ENTOSPLETINIB

Details

Stereochemistry	ACHIRAL
Molecular Formula	C23H21N7O
Molecular Weight	411.4591
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

C1CN(CCO1)C2=CC=C(NC3=NC(=CN4C=CN=C34)C5=CC6=C(C=NN6)C=C5)C=C2

InChI

InChIKey=XSMSNFMDVXXHGJ-UHFFFAOYSA-N

InChI=1S/C23H21N7O/c1-2-17-14-25-28-20(17)13-16(1)21-15-30-8-7-24-23(30)22(27-21)26-18-3-5-19(6-4-18)29-9-11-31-12-10-29/h1-8,13-15H,9-12H2,(H,25,28)(H,26,27)

HIDE SMILES / InChI

Molecular Formula	C23H21N7O
Molecular Weight	411.4591
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/24779514
Curator's Comment: description was created based on several sources, including: http://adisinsight.springer.com/drugs/800032822 | https://www.ncbi.nlm.nih.gov/pubmed/25696919

Entospletinib (GS-9973) is an adenosine triphosphate competitive inhibitor of Syk that disrupts kinase activity, which is currently in clinical trials for multiple B-cell malignancies. The most common treatment-emergent serious adverse events included dyspnea, pneumonia, febrile neutropenia, dehydration, and pyrexia.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Tyrosine-protein kinase SYK 21 Target ID: CHEMBL2599 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24779514	Inhibitor 8297		26.0 nM [EC50]

Conditions

Condition	Modality	Highest Phase	Product
Chronic lymphocytic leukemia 59 Sources: https://www.ncbi.nlm.nih.gov/pubmed/25696919	Primary	Phase II 1132	Unknown Approved Use Unknown
Non-Hodgkin's lymphoma 79 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26968534	Primary	Phase II 1132	Unknown Approved Use Unknown
Mantle cell lymphoma 24 Sources: https://clinicaltrials.gov/ct2/show/NCT01796470	Primary	Phase II 1132	Unknown Approved Use Unknown

C_max

Value	Dose	Analyte	Population
2799 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27785737	1200 mg 2 times / day multiple, oral dose: 1200 mg route of administration: Oral experiment type: MULTIPLE co-administered:	ENTOSPLETINIB plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FED
3427 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27785737	1200 mg 2 times / day multiple, oral dose: 1200 mg route of administration: Oral experiment type: MULTIPLE co-administered:	ENTOSPLETINIB plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
1059.8 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27785737	1200 mg single, oral dose: 1200 mg route of administration: Oral experiment type: SINGLE co-administered:	ENTOSPLETINIB plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

AUC

Value	Dose	Analyte	Population
22788 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27785737	1200 mg 2 times / day multiple, oral dose: 1200 mg route of administration: Oral experiment type: MULTIPLE co-administered:	ENTOSPLETINIB plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FED
26775 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27785737	1200 mg 2 times / day multiple, oral dose: 1200 mg route of administration: Oral experiment type: MULTIPLE co-administered:	ENTOSPLETINIB plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
9744.4 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27785737	1200 mg single, oral dose: 1200 mg route of administration: Oral experiment type: SINGLE co-administered:	ENTOSPLETINIB plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

T_1/2

Value	Dose	Analyte	Population
8.95 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27785737	1200 mg 2 times / day multiple, oral dose: 1200 mg route of administration: Oral experiment type: MULTIPLE co-administered:	ENTOSPLETINIB plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FED
13.9 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27785737	1200 mg 2 times / day multiple, oral dose: 1200 mg route of administration: Oral experiment type: MULTIPLE co-administered:	ENTOSPLETINIB plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
9.59 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27785737	1200 mg single, oral dose: 1200 mg route of administration: Oral experiment type: SINGLE co-administered:	ENTOSPLETINIB plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

Doses

Dose	Population	Adverse events
1200 mg 2 times / day multiple, oral Highest studied dose Dose: 1200 mg, 2 times / day Route: oral Route: multiple Dose: 1200 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/27785737 Page: p.199	healthy, ADULT n = 8 Health Status: healthy Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 8 Sources: https://pubmed.ncbi.nlm.nih.gov/27785737 Page: p.199	Sources: https://pubmed.ncbi.nlm.nih.gov/27785737 Page: p.199
800 mg 2 times / day multiple, oral Studied dose Dose: 800 mg, 2 times / day Route: oral Route: multiple Dose: 800 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/25696919	unhealthy, ADULT n = 186 Health Status: unhealthy Condition: chronic lymphocytic leukemia Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 186 Sources: https://pubmed.ncbi.nlm.nih.gov/25696919	Disc. AE: Fatigue, ALT increased... AEs leading to discontinuation/dose reduction: Fatigue (2.2%) ALT increased (1.6%) Headache (1.6%) AST increased (1%) Sources: https://pubmed.ncbi.nlm.nih.gov/25696919

AEs

AE	Significance	Dose	Population
AST increased	1% Disc. AE	800 mg 2 times / day multiple, oral Studied dose Dose: 800 mg, 2 times / day Route: oral Route: multiple Dose: 800 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/25696919	unhealthy, ADULT n = 186 Health Status: unhealthy Condition: chronic lymphocytic leukemia Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 186 Sources: https://pubmed.ncbi.nlm.nih.gov/25696919
ALT increased	1.6% Disc. AE	800 mg 2 times / day multiple, oral Studied dose Dose: 800 mg, 2 times / day Route: oral Route: multiple Dose: 800 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/25696919	unhealthy, ADULT n = 186 Health Status: unhealthy Condition: chronic lymphocytic leukemia Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 186 Sources: https://pubmed.ncbi.nlm.nih.gov/25696919
Headache	1.6% Disc. AE	800 mg 2 times / day multiple, oral Studied dose Dose: 800 mg, 2 times / day Route: oral Route: multiple Dose: 800 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/25696919	unhealthy, ADULT n = 186 Health Status: unhealthy Condition: chronic lymphocytic leukemia Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 186 Sources: https://pubmed.ncbi.nlm.nih.gov/25696919
Fatigue	2.2% Disc. AE	800 mg 2 times / day multiple, oral Studied dose Dose: 800 mg, 2 times / day Route: oral Route: multiple Dose: 800 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/25696919	unhealthy, ADULT n = 186 Health Status: unhealthy Condition: chronic lymphocytic leukemia Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 186 Sources: https://pubmed.ncbi.nlm.nih.gov/25696919

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1587	inhibitor 1767 substrate 1037	inhibitor 1852

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2C19 1478 CYP1A2 1524 UGT1A1 204 OATP1B1 788 OATP1B3 706 BCRP 699 P-gp 1461	CYP3A 191 HLM 31

Drug as perpetrator

Target	Modality	Activity
CYP1A2 1692	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/24779514/	unspecified [IC50 >10 uM]
CYP2C19 1553	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/24779514/	unspecified [IC50 >10 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/24779514/	unspecified [IC50 >10 uM]
CYP2D6 1891	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/24779514/	unspecified [IC50 >10 uM]
CYP3A4 1925	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/24779514/	unspecified [IC50 >10 uM]
UGT1A1 254	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/27785737/	yes [IC50 ~2.5 uM]
BCRP 773	inhibitor 3277 Sources: https://ascopubs.org/doi/abs/10.1200/JCO.2016.34.15_suppl.e14097	yes
OATP1B1 803	inhibitor 3277 Sources: https://ascopubs.org/doi/abs/10.1200/JCO.2016.34.15_suppl.e14097	yes
OATP1B3 715	inhibitor 3277 Sources: https://ascopubs.org/doi/abs/10.1200/JCO.2016.34.15_suppl.e14097	yes
P-gp 1650	inhibitor 3277 Sources: https://ascopubs.org/doi/abs/10.1200/JCO.2016.34.15_suppl.e14097	yes

Drug as victim

Target	Modality	Activity	Clinical evidence
HLM 31	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/24779514/	yes
CYP2C9 1037	substrate 3367 Sources: https://ascopubs.org/doi/abs/10.1200/JCO.2016.34.15_suppl.e14097	yes	yes (co-administration study) Comment: Fluconazole increased Cmax and AUCtau by 32% and 41%. Sources: https://ascopubs.org/doi/abs/10.1200/JCO.2016.34.15_suppl.e14097
CYP3A 191	substrate 3367 Sources: https://ascopubs.org/doi/abs/10.1200/JCO.2016.34.15_suppl.e14097	yes	yes (co-administration study) Comment: Rifampicin decreased Cmax and AUCtau by 58% and 71%. Sources: https://ascopubs.org/doi/abs/10.1200/JCO.2016.34.15_suppl.e14097

Sourcing

Vendor/Aggregator	ID	URL
001 Chemical	DY443093	https://www.001chemical.com/chem/search?q=DY443093
1PlusChem LLC	1P000K85	https://www.1pchem.com/search?query=1P000K85
AK Scientific	2440AH	https://aksci.com/item_detail.php?cat=2440AH
AK Scientific	SYN5725	https://aksci.com/item_detail.php?cat=SYN5725
AOBIOUS INC	AOB87385	http://aobious.com/aobious/search?search_query=AOB87385
Aceschem	ACS019978	https://www.aceschem.com/catalog/search.do?q=ACS019978
ApexBio Technology	B3553	https://www.apexbt.com/catalogsearch/result/?q=B3553
AstaTech	91452	http://astatechinc.com/CPSResult.php?CRNO=91452
BLD Pharm	BD399082	http://www.bldpharm.com/search/Search.html?keyword=BD399082
Capot Chemical	34087	https://www.capotchem.com/search.do?q=34087
Cayman Chemical	17653	http://www.caymanchem.com/app/template/Product.vm/catalog/17653
Chem Scene	CS-2791	http://www.chemscene.com/goproductList/searchProductList?productObj=CS-2791
ChemShuttle	136524	https://www.chemshuttle.com/catalogsearch/result/?q=136524
Debye Scientific	DA-36929	https://www.debyesci.com/index.php?id=product&ext[cno]=DA-36929
Excenen	EX-A1120	http://www.excenen.com/searchresultlist.php?id=EX-A1120
Hairui	HR33128	http://www.hairuichem.com/en/product/search.do?q=HR33128
KeyOrganics	AS-17026	http://www.keyorganicsinc.com/bionet/catalogsearch/result?q=AS-17026
MedChem Express	HY-15968	https://www.medchemexpress.com/search.html?q=HY-15968&ft=&fa=&fp=
MolPort	MolPort-035-395-879	https://www.molport.com/shop/molecule-link/MolPort-035-395-879
Molcore	MC443093	http://www.molcore.com/CatMC443093.html
MuseChem	I000901	https://www.musechem.com/product/I000901.html
Selleck Chemicals	S7523	http://www.selleckchem.com/search.html?searchDTO.searchParam=S7523
ShangHai Biochempartner	BCP001143	http://www.biochempartner.com/search_BCP001143
ShangHai Biochempartner	BCP09582	http://www.biochempartner.com/search_BCP09582
eMolecules	49839446	https://orderbb.emolecules.com/search/#?query=49839446
eNovation Chemicals	D409773	https://www.enovationchem.com/Products.asp?SEARCHTEXT=D409773&searchbtn.x=0&searchbtn.y=0
mcule	MCULE-2016479441	https://mcule.com/MCULE-2016479441/

PubMed

Title	Date	PubMed
Discovery of GS-9973, a selective and orally efficacious inhibitor of spleen tyrosine kinase.	2014 May 8	24779514
An open-label phase 2 trial of entospletinib (GS-9973), a selective spleen tyrosine kinase inhibitor, in chronic lymphocytic leukemia.	2015 Apr 9	25696919
Phase 2 study of idelalisib and entospletinib: pneumonitis limits combination therapy in relapsed refractory CLL and NHL.	2016 May 19	26968534
Diffuse large B-cell lymphoma patient-derived xenograft models capture the molecular and biological heterogeneity of the disease.	2016 May 5	26773040

Patents

Sample Use Guides

In Vivo Use Guide

800 mg twice daily

Route of Administration: Oral

In Vitro Use Guide

Complete Mcl-1 downregulation was consistently achieved only with SYK inhibitor entospletinib (2h with 1uM of GS-9973).

Substance Class	Chemical Created by `admin` on `Sat Dec 16 10:45:48 GMT 2023` Edited by `admin` on `Sat Dec 16 10:45:48 GMT 2023`
Record UNII	6I3O3W6O3B
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

ENTOSPLETINIB

Official Name

English

GS-9973

Code

English

SYK INHIBITOR GS-9973

Code

English

ENTOSPLETINIB [USAN]

Common Name

English

6-(1H-INDAZOL-6-YL)-N-(4-(MORPHOLIN-4-YL)PHENYL)IMIDAZO(1,2-A)PYRAZIN-8-AMINE

Systematic Name

English

Entospletinib [WHO-DD]

Common Name

English

IMIDAZO(1,2-A)PYRAZIN-8-AMINE, 6-(1H-INDAZOL-6-YL)-N-(4-(4-MORPHOLINYL)PHENYL)-

Systematic Name

English

entospletinib [INN]

Common Name

English

Classification Tree Code System Code

EU-Orphan Drug

EU/3/17/1922