ZOSUQUIDAR

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C32H31F2N3O2
Molecular Weight	527.6042
Optical Activity	UNSPECIFIED
Defined Stereocenters	4 / 4
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

[H][C@]12C3=CC=CC=C3[C@H](N4CCN(C[C@@H](O)COC5=CC=CC6=NC=CC=C56)CC4)C7=CC=CC=C7[C@@]1([H])C2(F)F

InChI

InChIKey=IHOVFYSQUDPMCN-DBEBIPAYSA-N

InChI=1S/C32H31F2N3O2/c33-32(34)29-22-7-1-3-9-24(22)31(25-10-4-2-8-23(25)30(29)32)37-17-15-36(16-18-37)19-21(38)20-39-28-13-5-12-27-26(28)11-6-14-35-27/h1-14,21,29-31,38H,15-20H2/t21-,29-,30+,31-/m1/s1

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/8797588
Curator's Comment: Description was created based on several sources, including

Zosuquidar (LY-335979) is an experimental antineoplastic drug. It is is a potent modulator of P-glycoprotein-mediated multi-drug resistance with Ki of 60 nM. Zosuqidar was initially characterized by Syntex Corporation, which was acquired by Roche in 1990. Roche licensed the drug to Eli Lilly in 1997. It was granted orphan drug status by the FDA in 2006 for AML. Zosuquidar Trihydrochloride had been in phase III clinical trials by Kanisa Pharmaceuticals for the treatment of acute myeloid leukaemia. However, this research has been discontinued.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
P-glycoprotein 1 54 Target ID: CHEMBL4302 Sources: https://www.ncbi.nlm.nih.gov/pubmed/8797588	Inhibitor 8297		60.0 nM [Ki]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Acute myeloid leukemia 136 Sources: http://adisinsight.springer.com/drugs/800005159 https://clinicaltrials.gov/ct2/show/NCT00046930	Primary		Phase III 656	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
0.31 μM EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15809877	300 mg/m² 2 times / day multiple, oral dose: 300 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered: VINORELBINE	VINORELBINE	ZOSUQUIDAR plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: FASTED

AUC

Value	Dose	Co-administered	Analyte	Population
1111 μg × h/L EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15809877	300 mg/m² 2 times / day multiple, oral dose: 300 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered: VINORELBINE	VINORELBINE	ZOSUQUIDAR plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: FASTED

T_1/2

Value	Dose	Co-administered	Analyte	Population
16.7 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/15809877	300 mg/m² 2 times / day multiple, oral dose: 300 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered: VINORELBINE	VINORELBINE	ZOSUQUIDAR plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: FASTED

Doses

Dose	Population	Adverse events
300 mg/m2 2 times / day multiple, oral MTD Dose: 300 mg/m2, 2 times / day Route: oral Route: multiple Dose: 300 mg/m2, 2 times / day Co-administed with:: vinorelbine(22.5 mg/m2 IV weekly for 3 weeks every 28 days) Sources: https://pubmed.ncbi.nlm.nih.gov/15809877 Page: p.157, 158	unhealthy, ADULT n = 3 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/15809877 Page: p.157, 158	DLT: febrile neutropeni... Other AEs: Stomatitis, Neutropenia... Dose limiting toxicities: febrile neutropeni (grade 4, 33.3%) Other AEs: Stomatitis (grade 3) Neutropenia (grade 3) Sources: https://pubmed.ncbi.nlm.nih.gov/15809877 Page: p.157, 158

AEs

AE	Significance	Dose	Population
Neutropenia	grade 3	300 mg/m2 2 times / day multiple, oral MTD Dose: 300 mg/m2, 2 times / day Route: oral Route: multiple Dose: 300 mg/m2, 2 times / day Co-administed with:: vinorelbine(22.5 mg/m2 IV weekly for 3 weeks every 28 days) Sources: https://pubmed.ncbi.nlm.nih.gov/15809877 Page: p.157, 158	unhealthy, ADULT n = 3 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/15809877 Page: p.157, 158
Stomatitis	grade 3	300 mg/m2 2 times / day multiple, oral MTD Dose: 300 mg/m2, 2 times / day Route: oral Route: multiple Dose: 300 mg/m2, 2 times / day Co-administed with:: vinorelbine(22.5 mg/m2 IV weekly for 3 weeks every 28 days) Sources: https://pubmed.ncbi.nlm.nih.gov/15809877 Page: p.157, 158	unhealthy, ADULT n = 3 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/15809877 Page: p.157, 158
febrile neutropeni	grade 4, 33.3% DLT	300 mg/m2 2 times / day multiple, oral MTD Dose: 300 mg/m2, 2 times / day Route: oral Route: multiple Dose: 300 mg/m2, 2 times / day Co-administed with:: vinorelbine(22.5 mg/m2 IV weekly for 3 weeks every 28 days) Sources: https://pubmed.ncbi.nlm.nih.gov/15809877 Page: p.157, 158	unhealthy, ADULT n = 3 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/15809877 Page: p.157, 158

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1587	inhibitor 1767	inhibitor 1852

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2B6 810 MRP1 106 BCRP 699 CYP1A2 1524 P-gp 1461 MRP2 383	CYP3A 191

Drug as perpetrator

Target	Modality	Activity
CYP1A2 1692	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/10411602/	likely [Inhibition 50 uM]
BCRP 773	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/22359351/	no
MRP1 172	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/10411602/	no
MRP2 475	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/10411602/	no
CYP2D6 1891	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645840#sid=440681697	yes [IC50 10.684 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/10411602/ \| https://pubchem.ncbi.nlm.nih.gov/bioassay/1645842#sid=440681697	yes [Ki 12.3 uM]
CYP2B6 1001	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/10411602/	yes [Ki 25.3 uM]
CYP3A4 1925	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/10411602/	yes [Ki 3.8 uM]
P-gp 1650	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/29440498/ \| https://pubmed.ncbi.nlm.nih.gov/10411602/	yes

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
CYP3A 191	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/9443851/	likely

PubMed

Title	Date	PubMed
Bioanalysis of zosuquidar trihydrochloride (LY335979) in small volumes of human and murine plasma by ion-pairing reversed-phase high-performance liquid chromatography.	2003 Dec 5	14630360
A population pharmacokinetic model for paclitaxel in the presence of a novel P-gp modulator, Zosuquidar Trihydrochloride (LY335979).	2003 Jul	12848775
Modulation of drug resistance transporters as a strategy for treating myelodysplastic syndrome.	2004 Dec	15494300
A Phase I trial of a potent P-glycoprotein inhibitor, zosuquidar trihydrochloride (LY335979), administered intravenously in combination with doxorubicin in patients with advanced malignancy.	2004 May 15	15161679
Phase I study of docetaxel in combination with the P-glycoprotein inhibitor, zosuquidar, in resistant malignancies.	2004 Nov 1	15534095
Phase I study of the multidrug resistance inhibitor zosuquidar administered in combination with vinorelbine in patients with advanced solid tumours.	2005 Aug	15809877
Phase I study of pegylated liposomal doxorubicin and the multidrug-resistance modulator, valspodar.	2005 Jul 11	15942626
Potential for improvement of docetaxel-based chemotherapy: a pharmacological review.	2005 Jul 25	16012521
Dependence of nelfinavir brain uptake on dose and tissue concentrations of the selective P-glycoprotein inhibitor zosuquidar in rats.	2006 Apr	16434546
Pharmacological strategies for overcoming multidrug resistance.	2006 Jul	16842217
Influence of breast cancer resistance protein (Abcg2) and p-glycoprotein (Abcb1a) on the transport of imatinib mesylate (Gleevec) across the mouse blood-brain barrier.	2007 Sep	17696988
Inhibition of P-glycoprotein activity at the primate blood-brain barrier increases the distribution of nelfinavir into the brain but not into the cerebrospinal fluid.	2007 Sep	17591677
Modulation of the brain distribution of imatinib and its metabolites in mice by valspodar, zosuquidar and elacridar.	2007 Sep	17380257
Gateways to clinical trials.	2008 Apr	18597009
Resistance to chemotherapy: new treatments and novel insights into an old problem.	2008 Aug 5	18665178
Zosuquidar restores drug sensitivity in P-glycoprotein expressing acute myeloid leukemia (AML).	2008 Feb 13	18271955
ABC transporters and the accumulation of imatinib and its active metabolite CGP74588 in rat C6 glioma cells.	2008 Mar	18337118
Drug transporters: recent advances concerning BCRP and tyrosine kinase inhibitors.	2008 Mar 11	18253130
Organic anion-transporting polypeptide 1B1 mediates transport of Gimatecan and BNP1350 and can be inhibited by several classic ATP-binding cassette (ABC) B1 and/or ABCG2 inhibitors.	2009 Apr	19139163
A phase I trial of continuous infusion of the multidrug resistance inhibitor zosuquidar with daunorubicin and cytarabine in acute myeloid leukemia.	2009 Aug	19108889
Influence of the dual ABCB1 and ABCG2 inhibitor tariquidar on the disposition of oral imatinib in mice.	2009 Jul 10	19591692
Leukemic blast and natural killer cell P-glycoprotein function and inhibition in a clinical trial of zosuquidar infusion in acute myeloid leukemia.	2009 Jun	18976810
P-gp activity is a critical resistance factor against AVE9633 and DM4 cytotoxicity in leukaemia cell lines, but not a major mechanism of chemoresistance in cells from acute myeloid leukaemia patients.	2009 Jun 23	19549303
A randomized, placebo-controlled, double-blind phase 2 study of docetaxel compared to docetaxel plus zosuquidar (LY335979) in women with metastatic or locally recurrent breast cancer who have received one prior chemotherapy regimen.	2009 Sep	19241078
Challenges in treating older patients with acute myeloid leukemia.	2010	20628485
Gateways to clinical trials.	2010 Jan-Feb	20383346
Zosuquidar, a novel modulator of P-glycoprotein, does not improve the outcome of older patients with newly diagnosed acute myeloid leukemia: a randomized, placebo-controlled trial of the Eastern Cooperative Oncology Group 3999.	2010 Nov 18	20716770
PXR-mediated induction of P-glycoprotein by anticancer drugs in a human colon adenocarcinoma-derived cell line.	2010 Sep	20041327

Patents

Sample Use Guides

In Vivo Use Guide

Zosuquidar 550 mg/day by continuous intravenous infusion through a central venous catheter over approximately 6 hours on days 1, 2, and 3.

Route of Administration: Intravenous

In Vitro Use Guide

Zosuquidar (LY-335979) alone shows the cytotoxicity to drug-sensitive and MDR cell lines with IC50 ranging from 6 uM-16 uM and produces its ability to completely reverse the resistance of the oncolytics (vinblastine, doxorubicin, or etoposide) to the MDR cell lines P388/ADR, MCF7/ADR, 2780AD, or UCLA-P3.003VLB at concentration of 0.1 and 0.5 uM

Name

Type

Language

ZOSUQUIDAR

Official Name

English

ZOSUQUIDAR [MI]

Common Name

English

zosuquidar [INN]

Common Name

English

Zosuquidar [WHO-DD]

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C1744