INDIBULIN

Details

Stereochemistry	ACHIRAL
Molecular Formula	C22H16ClN3O2
Molecular Weight	389.834
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

ClC1=CC=C(CN2C=C(C(=O)C(=O)NC3=CC=NC=C3)C4=CC=CC=C24)C=C1

InChI

InChIKey=SOLIIYNRSAWTSQ-UHFFFAOYSA-N

InChI=1S/C22H16ClN3O2/c23-16-7-5-15(6-8-16)13-26-14-19(18-3-1-2-4-20(18)26)21(27)22(28)25-17-9-11-24-12-10-17/h1-12,14H,13H2,(H,24,25,28)

HIDE SMILES / InChI

Description
Sources: https://www.cancer.gov/publications/dictionaries/cancer-drug?cdrid=587341 | http://adisinsight.springer.com/drugs/800011203 | https://www.ncbi.nlm.nih.gov/pubmed/11196193 | https://www.ncbi.nlm.nih.gov/pubmed/15703812 | https://www.ncbi.nlm.nih.gov/pubmed/19404582

Indibulin is a novel synthetic compound that was identified in a cell-based screening assay to discover cytotoxic drugs. Indibulin destabilizes microtubules and blocks cell cycle transition specifically at the G2-M phase. Indibulin effectively induces apoptosis through Bcl-2 phosphorylation and Bax translocation in human malignant glioma cells in a p53-independent manner. This agent has been shown to be active against multidrug-resistant (MDR) and taxane-resistant tumour cell lines. Indibulin was used in phase I/II clinical trials of patients with advanced solid tumours (metastatic breast cancer). Pharmacokinetic analysis showed a better tolerability underfeeding condition. Dose-limiting toxicities were nausea and vomiting, which seemed to be related to solvent lactic acid.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Tubulin 69 Target ID: CHEMBL2111464 Sources: https://www.ncbi.nlm.nih.gov/pubmed/11196193	Inhibitor 8297
G2/M transition of mitotic cell cycle 2 Target ID: GO:0000086 Sources: https://www.ncbi.nlm.nih.gov/pubmed/11196193	Blocker 537	0.036 µM [IC50]
Apoptosis 155 Target ID: map04210 Sources: https://www.ncbi.nlm.nih.gov/pubmed/15703812	Activator 1430

Conditions

Condition	Modality	Targets	Highest Phase	Product
Breast cancer 434 Sources: https://clinicaltrials.gov/ct2/show/NCT01113970 http://adisinsight.springer.com/drugs/800011203	Primary		Phase II 1132	Unknown Approved Use Unknown
Solid tumors 145 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19404582 https://www.ncbi.nlm.nih.gov/pubmed/17146730	Primary		Phase I 428	Unknown Approved Use Unknown

Doses

Dose	Population	Adverse events
600 mg 2 times / day multiple, oral (unknown) Highest studied dose Dose: 600 mg, 2 times / day Route: oral Route: multiple Dose: 600 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/19404582	unhealthy n = 5 Health Status: unhealthy Condition: cancer Sex: M+F Food Status: FASTED Population Size: 5 Sources: https://pubmed.ncbi.nlm.nih.gov/19404582	Other AEs: Nausea, Vomiting... Other AEs: Nausea (grade 1, 3 patients) Vomiting (grade 1, 3 patients) Fatigue (grade 2, 1 pt) Sources: https://pubmed.ncbi.nlm.nih.gov/19404582
80 mg 1 times / day multiple, oral (unknown) Highest studied dose Dose: 80 mg, 1 times / day Route: oral Route: multiple Dose: 80 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/17146730/	unhealthy n = 8 Health Status: unhealthy Condition: cancer Sex: M+F Food Status: UNKNOWN Population Size: 8 Sources: https://pubmed.ncbi.nlm.nih.gov/17146730/	DLT: vomiting, Nausea... Dose limiting toxicities: vomiting (2 patients) Nausea (grades 1-2, 2 patients) Sources: https://pubmed.ncbi.nlm.nih.gov/17146730/
100 mg 1 times / day multiple, oral (unknown) Studied dose Dose: 100 mg, 1 times / day Route: oral Route: multiple Dose: 100 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/19404582	unhealthy n = 3 Health Status: unhealthy Condition: cancer Sex: M+F Food Status: FASTED Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/19404582	DLT: elevated ALT levels, elevated AST levels... Dose limiting toxicities: elevated ALT levels (grade 3, 1 pt) elevated AST levels (grade 3, 1 pt) Sources: https://pubmed.ncbi.nlm.nih.gov/19404582
150 mg 1 times / day multiple, oral (unknown) Studied dose Dose: 150 mg, 1 times / day Route: oral Route: multiple Dose: 150 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/19404582	unhealthy n = 3 Health Status: unhealthy Condition: cancer Sex: M+F Food Status: FASTED Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/19404582	DLT: fatigue... Dose limiting toxicities: fatigue (grade 3, 1 pt) Sources: https://pubmed.ncbi.nlm.nih.gov/19404582
250 mg 1 times / day multiple, oral (unknown) Studied dose Dose: 250 mg, 1 times / day Route: oral Route: multiple Dose: 250 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/19404582	unhealthy n = 3 Health Status: unhealthy Condition: cancer Sex: M+F Food Status: FED Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/19404582	DLT: increased AP, Gamma glutamyl transpeptidase increased... Dose limiting toxicities: increased AP (grade 3, 1 pt) Gamma glutamyl transpeptidase increased (grade 4, 1 pt) Sources: https://pubmed.ncbi.nlm.nih.gov/19404582

AEs

AE	Significance	Dose	Population
Nausea	grade 1, 3 patients	600 mg 2 times / day multiple, oral (unknown) Highest studied dose Dose: 600 mg, 2 times / day Route: oral Route: multiple Dose: 600 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/19404582	unhealthy n = 5 Health Status: unhealthy Condition: cancer Sex: M+F Food Status: FASTED Population Size: 5 Sources: https://pubmed.ncbi.nlm.nih.gov/19404582
Vomiting	grade 1, 3 patients	600 mg 2 times / day multiple, oral (unknown) Highest studied dose Dose: 600 mg, 2 times / day Route: oral Route: multiple Dose: 600 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/19404582	unhealthy n = 5 Health Status: unhealthy Condition: cancer Sex: M+F Food Status: FASTED Population Size: 5 Sources: https://pubmed.ncbi.nlm.nih.gov/19404582
Fatigue	grade 2, 1 pt	600 mg 2 times / day multiple, oral (unknown) Highest studied dose Dose: 600 mg, 2 times / day Route: oral Route: multiple Dose: 600 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/19404582	unhealthy n = 5 Health Status: unhealthy Condition: cancer Sex: M+F Food Status: FASTED Population Size: 5 Sources: https://pubmed.ncbi.nlm.nih.gov/19404582
vomiting	2 patients DLT, Disc. AE	80 mg 1 times / day multiple, oral (unknown) Highest studied dose Dose: 80 mg, 1 times / day Route: oral Route: multiple Dose: 80 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/17146730/	unhealthy n = 8 Health Status: unhealthy Condition: cancer Sex: M+F Food Status: UNKNOWN Population Size: 8 Sources: https://pubmed.ncbi.nlm.nih.gov/17146730/
Nausea	grades 1-2, 2 patients DLT	80 mg 1 times / day multiple, oral (unknown) Highest studied dose Dose: 80 mg, 1 times / day Route: oral Route: multiple Dose: 80 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/17146730/	unhealthy n = 8 Health Status: unhealthy Condition: cancer Sex: M+F Food Status: UNKNOWN Population Size: 8 Sources: https://pubmed.ncbi.nlm.nih.gov/17146730/
elevated ALT levels	grade 3, 1 pt DLT, Disc. AE	100 mg 1 times / day multiple, oral (unknown) Studied dose Dose: 100 mg, 1 times / day Route: oral Route: multiple Dose: 100 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/19404582	unhealthy n = 3 Health Status: unhealthy Condition: cancer Sex: M+F Food Status: FASTED Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/19404582
elevated AST levels	grade 3, 1 pt DLT, Disc. AE	100 mg 1 times / day multiple, oral (unknown) Studied dose Dose: 100 mg, 1 times / day Route: oral Route: multiple Dose: 100 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/19404582	unhealthy n = 3 Health Status: unhealthy Condition: cancer Sex: M+F Food Status: FASTED Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/19404582
fatigue	grade 3, 1 pt DLT	150 mg 1 times / day multiple, oral (unknown) Studied dose Dose: 150 mg, 1 times / day Route: oral Route: multiple Dose: 150 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/19404582	unhealthy n = 3 Health Status: unhealthy Condition: cancer Sex: M+F Food Status: FASTED Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/19404582
increased AP	grade 3, 1 pt DLT	250 mg 1 times / day multiple, oral (unknown) Studied dose Dose: 250 mg, 1 times / day Route: oral Route: multiple Dose: 250 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/19404582	unhealthy n = 3 Health Status: unhealthy Condition: cancer Sex: M+F Food Status: FED Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/19404582
Gamma glutamyl transpeptidase increased	grade 4, 1 pt DLT	250 mg 1 times / day multiple, oral (unknown) Studied dose Dose: 250 mg, 1 times / day Route: oral Route: multiple Dose: 250 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/19404582	unhealthy n = 3 Health Status: unhealthy Condition: cancer Sex: M+F Food Status: FED Population Size: 3 Sources: https://pubmed.ncbi.nlm.nih.gov/19404582

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1587	inhibitor 1767	inhibitor 1852

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
P-gp 1461	MRP 7 P-gp 1537

Drug as perpetrator

Target	Modality	Activity
CYP2D6 1891	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645840#sid=174007308	no
P-gp 1650	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1346987#sid=174007308	yes [IC50 0.0332 uM]
CYP3A4 1925	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645841#sid=174007308	yes [IC50 0.1068 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645842#sid=174007308	yes [IC50 0.3011 uM]

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
MRP 7	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/11196193/	no
P-gp 1537	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/11196193/	no

Sourcing

Vendor/Aggregator	ID	URL
AChemBlock	10069	http://www.achemblock.com/catalogsearch/result/?q=10069
Angene	AGN-PC-0WHDN4	http://www.angenechemical.com/productshow/AGN-PC-0WHDN4.html
BLD Pharm	BD251733	http://www.bldpharm.com/search/Search.html?keyword=BD251733
BOC Sciences	204205-90-3	http://www.bocsci.com/description.asp?cas=204205-90-3
Chem Scene	CS-0007536	http://www.chemscene.com/goproductList/searchProductList?productObj=CS-0007536
ChemDiv	BB54-1721	http://chemistryondemand.com:8080/eShop/search_results.jsp?idnumber=BB54-1721
Hairui	HR146237	http://www.hairuichem.com/en/product/search.do?q=HR146237
Lab Network	LN00334066	https://labnetwork.com/frontend-app/p/#!/moleculedetails/LN00334066
Lab Seeker	SC-84469	http://www.labseeker.com/search.php?keywords=SC-84469&category=0
MedChem Express	HY-13649	https://www.medchemexpress.com/search.html?q=HY-13649&ft=&fa=&fp=
MolPort	MolPort-002-739-496	https://www.molport.com/shop/molecule-link/MolPort-002-739-496
MuseChem	I007312	https://www.musechem.com/product/I007312.html
Princeton BioMolecular Research	OSSL_660408	http://www.princetonbio.com/order_online?common_id=OSSL_660408
Princeton BioMolecular Research	PBMR221836	http://www.princetonbio.com/order_online?common_id=PBMR221836
TimTec	SBB013544	http://www.echemstore.com/catalogsearch/result/?q=SBB013544
TimTec	ST099617	http://www.echemstore.com/catalogsearch/result/?q=ST099617
Tocris	3728	https://www.tocris.com/search.php?Type=QuickSearch&Value=3728
Toronto Research Chemicals	I533753	https://www.trc-canada.com/product-detail/?CatNum=I533753
Toronto Research Chemicals	L486208	https://www.trc-canada.com/product-detail/?CatNum=L486208
Wonderchem	WD05K0U	http://www.wonder-chem.com/search.html?text=WD05K0U
eMolecules	1986394	https://orderbb.emolecules.com/search/#?query=1986394
eNovation Chemicals	D500720	https://www.enovationchem.com/Products.asp?SEARCHTEXT=D500720&searchbtn.x=0&searchbtn.y=0
mcule	MCULE-2626264660	https://mcule.com/MCULE-2626264660/

PubMed

Title	Date	PubMed
D-24851, a novel synthetic microtubule inhibitor, exerts curative antitumoral activity in vivo, shows efficacy toward multidrug-resistant tumor cells, and lacks neurotoxicity.	2001 Jan 1	11196193
Quantitative analysis of D-24851, a novel anticancer agent, in human plasma and urine by liquid chromatography coupled with tandem mass spectrometry.	2004	15216507
Stable isotopically labeled internal standards in quantitative bioanalysis using liquid chromatography/mass spectrometry: necessity or not?	2005	15645520
Microtubule inhibitor D-24851 induces p53-independent apoptotic cell death in malignant glioma cells through Bcl-2 phosphorylation and Bax translocation.	2005 Mar	15703812
In vivo evaluation of indolyl glyoxamides in the phenotypic sea urchin embryo assay.	2007 Dec	17991295
Phase I dose-finding and pharmacokinetic trial of orally administered indibulin (D-24851) to patients with solid tumors.	2007 Jun	17146730
Antirestenotic effects of a novel polymer-coated d-24851 eluting stent. Experimental data in a rabbit iliac artery model.	2007 Nov-Dec	17828426
Design, synthesis and cytotoxicity of novel podophyllotoxin derivatives.	2008 Jun	18520089
Side chain modifications of (indol-3-yl)glyoxamides as antitumor agents.	2008 Oct	18821257
Indibulin, a novel microtubule inhibitor, discriminates between mature neuronal and nonneuronal tubulin.	2009 Jan 1	19118000
Dose-finding and pharmacokinetic study of orally administered indibulin (D-24851) to patients with advanced solid tumors.	2010 Apr	19404582
Gateways to clinical trials.	2010 Dec	21225012
Gateways to clinical trials.	2010 Jan-Feb	20383346

Patents

Sample Use Guides

In Vivo Use Guide

100 mg, 150 mg, 250 mg, 350 mg and 600 mg once daily (QD), 450 mg and 600 mg twice daily (BID). After a washout period, patients received indibulin at the pre-defined daily dose for 14 days every 3 weeks (multiple dose part).

Route of Administration: Oral

In Vitro Use Guide

To examine the cytotoxic effects of indibulin on malignant glioma cells, the four human glioma cell lines, which have different p53 status (U373-MG and T98G have mutated p53, and U87-MG and D54 have wild-type p53), were treated with different concentrations of indibulin for 2 days. The viability of all cell lines was reduced in a dose-dependent manner. The IC50s for indibulin in U373-MG, T98G, U87-MG, and D54 cells were 150, 180, 120, and 190 nM, respectively.

Name

Type

Language

INDIBULIN

Official Name

English

ZIO-301

Code

English

2-{1-[(4-Chlorophenyl)methyl]-1H-indol-3-yl}-2-oxo-N-(pyridin-4-yl)acetamide

Systematic Name

English

indibulin [INN]

Common Name

English

D-24851

Code

English

INDIBULIN [USAN]

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C25974