BMS-599626

Investigational

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C27H27FN8O3
Molecular Weight	530.5535
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CC1=C2N(C=C1NC(=O)OC[C@@H]3COCCN3)N=CN=C2NC4=CC5=C(C=C4)N(CC6=CC=CC(F)=C6)N=C5

InChI

InChIKey=LUJZZYWHBDHDQX-QFIPXVFZSA-N

InChI=1S/C27H27FN8O3/c1-17-23(34-27(37)39-15-22-14-38-8-7-29-22)13-36-25(17)26(30-16-32-36)33-21-5-6-24-19(10-21)11-31-35(24)12-18-3-2-4-20(28)9-18/h2-6,9-11,13,16,22,29H,7-8,12,14-15H2,1H3,(H,34,37)(H,30,32,33)/t22-/m0/s1

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/17062696
Curator's Comment: description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/19821562 | https://www.ncbi.nlm.nih.gov/pubmed/20119866

BMS 599626 is a selective and efficacious inhibitor of HER1 and HER2 with IC50 of 20 nM and 30 nM. BMS-599626 is identified as an ATP-competitive inhibitor for HER1 and as an ATP-noncompetitive inhibitor for HER2. BMS-599626 inhibits the proliferation of tumor cells expressing high levels of HER1 and/or HER2, including Sal2, BT474, N87, KPL-4, HCC202, HCC1954, HCC1419, AU565, ZR-75-30, MDA-MB-175, GEO, and PC9 cells. In a phase I trial of solid tumour patients receiving BMS 599626 no doselimiting toxicities were observed during the first cycle. Grade 1 or 2 drugrelated effects were reported and included diarrhoea, nausea, vomiting, rash, fatigue, musculoskeletal pain/cramp and cough. BristolMyers Squibb discontinued development of BMS 599626 for cancer in July 2015

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Epidermal growth factor receptor erbB1 58 Target ID: CHEMBL203 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17062696	Inhibitor 8297	20.0 nM [IC50]
Receptor protein-tyrosine kinase erbB-2 35 Target ID: CHEMBL1824 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17062696	Inhibitor 8297	30.0 nM [IC50]
Receptor protein-tyrosine kinase erbB-4 12 Target ID: CHEMBL3009 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17062696	Inhibitor 8297	190.0 nM [IC50]
Epidermal growth factor receptor erbB1 58 Target ID: CHEMBL203 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17062696	Inhibitor 8297	22.0 nM [IC50]
Receptor protein-tyrosine kinase erbB-2 35 Target ID: CHEMBL1824 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17062696	Inhibitor 8297	32.0 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Cancer metastases 1 Sources: https://clinicaltrials.gov/ct2/show/NCT00093730	Primary		Phase I 428	Unknown Approved Use Unknown

C_max

Value	Dose	Analyte	Population
120 ng/mL EXPERIMENT https://ascopubs.org/doi/abs/10.1200/jco.2005.23.16_suppl.3152	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:	BMS-599626 plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
162 ng/mL EXPERIMENT https://ascopubs.org/doi/abs/10.1200/jco.2005.23.16_suppl.3152	100 mg 1 times / day single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:	BMS-599626 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
377 ng/mL EXPERIMENT https://ascopubs.org/doi/abs/10.1200/jco.2005.23.16_suppl.3152	100 mg 1 times / day multiple, oral dose: 100 mg route of administration: Oral experiment type: MULTIPLE co-administered:	BMS-599626 plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

AUC

Value	Dose	Analyte	Population
2610 ng × h/mL EXPERIMENT https://ascopubs.org/doi/abs/10.1200/jco.2005.23.16_suppl.3152	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:	BMS-599626 plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
2920 ng × h/mL EXPERIMENT https://ascopubs.org/doi/abs/10.1200/jco.2005.23.16_suppl.3152	100 mg 1 times / day single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:	BMS-599626 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
8300 ng × h/mL EXPERIMENT https://ascopubs.org/doi/abs/10.1200/jco.2005.23.16_suppl.3152	100 mg 1 times / day multiple, oral dose: 100 mg route of administration: Oral experiment type: MULTIPLE co-administered:	BMS-599626 plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
20 h EXPERIMENT https://ascopubs.org/doi/abs/10.1200/jco.2005.23.16_suppl.3152	100 mg 1 times / day multiple, oral dose: 100 mg route of administration: Oral experiment type: MULTIPLE co-administered:		BMS-599626 plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1587	inhibitor 1767	inhibitor 1852	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1524 CYP2C19 1478 BCRP 699 MRP1 106 P-gp 1461 MRP7 1

Drug as perpetrator

Target	Modality	Activity
P-gp 1650	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/32899268/ \| https://pubchem.ncbi.nlm.nih.gov/bioassay/1346987#sid=363677419	inconclusive [IC50 18.3564 uM]
MRP7 2	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/32899268/	likely
CYP1A2 1692	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/19821562/	no [IC50 >40 uM]
CYP2D6 1891	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/19821562/	no [IC50 >40 uM]
MRP1 172	inhibitor 3277 Sources: up to 300 nM	no
CYP3A4 1925	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/19821562/	yes [IC50 1.6 uM]
CYP2C19 1553	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/19821562/	yes [IC50 10 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/19821562/	yes [IC50 12 uM]
BCRP 773	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/32899268/	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://pubmed.ncbi.nlm.nih.gov/19821562/

PubMed

Title	Date	PubMed
Discovery and preclinical evaluation of [4-[[1-(3-fluorophenyl)methyl]-1H-indazol-5-ylamino]-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yl]carbamic acid, (3S)-3-morpholinylmethyl ester (BMS-599626), a selective and orally efficacious inhibitor of human epidermal growth factor receptor 1 and 2 kinases.	2009 Nov 12	19821562
Phase I safety, pharmacokinetic and pharmacodynamic trial of BMS-599626 (AC480), an oral pan-HER receptor tyrosine kinase inhibitor, in patients with advanced solid tumors.	2012 Feb	21576284

Patents

Sample Use Guides

In Vivo Use Guide

Antitumor activity of BMS-599626 was evaluated in mouse xenograft models. For oral administration to mice, BMS-599626 was dissolved in a mixture of propylene glycol/water (50:50). BMS-599626 was administered once-daily to female nude mice with Sal2 mouse salivary gland tumors at doses of 60 mg/kg, 120 mg/kg and 240 mg/kg for 14 days. In separate experiment BMS-599626 was administered once-daily to female nude mice bearing KPL-4 human breast tumors at doses of of 60 mg/kg and 120 mg/kg for 21 days.

Route of Administration: Oral

In Vitro Use Guide

BMS-599626 (in submicromolar concentrations) inhibits the proliferation of tumor cells expressing high levels of HER1 and/or HER2, including Sal2, BT474, N87, KPL-4, HCC202, HCC1954, HCC1419, AU565, ZR-75-30, MDA-MB-175, GEO, and PC9 cells. In proliferation assay. Following the addition of BMS-599626 (diluted in culture medium), the cells were cultured for 72 hours and cell viability was determined by measuring the conversion of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide dye.

Name

Type

Language

BMS-599626

Common Name

English

BMS 599626 [WHO-DD]

Common Name

English

AC-480

Code

English

BMS 599626

Common Name

English

AC480

Code

English

CARBAMIC ACID, N-(4-((1-((3-FLUOROPHENYL)METHYL)-1H-INDAZOL-5-YL)AMINO)-5-METHYLPYRROLO(2,1-F)(1,2,4)TRIAZIN-6-YL)-, (3S)-3-MORPHOLINYLMETHYL ESTER

Common Name

English

Code System Code Type Description

PUBCHEM

10437018