?q=5291-32-7&cat=
Chemspace	CSSB00009872268	https://chem-space.com/CSSB00009872268
DC Chemicals	DC10070	http://www.dcchemicals.com/product_show-PRIMA_1MET_APR_246_.html
Excenen	EX-A2772	https://www.excenen.com/searchresultlist.php?id=5291-32-7
Lab Network	LN01298292	https://labnetwork.com/frontend-app/p/#!/moleculedetails/LN01298292
MedChem Express	HY-19980	https://www.medchemexpress.com/PRIMA-1Met.html
MolPort	MolPort-023-276-906	https://www.molport.com/shop/molecule-link/MolPort-023-276-906
Molcore	MC455017	https://www.molcore.com/product/5291-32-7
MuseChem	R061578	https://www.musechem.com/product/R061578.html
Selleck Chemicals	S7724	http://www.selleckchem.com/products/apr-246-prima-1met.html
Smolecule	S548225	http://www.smolecule.com/products/s548225
Synblock Inc	SB19737	http://www.synblock.com/product/5291-32-7.html
THE BioTek	bt-287634	https://www.thebiotek.com/product/inhibitors/bt-287634
Tocris	3710	https://www.tocris.com/products/prima-1met_3710
abcr GmbH	AB479716	http://www.abcr.com/shop/en/AB479716
eNovation Chemicals	D573021	https://www.enovationchem.com/ProductDetails.asp?ProductID=D573021
eNovation Chemicals	D663239	https://www.enovationchem.com/ProductDetails.asp?ProductID=D663239

PubMed

Title	Date	PubMed

Patents

Sample Use Guides

In Vivo Use Guide

APR-246 was administered as a 2-hour intravenous infusion once per day for 4 consecutive days in 22 patients with hematologic malignancies and prostate cancer. Acute myeloid leukemia (AML; n = 7) and prostate cancer (n = 7) were the most frequent diagnoses. Starting dose was 2 mg/kg with dose escalations up to 90 mg/kg. Maximum-tolerated dose was defined as 60 mg/kg.

Route of Administration: Intravenous

In Vitro Use Guide

APR-246 (PRIMA-1MET) treatment of epithelial ovarian cancer cell lines resulted in rapid apoptosis at various concentrations (24 h IC50 2.6-20.1 µM).

Name

Type

Language

EPRENETAPOPT

Official Name

English

EPRENETAPOPT [USAN]

Common Name

English

eprenetapopt [INN]

Common Name

English

APR-246

Code

English

3-QUINUCLIDINONE, 2-(HYDROXYMETHYL)-2-(METHOXYMETHYL)-

Systematic Name

English

PRIMA-1MET

Code

English

Eprenetapopt [WHO-DD]

Common Name

English

1-AZABICYCLO(2.2.2)OCTAN-3-ONE, 2-(HYDROXYMETHYL)-2-(METHOXYMETHYL)-

Systematic Name

English

Classification Tree Code System Code

FDA ORPHAN DRUG

797420