ENMD-981693

Investigational

Details

Stereochemistry	ACHIRAL
Molecular Formula	C21H25N7
Molecular Weight	375.4701
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	1
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CN1CCN(CC1)C2=CC(NC3=NNC(C)=C3)=NC(\C=C\C4=CC=CC=C4)=N2

InChI

InChIKey=BLQYVHBZHAISJM-CMDGGOBGSA-N

InChI=1S/C21H25N7/c1-16-14-20(26-25-16)23-19-15-21(28-12-10-27(2)11-13-28)24-18(22-19)9-8-17-6-4-3-5-7-17/h3-9,14-15H,10-13H2,1-2H3,(H2,22,23,24,25,26)/b9-8+

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/21177375
Curator's Comment: description was created based on several sources, including http://www.casipharmaceuticals.com/investor-relations/news//entremed-stockholders-approve-name-change-to-casi-pharmaceuticals?/about-us/news/entremed-stockholders-approve-name-change-to-casi-pharmaceuticals

ENMD-2076 is an orally-active, Aurora A/angiogenic kinase inhibitor. urora kinases are key regulators of mitosis (cell division), and are often over-expressed in human cancers. ENMD-2076 also targets the VEGFR, Flt-3 and FGFR3 kinases, which have been shown to play important roles in the pathology of several cancers. ENMD-2076 is tested in phase 2 clinical trials against ovarian cancer, breast cance, hepatocellular carcinoma and other malignancies.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Serine/threonine-protein kinase Aurora-A 37 Target ID: CHEMBL4722 Sources: https://www.ncbi.nlm.nih.gov/pubmed/21177375	Inhibitor 8297	14.0 nM [IC50]
Tyrosine-protein kinase receptor FLT3 43 Target ID: CHEMBL1974 Sources: https://www.ncbi.nlm.nih.gov/pubmed/21177375	Inhibitor 8297	1.86 nM [IC50]
Vascular endothelial growth factor receptor 3 41 Target ID: CHEMBL1955 Sources: https://www.ncbi.nlm.nih.gov/pubmed/21177375	Inhibitor 8297	15.0 nM [IC50]
Fibroblast growth factor receptor 3 32 Target ID: CHEMBL2742 Sources: http://www.casipharmaceuticals.com/investor-relations/news//entremed-stockholders-approve-name-change-to-casi-pharmaceuticals?/about-us/news/entremed-stockholders-approve-name-change-to-casi-pharmaceuticals	Inhibitor 8297

Conditions

Condition	Modality	Highest Phase	Product
Ovarian cancer 157 Sources: https://www.ncbi.nlm.nih.gov/pubmed/22921155	Primary	Phase II 1132	Unknown Approved Use Unknown
Triple-negative breast cancer 12 Sources: https://clinicaltrials.gov/ct2/show/NCT01639248	Primary	Phase II 1132	Unknown Approved Use Unknown
Hepatocellular carcinoma 83 Sources: https://clinicaltrials.gov/ct2/show/NCT02234986	Primary	Phase II 1132	Unknown Approved Use Unknown
Fallopian tube cancer 17 Sources: https://clinicaltrials.gov/ct2/show/NCT01104675	Primary	Phase II 1132	Unknown Approved Use Unknown

C_max

Value	Dose	Analyte	Population
233 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21131552/	80 mg/m² 1 times / day multiple, oral dose: 80 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	ENMD-2076 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
218 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21131552/	60 mg/m² 1 times / day multiple, oral dose: 60 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	ENMD-2076 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
314 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21131552/	120 mg/m² 1 times / day multiple, oral dose: 120 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	ENMD-2076 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
557 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21131552/	200 mg/m² 1 times / day multiple, oral dose: 200 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	ENMD-2076 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
558 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21131552/	160 mg/m² 1 times / day multiple, oral dose: 160 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	ENMD-2076 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

AUC

Value	Dose	Analyte	Population
14.66 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21131552/	80 mg/m² 1 times / day multiple, oral dose: 80 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	ENMD-2076 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
15.26 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21131552/	60 mg/m² 1 times / day multiple, oral dose: 60 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	ENMD-2076 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
16.74 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21131552/	120 mg/m² 1 times / day multiple, oral dose: 120 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	ENMD-2076 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
34.5 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21131552/	200 mg/m² 1 times / day multiple, oral dose: 200 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	ENMD-2076 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
34.6 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21131552/	160 mg/m² 1 times / day multiple, oral dose: 160 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	ENMD-2076 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

T_1/2

Value	Dose	Analyte	Population
51 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21131552/	80 mg/m² 1 times / day multiple, oral dose: 80 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	ENMD-2076 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
53.1 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21131552/	60 mg/m² 1 times / day multiple, oral dose: 60 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	ENMD-2076 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
44.9 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21131552/	120 mg/m² 1 times / day multiple, oral dose: 120 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	ENMD-2076 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
47.6 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21131552/	200 mg/m² 1 times / day multiple, oral dose: 200 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	ENMD-2076 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
46.1 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21131552/	160 mg/m² 1 times / day multiple, oral dose: 160 mg/m² route of administration: Oral experiment type: MULTIPLE co-administered:	ENMD-2076 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1587	inhibitor 1767	inhibitor 1852

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
P-gp 1461

Drug as perpetrator

Target	Modality	Activity
CYP2D6 1891	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645840#sid=363677247	inconclusive [IC50 21.3174 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645842#sid=363677247	no
CYP3A4 1925	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645841#sid=363677247	no
P-gp 1650	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1346987#sid=363677247	yes [IC50 7.3078 uM]

PubMed

Title	Date	PubMed
Discovery and development of aurora kinase inhibitors as anticancer agents.	2009 May 14	19320489
Preclinical activity of a novel multiple tyrosine kinase and aurora kinase inhibitor, ENMD-2076, against multiple myeloma.	2010 Aug	20560971
ENMD-2076 is an orally active kinase inhibitor with antiangiogenic and antiproliferative mechanisms of action.	2011 Jan	21177375

Patents

Sample Use Guides

In Vivo Use Guide

ENMD-2067 will be taken orally at a dose of 275 mg, once a day, everyday. Patients with a body surface area of less than 1.65 m2 will receive a starting dose of 250 mg, once a day, everyday.

Route of Administration: Oral

In Vitro Use Guide

The antiproliferative effect of ENMD-2076 on adherent tumor cell lines was measured by plating 500 cells per well in a 96-well plate and incubating with 9 doses of compound, spanning 0.3 nmol/L to 125 mmol/L, for 96 hours. Cellular proliferation was measured using the sulforhodamine B (SRB; Sigma Aldrich) assay. ENMD-2076 inhibits proliferation of PANC-1, HCT116, A549 tumor cells with IC50 0.12 - 0.26 uM.

Name

Type

Language

ENMD-981693

Common Name

English

ENMD-2076 FREE BASE

Common Name

English

ENMD 981693

Code

English

4-PYRIMIDINAMINE, 6-(4-METHYL-1-PIPERAZINYL)-N-(5-METHYL-1H-PYRAZOL-3-YL)-2-((1E)-2-PHENYLETHENYL)-

Systematic Name

English

(E)-N-(5-METHYL-1H-PYRAZOL-3-YL)-6-(4-METHYLPIPERAZIN-1-YL)-2-STYRYLPYRIMIDIN-4-AMINE

Systematic Name

English

R-440

Code

English

RO-317453

Code

English

Code System Code Type Description

FDA UNII

J6U9WP10T7