VERUBULIN HYDROCHLORIDE

Investigational

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

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

Description

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	Binding Agent 1,064

Conditions

Condition	Modality	Highest Phase	Product
Glioblastoma multiforme 30	Primary	Phase II 1,132	Unknown
Melanoma 88	Primary	Phase II 1,132	Unknown
Solid tumors 145	Primary	Phase I 428	Unknown

C_max

Value	Dose	Analyte	Population
21.3 ng/mL	3.3 mg/m² 1 times / week multiple, intravenous	VERUBULIN plasma	Homo sapiens
30.7 ng/mL	3.9 mg/m² 1 times / week multiple, intravenous	VERUBULIN plasma	Homo sapiens
62 ng/mL	4.5 mg/m² 1 times / week multiple, intravenous	VERUBULIN plasma	Homo sapiens

AUC

Value	Dose	Analyte	Population
116.8 ng × h/mL	3.3 mg/m² 1 times / week multiple, intravenous	VERUBULIN plasma	Homo sapiens
139.3 ng × h/mL	3.9 mg/m² 1 times / week multiple, intravenous	VERUBULIN plasma	Homo sapiens
183.6 ng × h/mL	4.5 mg/m² 1 times / week multiple, intravenous	VERUBULIN plasma	Homo sapiens

T_1/2

Value	Dose	Analyte	Population
6.4 h	3.3 mg/m² 1 times / week multiple, intravenous	VERUBULIN plasma	Homo sapiens
7.5 h	3.9 mg/m² 1 times / week multiple, intravenous	VERUBULIN plasma	Homo sapiens
5.7 h	4.5 mg/m² 1 times / week multiple, intravenous	VERUBULIN plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
4.5 mg/m2 1 times / week multiple, intravenous Highest studied dose	unhealthy, ADULT n = 7	DLT: Myocardial infarction...
3.3 mg/m2 1 times / week multiple, intravenous MTD	unhealthy, ADULT n = 13
3.3 mg/m2 1 times / week multiple, intravenous MTD	unhealthy, ADULT n = 31	Disc. AE: Myocardial infarction...
3.9 mg/m2 1 times / week multiple, intravenous Studied dose	unhealthy, ADULT n = 6	DLT: Myocardial infarction...

Showing 1 to 4 of 4 entries

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AEs

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AE	Significance	Dose	Population
Myocardial infarction	grade 3, 14.3% DLT	4.5 mg/m2 1 times / week multiple, intravenous Highest studied dose	unhealthy, ADULT n = 7
Myocardial infarction	grade 4, 3.2% Disc. AE	3.3 mg/m2 1 times / week multiple, intravenous MTD	unhealthy, ADULT n = 31
Myocardial infarction	grade 3, 16.7% DLT	3.9 mg/m2 1 times / week multiple, intravenous Studied dose	unhealthy, ADULT n = 6

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1,737			inhibitor 1,612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
	MRP1 107 P-gp 1,537 BCRP 561 CYP2C19 991 CYP1A2 1,054

Drug as victim

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Target	Modality	Activity
BCRP 561	substrate 3,367	no
MRP1 107	substrate 3,367	no
P-gp 1,537	substrate 3,367	no
CYP1A2 1,054	substrate 3,367	yes
CYP2C19 991	substrate 3,367	yes

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Tox targets

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Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1,647	inhibitor 1,626

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PubMed

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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

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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.

Show entries

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

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Classification Tree

Code System

Code

Designated

FDA ORPHAN DRUG

290809

Antimitotic Agent

NCI_THESAURUS

C25974

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Code System

Code

Type

Description

PUBCHEM

11638255

PRIMARY

USAN

UU-21

PRIMARY

EPA CompTox

DTXSID80238682

PRIMARY

CAS

917369-31-4

PRIMARY

NCI_THESAURUS

C64782

PRIMARY

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ACTIVE MOIETY


					X97O9FTB92

VERUBULIN

SUBSTANCE RECORD


					33380QZ0QW

VERUBULIN HYDROCHLORIDE

SMILES

InChI

CNS Activity

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Doses

AEs

Overview

OverviewOther

Drug as victim

Tox targets

PubMed

Patents

Sample Use Guides

C_max

T_1/2