AFURESERTIB HYDROCHLORIDE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C18H17Cl2FN4OS.ClH
Molecular Weight	463.784
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

Cl.CN1N=CC(Cl)=C1C2=C(Cl)SC(=C2)C(=O)N[C@H](CN)CC3=CC=CC(F)=C3

InChI

InChIKey=YFQJOPFTGMHYNV-YDALLXLXSA-N

InChI=1S/C18H17Cl2FN4OS.ClH/c1-25-16(14(19)9-23-25)13-7-15(27-17(13)20)18(26)24-12(8-22)6-10-3-2-4-11(21)5-10;/h2-5,7,9,12H,6,8,22H2,1H3,(H,24,26);1H/t12-;/m0./s1

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/24978597
Curator's Comment: Description was created based on several sources, including http://www.bloodjournal.org/content/118/21/1856 http://adisinsight.springer.com/drugs/800033693

Afuresertib (GSK2110183 ) is an orally bioavailable inhibitor of the serine/threonine protein kinase Akt (protein kinase B) with potential antineoplastic activity. Afuresertib binds to and inhibits the activity of Akt, which may result in inhibition of the PI3K/Akt signaling pathway and tumor cell proliferation and the induction of tumor cell apoptosis. Activation of the PI3K/Akt signaling pathway is frequently associated with tumorigenesis and dysregulated PI3K/Akt signaling may contribute to tumor resistance to a variety of antineoplastic agents. Preclinically, AKT inhibition by afuresertib can reverse platinum resistance in ovarian cancer cell lines isolated from patients with platinum-resistant ovarian cancer. Afuresertib is well tolerated and demonstrates clinical activity as monotherapy in heavily pretreated MM patients. Is in phase II clinical trials for Chronic lymphocytic leukaemia; Haematological malignancies; Histiocytosis.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Serine/threonine-protein kinase AKT 29 Target ID: CHEMBL4282 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24978597	Inhibitor 8297	0.08 nM [Ki]
Serine/threonine-protein kinase AKT2 17 Target ID: CHEMBL2431 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24978597	Inhibitor 8297	2.0 nM [Ki]
Serine/threonine-protein kinase AKT3 17 Target ID: CHEMBL4816 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24978597	Inhibitor 8297	2.6 nM [Ki]

Conditions

Condition	Modality	Highest Phase	Product
Hematologic malignancies 19 Sources: https://clinicaltrials.gov/ct2/show/NCT00881946	Primary	Phase II 1132	Unknown Approved Use Unknown
Langerhans cell histiocytosis 2 Sources: https://clinicaltrials.gov/ct2/show/NCT01395004	Primary	Phase II 1132	Unknown Approved Use Unknown
Recurrent platinum-resistant ovarian cancer 2 Sources: https://clinicaltrials.gov/ct2/show/NCT01653912	Primary	Phase II 1132	Unknown Approved Use Unknown

C_max

Value	Dose	Analyte	Population
949 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25075128/	150 mg 1 times / day multiple, oral dose: 150 mg route of administration: Oral experiment type: MULTIPLE co-administered:	AFURESERTIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
554 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25075128/	100 mg 1 times / day multiple, oral dose: 100 mg route of administration: Oral experiment type: MULTIPLE co-administered:	AFURESERTIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
531 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25075128/	125 mg 1 times / day multiple, oral dose: 125 mg route of administration: Oral experiment type: MULTIPLE co-administered:	AFURESERTIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Analyte	Population
13425 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25075128/	150 mg 1 times / day multiple, oral dose: 150 mg route of administration: Oral experiment type: MULTIPLE co-administered:	AFURESERTIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
6782 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25075128/	100 mg 1 times / day multiple, oral dose: 100 mg route of administration: Oral experiment type: MULTIPLE co-administered:	AFURESERTIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
7405 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25075128/	125 mg 1 times / day multiple, oral dose: 125 mg route of administration: Oral experiment type: MULTIPLE co-administered:	AFURESERTIB 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 1461 BCRP 699

Drug as perpetrator

Target	Modality	Activity
BCRP 773	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/31952518/	no
P-gp 1650	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/31952518/	no
CYP3A4 1925	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645841#sid=363680719	yes [IC50 0.3011 uM]
CYP2D6 1891	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645840#sid=363680719	yes [IC50 2.6837 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645842#sid=363680719	yes [IC50 9.5221 uM]

Sourcing

Vendor/Aggregator	ID	URL
001 Chemical	DY34177	https://www.001chemical.com/chem/search?q=DY34177
1PlusChem LLC	1P008TTY	https://www.1pchem.com/search?query=1P008TTY
1PlusChem LLC	1P008TTZ	https://www.1pchem.com/search?query=1P008TTZ
AChemBlock	L13491	http://www.achemblock.com/catalogsearch/result/?q=L13491
AChemBlock	M15668	http://www.achemblock.com/catalogsearch/result/?q=M15668
Angene	AGN-PC-0WCXBP	http://www.angenechemical.com/productshow/AGN-PC-0WCXBP.html
ApexBio Technology	B4811	https://www.apexbt.com/catalogsearch/result/?q=B4811
AstaTech	P14643	http://astatechinc.com/CPSResult.php?CRNO=P14643
Axon MedChem	2460	https://www.axonmedchem.com/product/2460
BLD Pharm	BD300977	http://www.bldpharm.com/search/Search.html?keyword=BD300977
BLD Pharm	BD629860	http://www.bldpharm.com/search/Search.html?keyword=BD629860
Cayman Chemical	17988	http://www.caymanchem.com/app/template/Product.vm/catalog/17988
Chem Scene	CS-3384	http://www.chemscene.com/goproductList/searchProductList?productObj=CS-3384
Chem Scene	CS-3385	http://www.chemscene.com/goproductList/searchProductList?productObj=CS-3385
ChemShuttle	152015	https://www.chemshuttle.com/catalogsearch/result/?q=152015
Excenen	EX-A1573	http://www.excenen.com/searchresultlist.php?id=EX-A1573
Excenen	EX-A1574	http://www.excenen.com/searchresultlist.php?id=EX-A1574
KeyOrganics	AS-56283	http://www.keyorganicsinc.com/bionet/catalogsearch/result?q=AS-56283
MedChem Express	HY-15727	https://www.medchemexpress.com/search.html?q=HY-15727A&ft=&fa=&fp=
MedChem Express	HY-15727A	https://www.medchemexpress.com/search.html?q=HY-15727A&ft=&fa=&fp=
MolPort	MolPort-039-063-478	https://www.molport.com/shop/molecule-link/MolPort-039-063-478
MolPort	MolPort-039-193-816	https://www.molport.com/shop/molecule-link/MolPort-039-193-816
MolPort	MolPort-042-676-197	https://www.molport.com/shop/molecule-link/MolPort-042-676-197
Molcore	MC34177	http://www.molcore.com/CatMC34177.html
Molnova	M10234	https://www.molnova.com/en/serch-list.html?keywords=M10234
Molnova	M10235	https://www.molnova.com/en/serch-list.html?keywords=M10235
MuseChem	I000266	https://www.musechem.com/product/I000266.html
Ryan Scientific	WH-4-023	https://ryansci.com/products?q=WH-4-023&list_q=&search_type=exact
Selleck Chemicals	S7521	http://www.selleckchem.com/search.html?searchDTO.searchParam=S7521
ShangHai Biochempartner	BCP08435	http://www.biochempartner.com/search_BCP08435
ShangHai Biochempartner	BCP19741	http://www.biochempartner.com/search_BCP19741
TargetMol	T1911	https://www.targetmol.com/search?keyword=T1911
eMolecules	108759016	https://orderbb.emolecules.com/search/#?query=108759016
eMolecules	205748941	https://orderbb.emolecules.com/search/#?query=205748941
eMolecules	301193176	https://orderbb.emolecules.com/search/#?query=301193176
eMolecules	301193432	https://orderbb.emolecules.com/search/#?query=301193432
eMolecules	50282579	https://orderbb.emolecules.com/search/#?query=50282579
eNovation Chemicals	D497621	https://www.enovationchem.com/Products.asp?SEARCHTEXT=D497621&searchbtn.x=0&searchbtn.y=0
eNovation Chemicals	D501891	https://www.enovationchem.com/Products.asp?SEARCHTEXT=D501891&searchbtn.x=0&searchbtn.y=0
mcule	MCULE-4025424570	https://mcule.com/MCULE-4025424570/
mcule	MCULE-4988273902	https://mcule.com/MCULE-4988273902/
mcule	MCULE-5404870108	https://mcule.com/MCULE-5404870108/
mcule	MCULE-8719640373	https://mcule.com/MCULE-8719640373/

PubMed

Title	Date	PubMed
Discovery of novel AKT inhibitors with enhanced anti-tumor effects in combination with the MEK inhibitor.	2014	24978597
A phase IIa study of afuresertib, an oral pan-AKT inhibitor, in patients with Langerhans cell histiocytosis.	2017 May	27804235

Patents

Sample Use Guides

In Vivo Use Guide

Seventy-three patients were treated at doses ranging from 25 to 150 mg per day. The MTD was established at 125 mg per day

Route of Administration: Oral

In Vitro Use Guide

Afuresertib inhibits the kinase activity of the E17K AKT1 mutant protein with EC50 of 0.2 nM. Afuresertib shows a concentration-dependent effect on multiple AKT substrate phosphorylation levels, including GSK3b, PRAS40, FOXO and Caspase 9. Overall 65% of the hematological cell lines are sensitive to afuresertib (EC50 < 1 uM).

Name

Type

Language

AFURESERTIB HYDROCHLORIDE

Official Name

English

2-THIOPHENECARBOXAMIDE, N-((1S)-2-AMINO-1-((3-FLUOROPHENYL)METHYL)ETHYL)-5-CHLORO-4-(4-CHLORO-1-METHYL-1H-PYRAZOL-5-YL)-, HYDROCHLORIDE (1:1)

Systematic Name

English

Afuresertib hydrochloride [WHO-DD]

Common Name

English

N-[(1S)-1-(Aminomethyl)-2-(3-fluorophenyl)ethyl]-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)thiophene-2-carboxamide monohydrochloride

Systematic Name

English

GSK-2110183B

Code

English

GSK2110183B

Code

English

AFURESERTIB HYDROCHLORIDE [USAN]

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C61074