LEXIBULIN

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C24H30N6O2
Molecular Weight	434.534
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CCC[C@H](NC1=NC(=NC=C1C)C2=CC(OC)=C(NC(=O)NCC)C=C2)C3=CC=CN=C3

InChI

InChIKey=MTJHLONVHHPNSI-IBGZPJMESA-N

InChI=1S/C24H30N6O2/c1-5-8-19(18-9-7-12-25-15-18)28-22-16(3)14-27-23(30-22)17-10-11-20(21(13-17)32-4)29-24(31)26-6-2/h7,9-15,19H,5-6,8H2,1-4H3,(H2,26,29,31)(H,27,28,30)/t19-/m0/s1

HIDE SMILES / InChI

Molecular Formula	C24H30N6O2
Molecular Weight	434.534
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/19887548
Curator's Comment: Description was created based on several sources, including http://eprints.whiterose.ac.uk/86822/ http://adisinsight.springer.com/drugs/800022992

CYT997 (Lexibulin) is a wholly synthetic compound that possesses highly potent cytotoxic activity in vitro through inhibition of microtubule polymerization. CYT997 (Lexibulin) is a potent microtubule polymerization inhibitor with IC50 of 10-100 nM in cancer cell lines. CYT997 (Lexibulin) blocks the cell cycle at the G(2)-M boundary, and Western blot analysis indicates an increase in phosphorylated Bcl-2, along with increased expression of cyclin B1. Caspase-3 activation is also observed in cells treated with CYT997 (Lexibulin) along with the generation of poly(ADP-ribose) polymerase. The compound possesses favorable pharmacokinetic properties, is orally bioavailable, and is efficacious per os in a range of in vivo cancer models, including some refractory to paclitaxel treatment. CYT997 (Lexibulin) exhibits vascular disrupting activity as measured in vitro by effects on the permeability of human umbilical vein endothelial cell monolayers, and in vivo by effects on tumor blood flow. CYT997 (Lexibulin) possesses a useful combination of pharmacologic and pharmacokinetic properties having considerable potential as a novel anticancer agent. Lexibulin was being developed by YM BioSciences as a vascular-disrupting agent (VDA) for the potential treatment of cancer, it was in phase II development on YM BioSciences ' pipeline. It appears that the development of lexibulin has been discontinued.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
KMS-12-PE 1 Target ID: CHEMBL2366257 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19907921	Inhibitor 8297	59.0 nM [IC50]
LP-1 1 Target ID: CHEMBL2366066 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19907921	Inhibitor 8297	83.5 nM [IC50]
microtubule polymerization 20 Target ID: GO:0046785 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19887548 \| https://www.ncbi.nlm.nih.gov/pubmed/19616947	Inhibitor 8297

Conditions

Condition	Modality	Targets	Highest Phase	Product
Glioblastoma multiforme 30 Sources: https://clinicaltrials.gov/ct2/show/NCT00650949	Primary		Phase II 1132	Unknown Approved Use Unknown
Relapsed and refractory multiple myeloma 1 Sources: https://clinicaltrials.gov/ct2/show/NCT00664378	Primary		Phase II 1132	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
376.2 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22451157	164 mg/m² 1 times / 2 weeks multiple, oral dose: 164 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:		LEXIBULIN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
320 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22451157	164 mg/m² single, oral dose: 164 mg/m² route of administration: Oral experiment type: SINGLE co-administered:		LEXIBULIN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

AUC

Value	Dose	Analyte	Population
5640 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20733579	358 mg/m² 1 times / 3 weeks multiple, intravenous dose: 358 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:	LEXIBULIN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
1315 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22451157	164 mg/m² 1 times / 2 weeks multiple, oral dose: 164 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	LEXIBULIN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
941.5 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22451157	164 mg/m² single, oral dose: 164 mg/m² route of administration: Oral experiment type: SINGLE co-administered:	LEXIBULIN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

T_1/2

Value	Dose	Analyte	Population
4.6 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/20733579	358 mg/m² 1 times / 3 weeks multiple, intravenous dose: 358 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:	LEXIBULIN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
2.44 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22451157	164 mg/m² 1 times / 2 weeks multiple, oral dose: 164 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	LEXIBULIN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
4.28 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/22451157	164 mg/m² single, oral dose: 164 mg/m² route of administration: Oral experiment type: SINGLE co-administered:	LEXIBULIN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

Doses

Dose	Population	Adverse events
164 mg/m2 1 times / 2 weeks multiple, oral MTD Dose: 164 mg/m2, 1 times / 2 weeks Route: oral Route: multiple Dose: 164 mg/m2, 1 times / 2 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/22451157 Page: p.130	unhealthy, ADULT n = 6 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/22451157 Page: p.130	DLT: Hypoxia, Fatigue... Other AEs: Anaemia... Dose limiting toxicities: Hypoxia (grade 3, 16.7%) Fatigue (grade 3, 16.7%) Fatigue (grade 3, 16.7%) Other AEs: Anaemia (grade 3, 16.7%) Sources: https://pubmed.ncbi.nlm.nih.gov/22451157 Page: p.130
358 mg/m2 1 times / 3 weeks multiple, intravenous MTD Dose: 358 mg/m2, 1 times / 3 weeks Route: intravenous Route: multiple Dose: 358 mg/m2, 1 times / 3 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/20733579 Page: p.600	unhealthy, ADULT n = 3 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/20733579 Page: p.600	DLT: Hypoxia, QT interval prolonged... Other AEs: Dyspnea... Dose limiting toxicities: Hypoxia (grade 3, 33.3%) QT interval prolonged (grade 3, 33.3%) Dyspnea (grade 4, 33.3%) Other AEs: Dyspnea (grade 3, 33.3%) Sources: https://pubmed.ncbi.nlm.nih.gov/20733579 Page: p.600

AEs

AE	Significance	Dose	Population
Anaemia	grade 3, 16.7%	164 mg/m2 1 times / 2 weeks multiple, oral MTD Dose: 164 mg/m2, 1 times / 2 weeks Route: oral Route: multiple Dose: 164 mg/m2, 1 times / 2 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/22451157 Page: p.130	unhealthy, ADULT n = 6 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/22451157 Page: p.130
Fatigue	grade 3, 16.7% DLT	164 mg/m2 1 times / 2 weeks multiple, oral MTD Dose: 164 mg/m2, 1 times / 2 weeks Route: oral Route: multiple Dose: 164 mg/m2, 1 times / 2 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/22451157 Page: p.130	unhealthy, ADULT n = 6 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/22451157 Page: p.130
Fatigue	grade 3, 16.7% DLT, Disc. AE	164 mg/m2 1 times / 2 weeks multiple, oral MTD Dose: 164 mg/m2, 1 times / 2 weeks Route: oral Route: multiple Dose: 164 mg/m2, 1 times / 2 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/22451157 Page: p.130	unhealthy, ADULT n = 6 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/22451157 Page: p.130
Hypoxia	grade 3, 16.7% DLT, Disc. AE	164 mg/m2 1 times / 2 weeks multiple, oral MTD Dose: 164 mg/m2, 1 times / 2 weeks Route: oral Route: multiple Dose: 164 mg/m2, 1 times / 2 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/22451157 Page: p.130	unhealthy, ADULT n = 6 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: FASTED Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/22451157 Page: p.130
Dyspnea	grade 3, 33.3%	358 mg/m2 1 times / 3 weeks multiple, intravenous MTD Dose: 358 mg/m2, 1 times / 3 weeks Route: intravenous Route: multiple Dose: 358 mg/m2, 1 times / 3 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/20733579 Page: p.600	unhealthy, ADULT n = 3 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/20733579 Page: p.600
QT interval prolonged	grade 3, 33.3% DLT	358 mg/m2 1 times / 3 weeks multiple, intravenous MTD Dose: 358 mg/m2, 1 times / 3 weeks Route: intravenous Route: multiple Dose: 358 mg/m2, 1 times / 3 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/20733579 Page: p.600	unhealthy, ADULT n = 3 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/20733579 Page: p.600
Hypoxia	grade 3, 33.3% DLT, Disc. AE	358 mg/m2 1 times / 3 weeks multiple, intravenous MTD Dose: 358 mg/m2, 1 times / 3 weeks Route: intravenous Route: multiple Dose: 358 mg/m2, 1 times / 3 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/20733579 Page: p.600	unhealthy, ADULT n = 3 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/20733579 Page: p.600
Dyspnea	grade 4, 33.3% DLT, Disc. AE	358 mg/m2 1 times / 3 weeks multiple, intravenous MTD Dose: 358 mg/m2, 1 times / 3 weeks Route: intravenous Route: multiple Dose: 358 mg/m2, 1 times / 3 weeks Sources: https://pubmed.ncbi.nlm.nih.gov/20733579 Page: p.600	unhealthy, ADULT n = 3 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/20733579 Page: p.600

Overview

CYP3A4	CYP2C9	CYP2D6	hERG

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
P-gp 1461

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
P-gp 1650	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1346987#sid=174007338	inconclusive [IC50 0.0008 uM]

PubMed

Title	Date	PubMed
The microtubule depolymerizing agent CYT997 effectively kills acute myeloid leukemia cells via activation of caspases and inhibition of PI3K/Akt/mTOR pathway proteins.	2013 Aug	24137178
Phase I, pharmacokinetic and pharmacodynamic evaluation of CYT997, an orally-bioavailable cytotoxic and vascular-disrupting agent.	2013 Feb	22451157
Structures of a diverse set of colchicine binding site inhibitors in complex with tubulin provide a rationale for drug discovery.	2016 Jan	26462166

Patents

Sample Use Guides

In Vivo Use Guide

Escalating doses (100mg/m^2 to 150mg/m^2), 24-hour intravenous infusion on Day 2 of a 21-day cycle

Route of Administration: Intravenous

In Vitro Use Guide

Treatment of NCI-H929 and U266 under standard culture conditions with 50 or 100 nM CYT997 (Lexibulin) for 72 h demonstrated almost complete cytostasis

Substance Class	Chemical Created by `admin` on `Sat Dec 16 16:56:20 GMT 2023` Edited by `admin` on `Sat Dec 16 16:56:20 GMT 2023`
Record UNII	2GTU230HA1
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

LEXIBULIN

Official Name

English

CYT 997

Code

English

CYT-997

Code

English

LEXIBULIN [USAN]

Common Name

English

1-ETHYL-3-(2-METHOXY-4-(5-METHYL-4-(((1S)-1-(PYRIDIN-3-YL)BUTYL)AMINO)PYRIMIDIN-2-YL)PHENYL)UREA

Systematic Name

English

UREA, N-ETHYL-N'-(2-METHOXY-4-(5-METHYL-4-(((1S)-1-(3-PYRIDINYL)BUTYL)AMINO)-2-PYRIMIDINYL)PHENYL)-

Systematic Name

English

CYT997

Code

English

lexibulin [INN]

Common Name

English

Lexibulin [WHO-DD]

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C25974