CI-1040

Investigational

Details

Stereochemistry	ACHIRAL
Molecular Formula	C17H14ClF2IN2O2
Molecular Weight	478.66
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

FC1=CC=C(C(=O)NOCC2CC2)C(NC3=CC=C(I)C=C3Cl)=C1F

InChI

InChIKey=GFMMXOIFOQCCGU-UHFFFAOYSA-N

InChI=1S/C17H14ClF2IN2O2/c18-12-7-10(21)3-6-14(12)22-16-11(4-5-13(19)15(16)20)17(24)23-25-8-9-1-2-9/h3-7,9,22H,1-2,8H2,(H,23,24)

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/16009947
Curator's Comment: description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/27249593 | https://www.ncbi.nlm.nih.gov/pubmed/10998351 | https://www.ncbi.nlm.nih.gov/pubmed/24130883

CI 1040 is an inhibitor of the mitogen-activated protein (MAP) kinase signal transduction pathway and has been shown to specifically inhibit MAP kinase kinase (MEK). CI 1040 was being developed by Parke-Davis (formerly a division of WarnerLambert, Now Pfizer) as an anticancer agent. It was the initial MEK inhibitor to undergo clinical evaluation based on promising preclinical activity. However, its development has been discontinued.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Dual specificity mitogen-activated protein kinase kinase 1 20 Target ID: CHEMBL3587 Sources: https://www.ncbi.nlm.nih.gov/pubmed/10998351	Inhibitor 8297

Conditions

Condition	Modality	Highest Phase	Product
Breast cancer 434 Sources: https://clinicaltrials.gov/ct2/show/NCT00033384	Primary	Phase II 1132	Unknown Approved Use Unknown
Colorectal cancer 101 Sources: https://clinicaltrials.gov/ct2/show/NCT00033384	Primary	Phase II 1132	Unknown Approved Use Unknown
Lung cancer 69 Sources: https://clinicaltrials.gov/ct2/show/NCT00033384	Primary	Phase II 1132	Unknown Approved Use Unknown
Pancreatic cancer 97 Sources: https://clinicaltrials.gov/ct2/show/NCT00033384	Primary	Phase II 1132	Unknown Approved Use Unknown

C_max

Value	Dose	Analyte	Population
11700 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/16009947	800 mg 2 times / day steady-state, oral dose: 800 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	PD-0184264 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FED
18000 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/16009947	800 mg 3 times / day steady-state, oral dose: 800 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	PD0184264 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FED
4420 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/16009947	1600 mg 1 times / day steady-state, oral dose: 1600 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	PD0184264 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

AUC

Value	Dose	Analyte	Population
114000 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/16009947	800 mg 2 times / day steady-state, oral dose: 800 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	PD-0184264 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FED
127000 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/16009947	800 mg 3 times / day steady-state, oral dose: 800 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	PD0184264 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FED
78100 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/16009947	1600 mg 1 times / day steady-state, oral dose: 1600 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	PD0184264 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

T_1/2

Value	Dose	Co-administered	Analyte	Population
20.9 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/16009947	800 mg 2 times / day steady-state, oral dose: 800 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		PD-0184264 plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FED

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inducer 781 inhibitor 1587	inhibitor 1767	inhibitor 1852

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP19A1 60 P-gp 1461	HLM 31 CYP1A1 349 CYP1A2 1054 CYP2C19 991 non-CYP/non-FMO amidase 1	CYP3A5 76 CYP3A7 15

Drug as perpetrator

Target	Modality	Activity
CYP19A1 60	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/743083#sid=144206914	no [IC50 0.1679 uM]
CYP2D6 1891	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645840#sid=170466835	no
PXR 46	activator 214 Sources: https://pubmed.ncbi.nlm.nih.gov/24819614/ \| https://pubchem.ncbi.nlm.nih.gov/bioassay/1346977#sid=170466835	yes [Activation 18.8336 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645842#sid=170466835	yes [IC50 0.6166 uM]
P-gp 1650	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1346987#sid=174006413	yes [IC50 18.3564 uM]
CYP3A4 1925	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/24819614/ \| https://pubchem.ncbi.nlm.nih.gov/bioassay/1645841#sid=170466835	yes [Inhibition 2.754 uM]
CYP3A4 1925	inducer 1573 Sources: https://pubmed.ncbi.nlm.nih.gov/24819614/	yes
CYP3A5 130	inducer 1573 Sources: https://pubmed.ncbi.nlm.nih.gov/24819614/	yes
CYP3A7 22	inducer 1573 Sources: https://pubmed.ncbi.nlm.nih.gov/24819614/	yes

Drug as victim

Target	Modality	Activity
CYP1A1 349	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/15497695/	yes
CYP1A2 1054	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/15497695/	yes
CYP2C19 991	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/15497695/	yes
HLM 31	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/18952427/	yes
non-CYP/non-FMO amidase 1	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/15497695/	yes

PubMed

Title	Date	PubMed
Pharmacological inhibitors of the mitogen-activated protein kinase (MAPK) kinase/MAPK cascade interact synergistically with UCN-01 to induce mitochondrial dysfunction and apoptosis in human leukemia cells.	2001 Jul 1	11431348
Therapeutic targeting of the MEK/MAPK signal transduction module in acute myeloid leukemia.	2001 Sep	11560954
Ras/Erk signaling is essential for activation of protein synthesis by Gq protein-coupled receptor agonists in adult cardiomyocytes.	2002 Nov 1	12411397
Feedback control of the protein kinase TAK1 by SAPK2a/p38alpha.	2003 Nov 3	14592977
Treatment with arsenic trioxide (ATO) and MEK1 inhibitor activates the p73-p53AIP1 apoptotic pathway in leukemia cells.	2004 Jul 15	15031205
Use of mitogenic cascade blockers for treatment of C-Raf induced lung adenoma in vivo: CI-1040 strongly reduces growth and improves lung structure.	2004 Jun 1	15171791
Stress- and mitogen-induced phosphorylation of the synapse-associated protein SAP90/PSD-95 by activation of SAPK3/p38gamma and ERK1/ERK2.	2004 May 15	14741046
Molecular cross-talk between MEK1/2 and mTOR signaling during recovery of 293 cells from hypertonic stress.	2004 Oct 29	15292274
ERK1/2 inhibition increases antiestrogen treatment efficacy by interfering with hypoxia-induced downregulation of ERalpha: a combination therapy potentially targeting hypoxic and dormant tumor cells.	2005 Oct 13	16007158
Synergistic interactions between DMAG and mitogen-activated protein kinase kinase 1/2 inhibitors in Bcr/abl+ leukemia cells sensitive and resistant to imatinib mesylate.	2006 Apr 1	16609040
Extracellular signal-regulated kinase inhibition slows disease progression in mice with polycystic kidney disease.	2006 Jun	16641154
Protein kinases as drug targets in cancer.	2006 Nov	17100568
MEK1/2 inhibition promotes Taxotere lethality in mammary tumors in vivo.	2006 Oct	16957420
Lovastatin inhibits the extracellular-signal-regulated kinase pathway in immortalized rat brain neuroblasts.	2007 Jan 1	16952276
Dual mitogen-activated protein kinase and epidermal growth factor receptor inhibition in biliary and pancreatic cancer.	2007 Mar	17363501
MEK blockade converts AML differentiating response to retinoids into extensive apoptosis.	2007 Mar 1	17077328
Cellular energetic status supervises the synthesis of bis-diphosphoinositol tetrakisphosphate independently of AMP-activated protein kinase.	2008 Aug	18460607
K-ras as a target for lung cancer therapy.	2008 Jun	18520303
The ground state of embryonic stem cell self-renewal.	2008 May 22	18497825
Simvastatin inhibits angiotensin II-induced abdominal aortic aneurysm formation in apolipoprotein E-knockout mice: possible role of ERK.	2009 Nov	19729613
Suppression of Erk signalling promotes ground state pluripotency in the mouse embryo.	2009 Oct	19710168
MEK inhibitors potentiate dexamethasone lethality in acute lymphoblastic leukemia cells through the pro-apoptotic molecule BIM.	2009 Oct	19404317
Induction of Bim expression contributes to the antitumor synergy between sorafenib and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase inhibitor CI-1040 in hepatocellular carcinoma.	2009 Sep 15	19737956
Response and resistance to MEK inhibition in leukaemias initiated by hyperactive Ras.	2009 Sep 17	19727076
Three-dimensional overlay culture models of human breast cancer reveal a critical sensitivity to mitogen-activated protein kinase kinase inhibitors.	2010 Mar	19952304
Hepatitis C virus RNA replication is regulated by Ras-Erk signalling.	2010 Mar	19889932

Patents

Sample Use Guides

In Vivo Use Guide

Oral doses of CI-1040 were initially administered once daily on an empty stomach. Testing through 1,600 mg QD revealed a plateau in drug exposure (AUC) and to increase absorption, multiple daily doses of CI-1040 including 800 mg BID and 800 mg tid were tested. In addition, food effect testing in patients at 800-mg and 1,600-mg dose levels revealed a significant increase in absorption when CI-1040 was administered with food. This observation led to retesting of the 800-mg QD, 800-mg BID and 800-mg tid dose levels administered with meals. Finally, once the MTD was determined, the weeklong holiday between treatment cycles was removed to test the safety of continuous dosing.

Route of Administration: Oral

In Vitro Use Guide

The cytotoxic effects of CI-1040 on AML U-937 cells was studied by ELISA and MTT assays. The CI-1040 was dissolved in dimethyl sulfoxide (DMSO) as 10 mM stock solutions and used in cell culture at final concentration 50 mg/ml. U-937 cells were treated with 0, 1, 5 and 20 mkM, CI-1040 for 24 hrs. Cells were lysed and whole extracts were analyzed by Western blot.

Name

Type

Language

CI-1040

Common Name

English

Benzamide, 2-[(2-chloro-4-iodophenyl)amino]-N-(cyclopropylmethoxy)-3,4-difluoro-

Systematic Name

English

CI 1040 [WHO-DD]

Common Name

English

PD-184352

Code

English

PD-18435

Code

English

2-[(2-Chloro-4-iodophenyl)amino]-N-(cyclopropylmethoxy)-3,4-difluorobenzamide

Systematic Name

English

Code System Code Type Description

CAS

212631-79-3