NAVITOCLAX DIHYDROCHLORIDE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C47H55ClF3N5O6S3.2ClH
Molecular Weight	1047.535
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

Cl.Cl.CC1(C)CCC(=C(CN2CCN(CC2)C3=CC=C(C=C3)C(=O)NS(=O)(=O)C4=CC(=C(N[C@H](CCN5CCOCC5)CSC6=CC=CC=C6)C=C4)S(=O)(=O)C(F)(F)F)C1)C7=CC=C(Cl)C=C7

InChI

InChIKey=WDVGRPCSLPVWKC-VROLVAQFSA-N

InChI=1S/C47H55ClF3N5O6S3.2ClH/c1-46(2)20-18-42(34-8-12-37(48)13-9-34)36(31-46)32-55-22-24-56(25-23-55)39-14-10-35(11-15-39)45(57)53-65(60,61)41-16-17-43(44(30-41)64(58,59)47(49,50)51)52-38(19-21-54-26-28-62-29-27-54)33-63-40-6-4-3-5-7-40;;/h3-17,30,38,52H,18-29,31-33H2,1-2H3,(H,53,57);2*1H/t38-;;/m1../s1

HIDE SMILES / InChI

Molecular Formula	ClH
Molecular Weight	36.461
Charge	0
Count

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

Molecular Formula	C47H55ClF3N5O6S3
Molecular Weight	974.613
Charge	0
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	1 / 1
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/18451170 | http://adisinsight.springer.com/drugs/800025430
Curator's Comment: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/18806758

Navitoclax (ABT-263) is an oral selective inhibitor of B-cell leukemia 2 (Bcl-2) family of proteins with potential antineoplastic activity. Navitoclax is a small molecular with the formula of C47H55ClF3N5O6S3 and Molecular Weight of 974. As a Bad-like Bh3 minetic, ABT-263 binds to Bcl-2 family proteins Bcl-2, Bcl-xl and Bcl-w, disrupts the interaction between Bcl-2/Bcl-xl /Bcl-w and pro-apoptotic proteins such as Bim, Bad and Bak, which trigger the caspases-initiated cell death pathway to induce apoptosis. Navitoclax has been in phase II clinical trials by Abbvie for the treatment of prostate cancer, chronic lymphocytic leukaemia and lymphoma. However, this research has been discontinued.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Apoptosis regulator Bcl-X 8 Target ID: CHEMBL4625 Sources: https://www.ncbi.nlm.nih.gov/pubmed/18451170 \| https://www.ncbi.nlm.nih.gov/pubmed/24881567 \| https://www.ncbi.nlm.nih.gov/pubmed/24215352	Inhibitor 8297	3.3 nM [IC50]
Apoptosis regulator Bcl-2 19 Target ID: CHEMBL4860 Sources: https://www.ncbi.nlm.nih.gov/pubmed/18451170 \| https://www.ncbi.nlm.nih.gov/pubmed/18806758	Inhibitor 8297	1.0 nM [Ki]
Apoptosis regulator Bcl-W 2 Target ID: CHEMBL4677 Sources: https://www.ncbi.nlm.nih.gov/pubmed/18451170 \| https://www.ncbi.nlm.nih.gov/pubmed/18806758	Inhibitor 8297	1.0 nM [Ki]

Conditions

Condition	Modality	Highest Phase	Product
Chronic lymphocytic leukemia 59 Sources: http://adisinsight.springer.com/drugs/800025430 https://clinicaltrials.gov/ct2/show/NCT01557777	Primary	Phase II 1132	Unknown Approved Use Unknown
Non-Hodgkin's lymphoma 79 Sources: http://adisinsight.springer.com/drugs/800025430 https://clinicaltrials.gov/ct2/show/NCT00406809	Primary	Phase II 1132	Unknown Approved Use Unknown
Small-cell lung cancer 41 Sources: http://adisinsight.springer.com/drugs/800025430 https://clinicaltrials.gov/ct2/show/NCT00445198	Primary	Phase II 1132	Unknown Approved Use Unknown
Mantle cell lymphoma 24 Sources: http://adisinsight.springer.com/drugs/800025430 https://clinicaltrials.gov/ct2/show/NCT00406809	Primary	Phase II 1132	Unknown Approved Use Unknown

Doses

Dose	Population	Adverse events
150 mg 1 times / day multiple, oral (starting) RP2D Dose: 150 mg, 1 times / day Route: oral Route: multiple Dose: 150 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/33236943	unhealthy n = 15 Health Status: unhealthy Condition: Follicular lymphoma Sex: M+F Food Status: UNKNOWN Population Size: 15 Sources: https://pubmed.ncbi.nlm.nih.gov/33236943	Disc. AE: Increased white blood cell count, Increased white blood cell count... AEs leading to discontinuation/dose reduction: Increased white blood cell count (serious, 2 patients) Increased white blood cell count (serious, 2 patients) Bacterial sepsis (serious, 2 patients) Bacterial sepsis (serious, 2 patients) Sources: https://pubmed.ncbi.nlm.nih.gov/33236943

AEs

AE	Significance	Dose	Population
Bacterial sepsis	serious, 2 patients Disc. AE	150 mg 1 times / day multiple, oral (starting) RP2D Dose: 150 mg, 1 times / day Route: oral Route: multiple Dose: 150 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/33236943	unhealthy n = 15 Health Status: unhealthy Condition: Follicular lymphoma Sex: M+F Food Status: UNKNOWN Population Size: 15 Sources: https://pubmed.ncbi.nlm.nih.gov/33236943
Bacterial sepsis	serious, 2 patients Disc. AE	150 mg 1 times / day multiple, oral (starting) RP2D Dose: 150 mg, 1 times / day Route: oral Route: multiple Dose: 150 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/33236943	unhealthy n = 15 Health Status: unhealthy Condition: Follicular lymphoma Sex: M+F Food Status: UNKNOWN Population Size: 15 Sources: https://pubmed.ncbi.nlm.nih.gov/33236943
Increased white blood cell count	serious, 2 patients Disc. AE	150 mg 1 times / day multiple, oral (starting) RP2D Dose: 150 mg, 1 times / day Route: oral Route: multiple Dose: 150 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/33236943	unhealthy n = 15 Health Status: unhealthy Condition: Follicular lymphoma Sex: M+F Food Status: UNKNOWN Population Size: 15 Sources: https://pubmed.ncbi.nlm.nih.gov/33236943
Increased white blood cell count	serious, 2 patients Disc. AE	150 mg 1 times / day multiple, oral (starting) RP2D Dose: 150 mg, 1 times / day Route: oral Route: multiple Dose: 150 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/33236943	unhealthy n = 15 Health Status: unhealthy Condition: Follicular lymphoma Sex: M+F Food Status: UNKNOWN Population Size: 15 Sources: https://pubmed.ncbi.nlm.nih.gov/33236943

Sourcing

Vendor/Aggregator	ID	URL
1PlusChem LLC	1P0037E4	https://www.1pchem.com/search?query=1P0037E4
AChemBlock	M22589	http://www.achemblock.com/catalogsearch/result/?q=M22589
AK Scientific	SYN5340	https://aksci.com/item_detail.php?cat=SYN5340
AK Scientific	X7535	https://aksci.com/item_detail.php?cat=X7535
AOBIOUS INC	AOB1912	http://aobious.com/aobious/search?search_query=AOB1912
Aceschem	ACF011785	https://www.aceschem.com/catalog/search.do?q=ACF011785
Ambeed	A204180	http://www.ambeed.com/search/Search.html?keyword=A204180
Angene	AGN-PC-0WA9V7	http://www.angenechemical.com/productshow/AGN-PC-0WA9V7.html
AstaTech	43102	http://astatechinc.com/CPSResult.php?CRNO=43102
BLD Pharm	BD225077	http://www.bldpharm.com/search/Search.html?keyword=BD225077
BOC Sciences	923564-51-6	http://www.bocsci.com/description.asp?cas=923564-51-6
Capot Chemical	16672	https://www.capotchem.com/search.do?q=16672
Cayman Chemical	11500	http://www.caymanchem.com/app/template/Product.vm/catalog/11500
Chem Scene	CS-0013	http://www.chemscene.com/goproductList/searchProductList?productObj=CS-0013
ChemShuttle	105149	https://www.chemshuttle.com/catalogsearch/result/?q=105149
Hairui	HR112571	http://www.hairuichem.com/en/product/search.do?q=HR112571
KeyOrganics	AS-16690	http://www.keyorganicsinc.com/bionet/catalogsearch/result?q=AS-16690
Matrix Scientific	145390	http://www.matrixscientific.com/145390.html
MedChem Express	HY-10087	https://www.medchemexpress.com/search.html?q=HY-10087&ft=&fa=&fp=
MolPort	MolPort-006-391-499	https://www.molport.com/shop/molecule-link/MolPort-006-391-499
Molnova	M16614	https://www.molnova.com/en/serch-list.html?keywords=M16614
MuseChem	R012099	https://www.musechem.com/product/R012099.html
Ryan Scientific	AWD_131-138	https://ryansci.com/products?q=AWD_131-138&list_q=&search_type=exact
Selleck Chemicals	S1001	http://www.selleckchem.com/search.html?searchDTO.searchParam=S1001
TargetMol	T2101	https://www.targetmol.com/search?keyword=T2101
Tetrahedron	TS75926	http://www.thsci.com/search.do?q=TS75926
Toronto Research Chemicals	A112500	https://www.trc-canada.com/product-detail/?CatNum=A112500
W&J PharmaChem	50C831899	http://wjpharmachem.com/new/searcht.php?keyword=50C831899
Wonderchem	WD070L2	http://www.wonder-chem.com/search.html?text=WD070L2
eMolecules	108761848	https://orderbb.emolecules.com/search/#?query=108761848
eMolecules	27515371	https://orderbb.emolecules.com/search/#?query=27515371
eMolecules	300470826	https://orderbb.emolecules.com/search/#?query=300470826
eNovation Chemicals	D210808	https://www.enovationchem.com/Products.asp?SEARCHTEXT=D210808&searchbtn.x=0&searchbtn.y=0
mcule	MCULE-1272682982	https://mcule.com/MCULE-1272682982/
mcule	MCULE-8985593038	https://mcule.com/MCULE-8985593038/

PubMed

Title	Date	PubMed
Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells.	1988 Sep 29	3262202
An informatics approach identifying markers of chemosensitivity in human cancer cell lines.	2000 Nov 1	11085534
A matter of life and death.	2002 Feb	12086884
Potential roles of antisense oligonucleotides in cancer therapy. The example of Bcl-2 antisense oligonucleotides.	2002 Nov	12445555
Novel therapies for chronic lymphocytic leukemia.	2004 Jun	15010151
An inhibitor of Bcl-2 family proteins induces regression of solid tumours.	2005 Jun 2	15902208
Discovery of an orally bioavailable small molecule inhibitor of prosurvival B-cell lymphoma 2 proteins.	2008 Nov 13	18841882
The Bcl-xL inhibitor, ABT-737, efficiently induces apoptosis and suppresses growth of hepatoma cells in combination with sorafenib.	2010 Oct	20799354
Vorinostat-induced apoptosis in mantle cell lymphoma is mediated by acetylation of proapoptotic BH3-only gene promoters.	2011 Jun 15	21652541
BCL2/BCL-X(L) inhibition induces apoptosis, disrupts cellular calcium homeostasis, and prevents platelet activation.	2011 Jun 30	21562047
Nrf2/p62 signaling in apoptosis resistance and its role in cadmium-induced carcinogenesis.	2014 Oct 10	25157103

Patents

Sample Use Guides

In Vivo Use Guide

Oral solution and tablets Phase 2a dosing under 21 day continuous dosing. 150 mg lead-in dose for 7-14 days followed by a 325 mg continuous once daily dose.

Route of Administration: Oral

In Vitro Use Guide

A wide range of cellular activity is observed with Navitoclax (ABT-263) having a 50% growth inhibition (EC50) of 110 nM against the most sensitive line (H146), whereas its activity in the least sensitive line (H82) results in an EC50 at 22 uM.

Substance Class	Chemical Created by `admin` on `Fri Dec 15 19:39:26 GMT 2023` Edited by `admin` on `Fri Dec 15 19:39:26 GMT 2023`
Record UNII	W8FZ00AY2S
Record Status	`Validated (UNII)`
Record Version

Download

Name

Type

Language

NAVITOCLAX DIHYDROCHLORIDE

Official Name

English

4-(4-((2-(4-CHLOROPHENYL)-5,5-DIMETHYLCYCLOHEX-1-EN-1-YL)METHYL)PIPERAZIN-1-YL)-N-((4- (((1R)-3-(MORPHOLIN-4-YL)-1-((PHENYLSULFANYL)METHYL)PROPYL)AMINO)-3-((TRIFLUOROMETHYL)SULFONYL)PHENYL)SULFONYL)BENZAMIDE DIHYDROCHLORIDE

Common Name

English

BENZAMIDE, 4-(4-((2-(4-CHLOROPHENYL)-5,5-DIMETHYL-1-CYCLOHEXEN-1-YL)METHYL)-1- PIPERAZINYL)-N-((4-(((1R)-3-(4-MORPHOLINYL)-1-((PHENYLTHIO)METHYL)PROPYL)AMINO)-3- ((TRIFLUOROMETHYL)SULFONYL)PHENYL)SULFONYL)-, HYDROCHLORIDE (1:2)

Common Name

English

Navitoclax dihydrochloride [WHO-DD]

Common Name

English

NAVITOCLAX DIHYDROCHLORIDE [USAN]

Common Name

English

A-855071.3

Code

English

4-(4-((2-(4-CHLOROPHENYL)-5,5-DIMETHYLCYCLOHEX-1-EN-1-YL)METHYL)PIPERAZIN-1-YL)-N-((4- (((2R)-4-(MORPHOLIN-4-YL)-1-(PHENYLSULFANYL)BUTAN-2-YL)AMINO)-3- ((TRIFLUOROMETHYL)SULFONYL)PHENYL)SULFONYL)BENZAMIDE DIHYDROCHLORIDE

Common Name

English

Classification Tree Code System Code

FDA ORPHAN DRUG

257408