DACTOLISIB TOSYLATE

Investigational

Details

Stereochemistry	ACHIRAL
Molecular Formula	C30H23N5O.C7H8O3S
Molecular Weight	641.738
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CC1=CC=C(C=C1)S(O)(=O)=O.CN2C(=O)N(C3=C4C=C(C=CC4=NC=C23)C5=CC6=C(C=CC=C6)N=C5)C7=CC=C(C=C7)C(C)(C)C#N

InChI

InChIKey=FWURTHAUPVXZHW-UHFFFAOYSA-N

InChI=1S/C30H23N5O.C7H8O3S/c1-30(2,18-31)22-9-11-23(12-10-22)35-28-24-15-19(21-14-20-6-4-5-7-25(20)32-16-21)8-13-26(24)33-17-27(28)34(3)29(35)36;1-6-2-4-7(5-3-6)11(8,9)10/h4-17H,1-3H3;2-5H,1H3,(H,8,9,10)

HIDE SMILES / InChI

Description
Sources: https://newdrugapprovals.org/2015/06/12/bez-235-nvp-bez235-dactolisib/
Curator's Comment: description was created based on several sources, including: http://adisinsight.springer.com/drugs/800026094 https://www.ncbi.nlm.nih.gov/pubmed/18606717

Dactolisib is a dual inhibitor of phosphatidylinositol 3-kinase (P13K) and the downstream mammalian target of rapamycin (mTOR) by binding to the ATP-binding cleft of these enzymes (inhibitor of PI3K/Akt/mTOR cascade). It is being investigated as a possible anti-cancer cancer agent and drug against Influenza virus infections. Frequently reported adverse events included nausea, vomiting, diarrhoea, fatigue/asthenia, anaemia, and anorexia.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Serine/threonine-protein kinase mTOR 35 Target ID: CHEMBL2842 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19671762 \| https://www.ncbi.nlm.nih.gov/pubmed/18606717	Inhibitor 8504	21.0 nM [IC50]
PI3-kinase p110-alpha subunit 41 Target ID: CHEMBL4005 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19671762 \| https://www.ncbi.nlm.nih.gov/pubmed/18606717	Inhibitor 8504	4.0 nM [IC50]
PI3-kinase p110-beta subunit 31 Target ID: CHEMBL3145 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19671762 \| https://www.ncbi.nlm.nih.gov/pubmed/18606717	Inhibitor 8504	76.0 nM [IC50]
PI3-kinase p110-gamma subunit 32 Target ID: CHEMBL3267 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19671762 \| https://www.ncbi.nlm.nih.gov/pubmed/18606717	Inhibitor 8504	7.0 nM [IC50]
PI3-kinase p110-delta subunit 43 Target ID: CHEMBL3130 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19671762 \| https://www.ncbi.nlm.nih.gov/pubmed/18606717	Inhibitor 8504	5.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Pancreatic neuroendocrine tumors 8 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26851029	Primary	Phase II 1147	Unknown Approved Use Unknown
Breast cancer 432 Sources: http://adisinsight.springer.com/drugs/800026094 https://newdrugapprovals.org/2015/06/12/bez-235-nvp-bez235-dactolisib/	Primary	Phase II 1147	Unknown Approved Use Unknown
Influenza virus infections 34 Sources: http://adisinsight.springer.com/drugs/800026094	Primary	Phase II 1147	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
45.2 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/28357727	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered: EVEROLIMUS	EVEROLIMUS	DACTOLISIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
101.8 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/28357727	400 mg single, oral dose: 400 mg route of administration: Oral experiment type: SINGLE co-administered: EVEROLIMUS	EVEROLIMUS	DACTOLISIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
243 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/28357727	800 mg single, oral dose: 800 mg route of administration: Oral experiment type: SINGLE co-administered: EVEROLIMUS	EVEROLIMUS	DACTOLISIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
468.5 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/28357727	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered: EVEROLIMUS	EVEROLIMUS	DACTOLISIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
830.8 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/28357727	400 mg single, oral dose: 400 mg route of administration: Oral experiment type: SINGLE co-administered: EVEROLIMUS	EVEROLIMUS	DACTOLISIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
2167.3 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/28357727	800 mg single, oral dose: 800 mg route of administration: Oral experiment type: SINGLE co-administered: EVEROLIMUS	EVEROLIMUS	DACTOLISIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
3.2 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/28357727	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered: EVEROLIMUS	EVEROLIMUS	DACTOLISIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
8.6 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/28357727	400 mg single, oral dose: 400 mg route of administration: Oral experiment type: SINGLE co-administered: EVEROLIMUS	EVEROLIMUS	DACTOLISIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
5.9 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/28357727	800 mg single, oral dose: 800 mg route of administration: Oral experiment type: SINGLE co-administered: EVEROLIMUS	EVEROLIMUS	DACTOLISIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

Sourcing

Vendor/Aggregator	ID	URL
1PlusChem LLC	1P008TV6	https://www.1pchem.com/search?query=1P008TV6
1PlusChem LLC	1P00GSBM	https://www.1pchem.com/search?query=1P00GSBM
A2B Chem	AH82402	http://a2bchem.com/prod/AH82402
AChemBlock	10290	http://www.achemblock.com/catalogsearch/result/?q=10290
AK Scientific	3486AH	https://aksci.com/item_detail.php?cat=3486AH
AK Scientific	X7430	https://aksci.com/item_detail.php?cat=X7430
AOBIOUS INC	AOB87110	http://aobious.com/aobious/search?search_query=AOB87110
ApexBio Technology	A8246	https://www.apexbt.com/catalogsearch/result/?q=A8246
AstaTech	41099	http://astatechinc.com/CPSResult.php?CRNO=41099
Axon MedChem	1281	https://www.axonmedchem.com/product/1281
BLD Pharm	BD629838	http://www.bldpharm.com/search/Search.html?keyword=BD629838
BOC Sciences	915019-65-7	http://www.bocsci.com/description.asp?cas=915019-65-7
Capot Chemical	16657	https://www.capotchem.com/search.do?q=16657
Cayman Chemical	10565	http://www.caymanchem.com/app/template/Product.vm/catalog/10565
Cayman Chemical	21185	http://www.caymanchem.com/app/template/Product.vm/catalog/21185
Chem Scene	CS-0080	http://www.chemscene.com/goproductList/searchProductList?productObj=CS-0080
Chem Scene	CS-0711	http://www.chemscene.com/goproductList/searchProductList?productObj=CS-0711
ChemShuttle	104794	https://www.chemshuttle.com/catalogsearch/result/?q=104794
eMolecules	114311714	https://orderbb.emolecules.com/search/#?query=114311714
eMolecules	18867474	https://orderbb.emolecules.com/search/#?query=18867474
eMolecules	44811472	https://orderbb.emolecules.com/search/#?query=44811472
Enamine	EN300-60135	https://www.enaminestore.com/catalog/EN300-60135
Excenen	EX-A404	http://www.excenen.com/searchresultlist.php?id=EX-A404
Exclusive Chemistry	2325	http://www.exchemistry.com/chem-catalog/product-2325.html
KeyOrganics	ES-0038	http://www.keyorganicsinc.com/bionet/catalogsearch/result?q=ES-0038
Lab Seeker	SC-50495	http://www.labseeker.com/search.php?keywords=SC-50495&category=0
LabSeeker	SC-50495	http://www.labseeker.com/search.php?keywords=SC-50495&category=0
Matrix Scientific	90884	http://www.matrixscientific.com/090884.html
mcule	MCULE-1407851271	https://mcule.com/MCULE-1407851271/
mcule	MCULE-7077128450	https://mcule.com/MCULE-7077128450/
MedChem Express	HY-15174	https://www.medchemexpress.com/search.html?q=HY-15174&ft=&fa=&fp=
MedChem Express	HY-50673	https://www.medchemexpress.com/search.html?q=HY-50673&ft=&fa=&fp=
Molnova	M16571	https://www.molnova.com/en/serch-list.html?keywords=M16571
MolPort	MolPort-005-737-784	https://www.molport.com/shop/molecule-link/MolPort-005-737-784
MolPort	MolPort-039-139-569	https://www.molport.com/shop/molecule-link/MolPort-039-139-569
MolPort	MolPort-044-561-823	https://www.molport.com/shop/molecule-link/MolPort-044-561-823
MuseChem	R043987	https://www.musechem.com/product/R043987.html
MuseChem	R066919	https://www.musechem.com/product/R066919.html
PI Chemicals	PI-42629	http://www.pipharm.com/catalog_products/PI-42629.html
Princeton BioMolecular Research	PBMR227128	http://www.princetonbio.com/order_online?common_id=PBMR227128
ShangHai Biochempartner	BCP000019	http://www.biochempartner.com/search_BCP000019
ShangHai Biochempartner	BCP00216	http://www.biochempartner.com/search_BCP00216
ShangHai Biochempartner	BCP16240	http://www.biochempartner.com/search_BCP16240
Synthonix	14315	https://synthonix.com/catalogsearch/result/?q=14315
TargetMol	T2235	https://www.targetmol.com/search?keyword=T2235
Tetrahedron	TS59327	http://www.thsci.com/search.do?q=TS59327
Toronto Research Chemicals	N925750	https://www.trc-canada.com/product-detail/?CatNum=N925750
Wonderchem	WD06ZUP	http://www.wonder-chem.com/search.html?text=WD06ZUP

PubMed

Title	Date	PubMed
Synergistic induction of cell death in haematological malignancies by combined phosphoinositide-3-kinase and BET bromodomain inhibition.	2015-07	25640480
Preclinical evaluation of the mTOR-PI3K inhibitor BEZ235 in nasopharyngeal cancer models.	2014-02-01	24041865
PI3Kδ inhibition augments the efficacy of rapamycin in suppressing proliferation of Epstein-Barr virus (EBV)+ B cell lymphomas.	2013-08	23841834
Dual inhibitor of phosphoinositide 3-kinase/mammalian target of rapamycin NVP-BEZ235 effectively inhibits cisplatin-resistant urothelial cancer cell growth through autophagic flux.	2013-07-18	23651616
Phosphatidylinositol 3-kinase/Akt signaling pathway activates the WNK-OSR1/SPAK-NCC phosphorylation cascade in hyperinsulinemic db/db mice.	2012-10	22949526
Antitumor action of the MET tyrosine kinase inhibitor crizotinib (PF-02341066) in gastric cancer positive for MET amplification.	2012-07	22729845
The synergistic interaction of MEK and PI3K inhibitors is modulated by mTOR inhibition.	2012-04-10	22415236
Modulators of sensitivity and resistance to inhibition of PI3K identified in a pharmacogenomic screen of the NCI-60 human tumor cell line collection.	2012	23029544
Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies.	2011-07	21633166
Comparison of the effects of the PI3K/mTOR inhibitors NVP-BEZ235 and GSK2126458 on tamoxifen-resistant breast cancer cells.	2011-06-01	21464613
A cell-based screen identifies ATR inhibitors with synthetic lethal properties for cancer-associated mutations.	2011-06	21552262
Dual targeting of phosphoinositide 3-kinase and mammalian target of rapamycin using NVP-BEZ235 as a novel therapeutic approach in human ovarian carcinoma.	2011-04-15	21372221
The dual PI3K/mTOR inhibitor BEZ235 is effective in lung cancer cell lines.	2011-03	21498705
Inhibition profiles of phosphatidylinositol 3-kinase inhibitors against PI3K superfamily and human cancer cell line panel JFCR39.	2010-04	20129775
Loss of Phosphatase and Tensin homologue deleted on chromosome 10 engages ErbB3 and insulin-like growth factor-I receptor signaling to promote antiestrogen resistance in breast cancer.	2009-05-15	19435893
Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity.	2008-07	18606717

Patents

Sample Use Guides

In Vivo Use Guide

400 or 300 mg twice daily

Route of Administration: Oral

In Vitro Use Guide

IC50 doses of dactolisib for P3 and U87 glioma cells were established at 12.7 nM and 15.8 nM, respectively.

Name

Type

Language

DACTOLISIB TOSILATE

Preferred Name

English

DACTOLISIB TOSYLATE

Official Name

English

DACTOLISIB TOSYLATE [USAN]

Common Name

English

Dactolisib tosilate [WHO-DD]

Common Name

English

NVP-BEZ235-NX

Code

English

BENZENEACETONITRILE, 4-(2,3-DIHYDRO-3-METHYL-2-OXO-8-(3-QUINOLINYL)-1H-IMIDAZO(4,5-C)QUINOLIN-1-YL)-.ALPHA.,.ALPHA.-DIMETHYL-, 4-METHYLBENZENESULFONATE (1:1)

Systematic Name

English

NVP-BEZ235-ANA

Code

English

Code System Code Type Description

PUBCHEM

49803145