VERUBULIN HYDROCHLORIDE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C17H17N3O.ClH
Molecular Weight	315.797
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

Cl.COC1=CC=C(C=C1)N(C)C2=NC(C)=NC3=CC=CC=C23

InChI

InChIKey=VYUWDIKZJLOZJL-UHFFFAOYSA-N

InChI=1S/C17H17N3O.ClH/c1-12-18-16-7-5-4-6-15(16)17(19-12)20(2)13-8-10-14(21-3)11-9-13;/h4-11H,1-3H3;1H

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	C17H17N3O
Molecular Weight	279.3364
Charge	0
Count

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

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/17575155
Curator's Comment: description was created based on several sources, including: http://adisinsight.springer.com/drugs/800022153 | http://www.prnewswire.com/news-releases/new-data-suggests-improved-tumor-response-for-the-combination-of-azixa-and-immune-checkpoint-inhibitors-in-the-treatment-of-cancer-300291030.html

Veribulin is a novel microtubule destabilizer that both functions as a potent cytotoxin and acts as a vascular disrupting agent (VDA). It binds to the same (or nearby) sites on β-tubulin as colchicine. It is capable of evading multidrug resistance pumps and, thus, achieves high CNS concentrations. It is efficacious in multiple xenograft models without CNS toxicity. Veribulin had previously demonstrated pre-clinical and clinical activity in multiple tumor types. Veribulin is in phase II clinical trial for the treatment of Glioblastoma and Malignant melanoma.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Tubulin beta 2 Target ID: Tubulin beta Sources: https://www.ncbi.nlm.nih.gov/pubmed/17575155	Binding Agent 1064

Conditions

Condition	Modality	Highest Phase	Product
Glioblastoma multiforme 30 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24740196	Primary	Phase II 1132	Unknown Approved Use Unknown
Melanoma 88 Sources: http://adisinsight.springer.com/drugs/800022153 https://clinicaltrials.gov/ct2/show/NCT00609011	Primary	Phase II 1132	Unknown Approved Use Unknown
Solid tumors 145 Sources: https://www.ncbi.nlm.nih.gov/pubmed/21159616 http://www.prnewswire.com/news-releases/new-data-suggests-improved-tumor-response-for-the-combination-of-azixa-and-immune-checkpoint-inhibitors-in-the-treatment-of-cancer-300291030.html	Primary	Phase I 428	Unknown Approved Use Unknown

C_max

Value	Dose	Analyte	Population
21.3 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21159616	3.3 mg/m² 1 times / week multiple, intravenous dose: 3.3 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:	VERUBULIN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
30.7 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21159616	3.9 mg/m² 1 times / week multiple, intravenous dose: 3.9 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:	VERUBULIN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
62 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21159616	4.5 mg/m² 1 times / week multiple, intravenous dose: 4.5 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:	VERUBULIN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Analyte	Population
116.8 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21159616	3.3 mg/m² 1 times / week multiple, intravenous dose: 3.3 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:	VERUBULIN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
139.3 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21159616	3.9 mg/m² 1 times / week multiple, intravenous dose: 3.9 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:	VERUBULIN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
183.6 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21159616	4.5 mg/m² 1 times / week multiple, intravenous dose: 4.5 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:	VERUBULIN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

T_1/2

Value	Dose	Analyte	Population
6.4 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21159616	3.3 mg/m² 1 times / week multiple, intravenous dose: 3.3 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:	VERUBULIN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
7.5 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21159616	3.9 mg/m² 1 times / week multiple, intravenous dose: 3.9 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:	VERUBULIN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN
5.7 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21159616	4.5 mg/m² 1 times / week multiple, intravenous dose: 4.5 mg/m² route of administration: Intravenous experiment type: MULTIPLE co-administered:	VERUBULIN plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

Doses

Dose	Population	Adverse events
4.5 mg/m2 1 times / week multiple, intravenous Highest studied dose Dose: 4.5 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 4.5 mg/m2, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/21159616 Page: p.3413	unhealthy, ADULT n = 7 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 7 Sources: https://pubmed.ncbi.nlm.nih.gov/21159616 Page: p.3413	DLT: Myocardial infarction... Dose limiting toxicities: Myocardial infarction (grade 3, 14.3%) Sources: https://pubmed.ncbi.nlm.nih.gov/21159616 Page: p.3413
3.3 mg/m2 1 times / week multiple, intravenous MTD Dose: 3.3 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 3.3 mg/m2, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/21159616 Page: p.3413	unhealthy, ADULT n = 13 Health Status: unhealthy Condition: cance Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 13 Sources: https://pubmed.ncbi.nlm.nih.gov/21159616 Page: p.3413	Sources: https://pubmed.ncbi.nlm.nih.gov/21159616 Page: p.3413
3.3 mg/m2 1 times / week multiple, intravenous MTD Dose: 3.3 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 3.3 mg/m2, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/24740196 Page: p.338	unhealthy, ADULT n = 31 Health Status: unhealthy Condition: glioblastoma Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 31 Sources: https://pubmed.ncbi.nlm.nih.gov/24740196 Page: p.338	Disc. AE: Myocardial infarction... AEs leading to discontinuation/dose reduction: Myocardial infarction (grade 4, 3.2%) Sources: https://pubmed.ncbi.nlm.nih.gov/24740196 Page: p.338
3.9 mg/m2 1 times / week multiple, intravenous Studied dose Dose: 3.9 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 3.9 mg/m2, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/21159616 Page: p.3413	unhealthy, ADULT n = 6 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/21159616 Page: p.3413	DLT: Myocardial infarction... Dose limiting toxicities: Myocardial infarction (grade 3, 16.7%) Sources: https://pubmed.ncbi.nlm.nih.gov/21159616 Page: p.3413

AEs

AE	Significance	Dose	Population
Myocardial infarction	grade 3, 14.3% DLT	4.5 mg/m2 1 times / week multiple, intravenous Highest studied dose Dose: 4.5 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 4.5 mg/m2, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/21159616 Page: p.3413	unhealthy, ADULT n = 7 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 7 Sources: https://pubmed.ncbi.nlm.nih.gov/21159616 Page: p.3413
Myocardial infarction	grade 4, 3.2% Disc. AE	3.3 mg/m2 1 times / week multiple, intravenous MTD Dose: 3.3 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 3.3 mg/m2, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/24740196 Page: p.338	unhealthy, ADULT n = 31 Health Status: unhealthy Condition: glioblastoma Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 31 Sources: https://pubmed.ncbi.nlm.nih.gov/24740196 Page: p.338
Myocardial infarction	grade 3, 16.7% DLT	3.9 mg/m2 1 times / week multiple, intravenous Studied dose Dose: 3.9 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 3.9 mg/m2, 1 times / week Sources: https://pubmed.ncbi.nlm.nih.gov/21159616 Page: p.3413	unhealthy, ADULT n = 6 Health Status: unhealthy Condition: cancer Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/21159616 Page: p.3413

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737			inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
	MRP1 107 P-gp 1537 BCRP 561 CYP2C19 991 CYP1A2 1054

Drug as victim

Target	Modality	Activity
BCRP 561	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/17575155/	no
MRP1 107	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/17575155/	no
P-gp 1537	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/17575155/	no
CYP1A2 1054	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/21159616/	yes
CYP2C19 991	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/21159616/	yes
CYP3A4 1737	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/21159616/	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://pubmed.ncbi.nlm.nih.gov/29457976/

PubMed

Title	Date	PubMed
Discovery of N-methyl-4-(4-methoxyanilino)quinazolines as potent apoptosis inducers. Structure-activity relationship of the quinazoline ring.	2010 Apr 1	20188546

Patents

Sample Use Guides

In Vivo Use Guide

Verubulin was administered at 3.3 mg/m(2) as a 2-h intravenous infusion once weekly for 3 consecutive weeks in a 4-week cycle.

Route of Administration: Intravenous

In Vitro Use Guide

Verubulin was highly active in HCT116 and SNU-398 cells with EC50 values of 3 nM and 2 nM, respectively, similar to its high activity in T47D cells.

Substance Class	Chemical Created by `admin` on `Fri Dec 15 15:50:58 GMT 2023` Edited by `admin` on `Fri Dec 15 15:50:58 GMT 2023`
Record UNII	33380QZ0QW
Record Status	`Validated (UNII)`
Record Version

Download

Name

Type

Language

VERUBULIN HYDROCHLORIDE

Official Name

English

VERUBULIN HYDROCHLORIDE [USAN]

Common Name

English

4-QUINAZOLINAMINE, N-(4-METHOXYPHENYL)-N,2-DIMETHYL-, HYDROCHLORIDE (1:1)

Systematic Name

English

AZIXA

Brand Name

English

VERUBULIN HCL

Common Name

English

N-(4-Methoxyphenyl)-N,2-dimethylquinazolin-4-amine hydrochloride

Systematic Name

English

Verubulin hydrochloride [WHO-DD]

Common Name

English

MPC-6827

Code

English

Classification Tree Code System Code

FDA ORPHAN DRUG

290809