XK-469

Details

Stereochemistry	RACEMIC
Molecular Formula	C17H12ClN2O4.Na
Molecular Weight	366.731
Optical Activity	( + / - )
Defined Stereocenters	0 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

[Na+].CC(OC1=CC=C(OC2=NC3=CC(Cl)=CC=C3N=C2)C=C1)C([O-])=O

InChI

InChIKey=OJENKXNXJPNEPU-UHFFFAOYSA-M

InChI=1S/C17H13ClN2O4.Na/c1-10(17(21)22)23-12-3-5-13(6-4-12)24-16-9-19-14-7-2-11(18)8-15(14)20-16;/h2-10H,1H3,(H,21,22);/q;+1/p-1

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/10518594 | https://www.ncbi.nlm.nih.gov/pubmed/18650079 | https://www.ncbi.nlm.nih.gov/pubmed/17103044

XK-469 (NSC 697887) is a synthetic quinoxaline phenoxypropionic acid derivative that possesses unusual solid tumor selectivity and activity against multidrug-resistant cancer cells. XK469 acts as a selective topoisomerase IIβ inhibitor. Other proposed mechanisms include XK469-induced inhibition of cyclin B1 ubiquitination and apoptosis via binding of the peripheral benzodiazepine receptor. A phase I study was performed to determine the safety and pharmacokinetics of XK469R in patients with various neoplasms.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
DNA topoisomerase II beta 14 Target ID: CHEMBL3396 Sources: https://www.ncbi.nlm.nih.gov/pubmed/10518594 \| https://www.ncbi.nlm.nih.gov/pubmed/10518594	Inhibitor 8297		160.0 µM [IC50]
Cyclin B1 ubiquitination 2 Target ID: Cyclin B1 ubiquitination Sources: https://www.ncbi.nlm.nih.gov/pubmed/11774253	Inhibitor 8297

Conditions

Condition	Modality	Targets	Highest Phase	Product
Solid tumors 145 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17103044	Primary		Phase I 428	Unknown Approved Use Unknown

C_max

Value	Dose	Analyte	Population
152 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17103044	260 mg/m² 1 times / day multiple, intravenous dose: 260 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:	XK-469 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
84.6 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17103044	260 mg single, intravenous dose: 260 mg route of administration: Intravenous experiment type: SINGLE co-administered:	XK-469 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
264 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/18425419	2750 mg 3 times / week multiple, intravenous dose: 2750 mg route of administration: Intravenous experiment type: MULTIPLE co-administered:	XK-469 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
211 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/18425419	1750 mg 3 times / week multiple, intravenous dose: 1750 mg route of administration: Intravenous experiment type: MULTIPLE co-administered:	XK-469 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Analyte	Population
2312 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17103044	260 mg/m² 1 times / day multiple, intravenous dose: 260 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:	XK-469 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
955 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17103044	260 mg single, intravenous dose: 260 mg route of administration: Intravenous experiment type: SINGLE co-administered:	XK-469 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
14863 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/18425419	2750 mg 3 times / week multiple, intravenous dose: 2750 mg route of administration: Intravenous experiment type: MULTIPLE co-administered:	XK-469 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
9150 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/18425419	1750 mg 3 times / week multiple, intravenous dose: 1750 mg route of administration: Intravenous experiment type: MULTIPLE co-administered:	XK-469 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

T_1/2

Value	Dose	Analyte	Population
53.9 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17103044	260 mg/m² 1 times / day multiple, intravenous dose: 260 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:	XK-469 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
55 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/18425419	2750 mg 3 times / week multiple, intravenous dose: 2750 mg route of administration: Intravenous experiment type: MULTIPLE co-administered:	XK-469 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
45 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/18425419	1750 mg 3 times / week multiple, intravenous dose: 1750 mg route of administration: Intravenous experiment type: MULTIPLE co-administered:	XK-469 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
0.7% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17103044	unknown, unknown		XK-469 plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

Doses

Dose	Population	Adverse events
2750 mg 3 times / 3 weeks multiple, intravenous (unknown) Highest studied dose Dose: 2750 mg, 3 times / 3 weeks Route: intravenous Route: multiple Dose: 2750 mg, 3 times / 3 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/18425419/	unhealthy n = 14 Health Status: unhealthy Condition: acute leukemia Sex: M+F Food Status: UNKNOWN Population Size: 14 Sources: https://pubmed.ncbi.nlm.nih.gov/18425419/	DLT: Hyperbilirubinemia, Mucositis... Other AEs: Vomiting, Diarrhea... Dose limiting toxicities: Hyperbilirubinemia (1 pt) Mucositis (grade 3, 2 patients) Other AEs: Vomiting (grade 2, 1 pt) Diarrhea (grade 3, 1 pt) Alopecia (grade 1, 1 pt) Rash (grade 3, 1 pt) Anorexia (grade 3, 1 pt) Nausea (grade 3, 1 pt) Sources: https://pubmed.ncbi.nlm.nih.gov/18425419/
260 mg/m2 1 times / day multiple, intravenous MTD Dose: 260 mg/m2, 1 times / day Route: intravenous Route: multiple Dose: 260 mg/m2, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/17103044/	unhealthy n = 6 Health Status: unhealthy Condition: solid tumours Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/17103044/	DLT: neutropenia... Other AEs: Nausea and vomiting, Fatigue... Dose limiting toxicities: neutropenia (grade 4, 1 pt) Other AEs: Nausea and vomiting (grade 1, 4 patients) Fatigue (grade 3, 1 pt) anemia (grade 2, 1 pt) Sources: https://pubmed.ncbi.nlm.nih.gov/17103044/
1750 mg 3 times / 3 weeks multiple, intravenous (total daily dose) RP2D Dose: 1750 mg, 3 times / 3 weeks Route: intravenous Route: multiple Dose: 1750 mg, 3 times / 3 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/18425419/	unhealthy n = 12 Health Status: unhealthy Condition: acute leukemia Sex: M+F Food Status: UNKNOWN Population Size: 12 Sources: https://pubmed.ncbi.nlm.nih.gov/18425419/	Other AEs: Diarrhea, Aspartate aminotransferase increase... Other AEs: Diarrhea (grade 1, 3 patients) Aspartate aminotransferase increase (grade 2, 1 pt) Alanine aminotransferase increase (grade 2, 1 pt) Anorexia (grade 1, 2 patients) Mucositis (grade 1, 2 patients) Rash (grade 1, 1 pt) Alopecia (grade 2, 1 pt) Vomiting (grade 1, 4 patients) Indigestion (grade 1, 1 pt) Nausea (grade 2, 1 pt) Dysgeusia (grade 1, 1 pt) Sources: https://pubmed.ncbi.nlm.nih.gov/18425419/
2200 mg 3 times / 3 weeks multiple, intravenous Studied dose Dose: 2200 mg, 3 times / 3 weeks Route: intravenous Route: multiple Dose: 2200 mg, 3 times / 3 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/18425419/	unhealthy n = 14 Health Status: unhealthy Condition: acute leukemia Sex: M+F Food Status: UNKNOWN Population Size: 14 Sources: https://pubmed.ncbi.nlm.nih.gov/18425419/	DLT: mucositis... Other AEs: Anorexia, Alopecia... Dose limiting toxicities: mucositis (1 pt) Other AEs: Anorexia (grade 2, 1 pt) Alopecia (grade 2, 1 pt) Nausea (grade 3, 1 pt) Aspartate aminotransferase increase (grade 1, 1 pt) Vomiting (grade 2, 2 patients) Rash (grade 2, 1 pt) Sources: https://pubmed.ncbi.nlm.nih.gov/18425419/
346 mg/m2 1 times / day multiple, intravenous (unknown) Studied dose Dose: 346 mg/m2, 1 times / day Route: intravenous Route: multiple Dose: 346 mg/m2, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/17103044/	unhealthy n = 2 Health Status: unhealthy Condition: solid tumours Sex: unknown Food Status: UNKNOWN Population Size: 2 Sources: https://pubmed.ncbi.nlm.nih.gov/17103044/	DLT: Febrile neutropenia, infection... Other AEs: anemia... Dose limiting toxicities: Febrile neutropenia (1 pt) infection (grade 3, 1 pt) Other AEs: anemia (grade 1, 1 pt) Sources: https://pubmed.ncbi.nlm.nih.gov/17103044/

AEs

PubMed

Title	Date	PubMed
XK469, a selective topoisomerase IIbeta poison.	1999 Oct 12	10518594
2-[4-(7-chloro-2-quinoxalinyloxy)phenoxy]-propionic acid (XK469) inhibition of topoisomerase IIbeta is not sufficient for therapeutic response in human Waldenstrom's macroglobulinemia xenograft model.	2002 Dec	12516964
II. Synthesis and biological evaluation of some bioisosteres and congeners of the antitumor agent, 2-(4-[(7-chloro-2-quinoxalinyl)oxy]phenoxy)propionic acid (XK469).	2002 Jul 4	12086498
Preclinical evaluation of 2-[4-(7-chloro-2-quinoxalinyloxy)phenoxy]-propionic acid as a modulator of etoposide in human Waldenstrom's macroglobulinemia xenograft model.	2003 Nov 15	14654565
Part 3: synthesis and biological evaluation of some analogs of the antitumor agents, 2-{4-[(7-chloro-2-quinoxalinyl)oxy]phenoxy}propionic acid, and 2-{4-[(7-bromo-2-quinolinyl)oxy]phenoxy}propionic acid.	2005 Feb 15	15670915
Synthetic modification of the 2-oxypropionic acid moiety in 2-{4-[(7-chloro-2-quinoxalinyl)oxy]phenoxy}propionic acid (XK469), and consequent antitumor effects. Part 4.	2005 Jun 2	15911307
Synthesis and biological evaluation of conformationally constrained analogs of the antitumor agents XK469 and SH80. Part 5.	2006 Apr 1	16337128
The role of autophagy in the death of L1210 leukemia cells initiated by the new antitumor agents, XK469 and SH80.	2007 Jan	17237296

Patents

Sample Use Guides

In Vivo Use Guide

XK469 was administered on days 1–5 of a 21 day cycle. Dose 260 mg/m2/day was defined as the maximum tolerated dose.

Route of Administration: Intravenous

In Vitro Use Guide

Induction of the Bax protein was insignificant when cells were exposed to 2 uM XK469, and there was no down-regulation of the Bcl-2 protein at 48 or 72 h. However, 5 uM XK469 induced Bax protein expression by 48 and 72 h and caused a decrease in constitutive levels of Bcl-2 by 72 h compared with control untreated cells. The Bax:Bcl-2 ratio was 11-fold in favor of Bax with 5 uM XK469.

Name

Type

Language

XK-469

Common Name

English

PROPANOIC ACID, 2-(4-((7-CHLORO-2-QUINOXALINYL)OXY)PHENOXY)-, SODIUM SALT

Systematic Name

English

XK 469 [WHO-DD]

Common Name

English

NSC-656889

Code

English

XB-469

Common Name

English

PROPANOIC ACID, 2-(4-((7-CHLORO-2-QUINOXALINYL)OXY)PHENOXY)-, SODIUM SALT, (±)-

Common Name

English

Code System Code Type Description

EPA CompTox

DTXSID70935673