IZORLISIB MESYLATE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C15H19N7O3S.CH4O3S
Molecular Weight	473.527
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CS(O)(=O)=O.CS(=O)(=O)N1CCC2=C(N=C(N=C12)N3CCOCC3)C4=CN=C(N)N=C4

InChI

InChIKey=QASDCQIMDVXWHK-UHFFFAOYSA-N

InChI=1S/C15H19N7O3S.CH4O3S/c1-26(23,24)22-3-2-11-12(10-8-17-14(16)18-9-10)19-15(20-13(11)22)21-4-6-25-7-5-21;1-5(2,3)4/h8-9H,2-7H2,1H3,(H2,16,17,18);1H3,(H,2,3,4)

HIDE SMILES / InChI

Molecular Formula	C15H19N7O3S
Molecular Weight	377.421
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Molecular Formula	CH4O3S
Molecular Weight	96.106
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/21558396
Curator's Comment: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/21316229

Chugai Pharma Europe is developing CH-5132799, a phosphatidylinositol-3-kinase (PI3K) inhibitor, for the treatment of solid tumours. CH-5132799 is a selective class I PI3K inhibitor with potent antitumor activity against tumors harboring the PIK3CA mutations. CH-5132799 selectively inhibits class I PI3Ks, PI3Kα (IC50 = 0.014 uM ), PI3Kβ (IC50 = 0.12 uM ), PI3Kδ (IC50 = 0.50 uM ), PI3Kγ (IC50 = 0.036 uM ), but shows less inhibition of class II PI3Ks, class III PI3k and mTOR and also no inhibitory activity (IC50 > 10 uM) against 26 protein kinases. CH-5132799 exhibits more inhibitory activities against PI3Kα with oncogenic mutations E542K (IC50 = 6.7 nM), E545K (IC50 = 6.7 nM) and H1047R (IC50 = 5.6 nM) than wild-type PI3Kα. CH-5132799 treated breast cnacer KPL-4 cells, which harbor the PIK3CA mutation, phosphorylation of Akt and its direct substrates, PRAS40 and FoxO1/3a and phosphorylation of downstream factors, including S6K, S6 and 4E-BP1, are effectively suppressed. Cancer cell lines harboring PIK3CA mutations are significantly sensitive to CH-5132799. CH-5132799 is orally available and showed significant antitumor activity in PI3K pathway-activated human cancer xenograft models in mice. CH-5132799 is in phase I study to evaluate safety, pharmacokinetics and activity of CH-5132799 administered orally as a single agent in patients with advanced solid tumors.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
PI3-kinase p110-alpha subunit 41 Target ID: CHEMBL4005 Sources: https://www.ncbi.nlm.nih.gov/pubmed/21558396	Inhibitor 8297	14.0 nM [IC50]
PI3-kinase p110-gamma subunit 32 Target ID: CHEMBL3267 Sources: https://www.ncbi.nlm.nih.gov/pubmed/21558396	Inhibitor 8297	36.0 nM [IC50]
PI3-kinase p110-beta subunit 31 Target ID: CHEMBL3145 Sources: https://www.ncbi.nlm.nih.gov/pubmed/21558396	Inhibitor 8297	0.12 µM [IC50]
PI3-kinase p110-delta subunit 43 Target ID: CHEMBL3130 Sources: https://www.ncbi.nlm.nih.gov/pubmed/21558396	Inhibitor 8297	0.5 µM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Solid tumors 145 Sources: http://adisinsight.springer.com/drugs/800033063 https://clinicaltrials.gov/ct2/show/NCT01222546	Primary		Phase I 428	Unknown Approved Use Unknown

C_max

Value	Dose	Analyte	Population
175 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25231405/	48 mg 2 times / day steady-state, oral dose: 48 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	CH-5132799 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
631 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25231405/	72 mg 2 times / day steady-state, oral dose: 72 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	CH-5132799 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
331 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25231405/	56 mg 2 times / day steady-state, oral dose: 56 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	CH-5132799 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
46.3 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25231405/	8 mg 1 times / day steady-state, oral dose: 8 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	CH-5132799 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
345 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25231405/	32 mg 1 times / day steady-state, oral dose: 32 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	CH-5132799 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
9.92 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25231405/	2 mg 1 times / day steady-state, oral dose: 2 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	CH-5132799 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
184 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25231405/	56 mg 1 times / day steady-state, oral dose: 56 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	CH-5132799 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
103 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25231405/	96 mg 1 times / day steady-state, oral dose: 96 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	CH-5132799 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Analyte	Population
1550 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25231405/	48 mg 2 times / day steady-state, oral dose: 48 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	CH-5132799 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
5580 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25231405/	72 mg 2 times / day steady-state, oral dose: 72 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	CH-5132799 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
5940 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25231405/	56 mg 2 times / day steady-state, oral dose: 56 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	CH-5132799 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
159 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25231405/	8 mg 1 times / day steady-state, oral dose: 8 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	CH-5132799 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
1740 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25231405/	32 mg 1 times / day steady-state, oral dose: 32 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	CH-5132799 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
48.8 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25231405/	2 mg 1 times / day steady-state, oral dose: 2 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	CH-5132799 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
748 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25231405/	56 mg 1 times / day steady-state, oral dose: 56 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	CH-5132799 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
961 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/25231405/	96 mg 1 times / day steady-state, oral dose: 96 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	CH-5132799 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	HLM 31

Drug as perpetrator

Target	Modality	Activity
CYP2C9 1819	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645842#sid=363677498	inconclusive [IC50 26.837 uM]
CYP2D6 1891	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645840#sid=363677498	no
CYP3A4 1925	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645841#sid=363677498	no
P-gp 1650	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1346987#sid=363677498	yes [IC50 1.2995 uM]

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
HLM 31	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/21316229/	yes

Sourcing

Vendor/Aggregator	ID	URL
001 Chemical	DY103027	https://www.001chemical.com/chem/search?q=DY103027
1PlusChem LLC	1P00035Y	https://www.1pchem.com/search?query=1P00035Y
AChemBlock	10302	http://www.achemblock.com/catalogsearch/result/?q=10302
AK Scientific	2316AH	https://aksci.com/item_detail.php?cat=2316AH
AK Scientific	SYN1146	https://aksci.com/item_detail.php?cat=SYN1146
AOBIOUS INC	AOB87718	http://aobious.com/aobious/search?search_query=AOB87718
Angene	AGN-PC-0WAAT7	http://www.angenechemical.com/productshow/AGN-PC-0WAAT7.html
ApexBio Technology	B2183	https://www.apexbt.com/catalogsearch/result/?q=B2183
AstaTech	40980	http://astatechinc.com/CPSResult.php?CRNO=40980
BLD Pharm	BD304616	http://www.bldpharm.com/search/Search.html?keyword=BD304616
Chem Scene	CS-0981	http://www.chemscene.com/goproductList/searchProductList?productObj=CS-0981
ChemShuttle	100843	https://www.chemshuttle.com/catalogsearch/result/?q=100843
Excenen	EX-A997	http://www.excenen.com/searchresultlist.php?id=EX-A997
KeyOrganics	AS-16285	http://www.keyorganicsinc.com/bionet/catalogsearch/result?q=AS-16285
Lab Network	LN01274541	https://labnetwork.com/frontend-app/p/#!/moleculedetails/LN01274541
Matrix Scientific	120675	http://www.matrixscientific.com/120675.html
MedChem Express	HY-15466	https://www.medchemexpress.com/search.html?q=HY-15466&ft=&fa=&fp=
MolPort	MolPort-023-219-217	https://www.molport.com/shop/molecule-link/MolPort-023-219-217
Molcore	MC103027	http://www.molcore.com/CatMC103027.html
Molnova	M17113	https://www.molnova.com/en/serch-list.html?keywords=M17113
MuseChem	I000098	https://www.musechem.com/product/I000098.html
Selleck Chemicals	S2699	http://www.selleckchem.com/search.html?searchDTO.searchParam=S2699
ShangHai Biochempartner	BCP000476	http://www.biochempartner.com/search_BCP000476
ShangHai Biochempartner	BCP02894	http://www.biochempartner.com/search_BCP02894
TargetMol	T2619	https://www.targetmol.com/search?keyword=T2619
Tetrahedron	TS86506	http://www.thsci.com/search.do?q=TS86506
Wonderchem	WD09T2D	http://www.wonder-chem.com/search.html?text=WD09T2D
eMolecules	37153246	https://orderbb.emolecules.com/search/#?query=37153246
eMolecules	49837449	https://orderbb.emolecules.com/search/#?query=49837449
eNovation Chemicals	D372419	https://www.enovationchem.com/Products.asp?SEARCHTEXT=D372419&searchbtn.x=0&searchbtn.y=0
mcule	MCULE-3177087409	https://mcule.com/MCULE-3177087409/
mcule	MCULE-4567777397	https://mcule.com/MCULE-4567777397/

PubMed

Title	Date	PubMed
Discovery and biological activity of a novel class I PI3K inhibitor, CH5132799.	2011 Mar 15	21316229

Patents

Sample Use Guides

In Vivo Use Guide

2 to 96 mg once daily or 48 to 72 mg twice daily

Route of Administration: Oral

In Vitro Use Guide

CH5132799 showed superior antiproliferative activity across the 4 tumor types (—breast, ovarian, prostate, and endometrial cancer), with 75% (45/60) of lines having an IC50 below 1 umol/L and 38% (23/60) of lines having an IC50 below 0.3 umol/L.

Substance Class	Chemical Created by `admin` on `Sat Dec 16 14:17:29 UTC 2023` Edited by `admin` on `Sat Dec 16 14:17:29 UTC 2023`
Record UNII	KR3Z81AB18
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

IZORLISIB MESYLATE

Common Name

English

PA-799 MESYLATE

Code

English

CH-5132799 MESILATE

Code

English

2-PYRIMIDINAMINE, 5-(6,7-DIHYDRO-7-(METHYLSULFONYL)-2-(4-MORPHOLINYL)-5H-PYRROLO(2,3-D)PYRIMIDIN-4-YL)-, MESYLATE

Systematic Name

English

CH-5132799 MESYLATE

Code

English

MEN 1611 [WHO-DD]

Common Name

English

IZORLISIB MESILATE

Common Name

English

CH5137291 MESYLATE

Code

English

CH-5137291 MESYLATE

Code

English

PA799 MESYLATE

Code

English

Code System Code Type Description

FDA UNII

KR3Z81AB18