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

Molecular Formula	C17H14ClF2IN2O2
Molecular Weight	478.66
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

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: Q02750 Gene ID: 5604.0 Gene Symbol: MAP2K1 Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/10395327	Inhibitor 8504		17.0 nM [IC50]
Dual specificity mitogen-activated protein kinase kinase 2 10 Target ID: P36507 Gene ID: 5605.0 Gene Symbol: MAP2K2 Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/18952427 \| https://www.ncbi.nlm.nih.gov/pubmed/21483442	Inhibitor 8504

Conditions

Condition	Modality	Highest Phase	Product
Breast cancer 432 Sources: https://clinicaltrials.gov/ct2/show/NCT00033384	Primary	Phase II 1147	Unknown Approved Use Unknown
Colorectal cancer 102 Sources: https://clinicaltrials.gov/ct2/show/NCT00033384	Primary	Phase II 1147	Unknown Approved Use Unknown
Lung cancer 70 Sources: https://clinicaltrials.gov/ct2/show/NCT00033384	Primary	Phase II 1147	Unknown Approved Use Unknown
Pancreatic cancer 98 Sources: https://clinicaltrials.gov/ct2/show/NCT00033384	Primary	Phase II 1147	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 1087 inhibitor 2252	inhibitor 2438	inhibitor 2507

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
P-gp 1741 CYP19A1 429	HLM 34 CYP1A1 389 CYP1A2 1197 CYP2C19 1119	CYP3A5 92 CYP3A7 15

Drug as perpetrator

Target	Modality	Activity
CYP2D6 2546	inhibitor 4027 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645840#sid=170466835	no
PXR 51	activator 342 Sources: https://pubmed.ncbi.nlm.nih.gov/24819614/ \| https://pubchem.ncbi.nlm.nih.gov/bioassay/1346977#sid=170466835	yes [Activation 18.8336 uM]
CYP19A1 430	inhibitor 4027 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/743083#sid=144206914	yes [IC50 0.1679 uM]
CYP2C9 2497	inhibitor 4027 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1645842#sid=170466835	yes [IC50 0.6166 uM]
P-gp 1932	inhibitor 4027 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1346987#sid=174006413	yes [IC50 18.3564 uM]
CYP3A4 2633	inhibitor 4027 Sources: https://pubmed.ncbi.nlm.nih.gov/24819614/ \| https://pubchem.ncbi.nlm.nih.gov/bioassay/1645841#sid=170466835	yes [Inhibition 2.754 uM]
CYP3A4 2633	inducer 1966 Sources: https://pubmed.ncbi.nlm.nih.gov/24819614/	yes
CYP3A5 201	inducer 1966 Sources: https://pubmed.ncbi.nlm.nih.gov/24819614/	yes
CYP3A7 22	inducer 1966 Sources: https://pubmed.ncbi.nlm.nih.gov/24819614/	yes

Drug as victim

Target	Modality	Activity
CYP1A1 389	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/15497695/	yes
CYP1A2 1197	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/15497695/	yes
CYP2C19 1119	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/15497695/	yes
HLM 34	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/18952427/	yes

PubMed

Title	Date	PubMed
Ras/Erk signaling is essential for activation of protein synthesis by Gq protein-coupled receptor agonists in adult cardiomyocytes.	2002 Nov 1	12411397
Combined treatment with the checkpoint abrogator UCN-01 and MEK1/2 inhibitors potently induces apoptosis in drug-sensitive and -resistant myeloma cells through an IL-6-independent mechanism.	2002 Nov 1	12384435
Beyond directed therapeutics--are two drugs always better than one?	2002 Nov-Dec	12642694
Targeting intracellular signal transduction. A new paradigm for a brave new world of molecularly targeted therapeutics.	2002 Oct	12512384
Cell-cycle arrest by PD184352 requires inhibition of extracellular signal-regulated kinases (ERK) 1/2 but not ERK5/BMK1.	2002 Sep 1	12069688
Chronic activation of extracellular-signal-regulated protein kinases by phenylephrine is required to elicit a hypertrophic response in cardiac myocytes.	2003 Apr 1	12513686
A conserved role for the MEK signalling pathway in neural tissue specification and posteriorisation in the invertebrate chordate, the ascidian Ciona intestinalis.	2003 Jan	12441299
Proliferation of cancer cells despite CDK2 inhibition.	2003 Mar	12676582
Specific blockade of the ERK pathway inhibits the invasiveness of tumor cells: down-regulation of matrix metalloproteinase-3/-9/-14 and CD44.	2003 May 16	12727228
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
Increased dissolution rate and bioavailability through comicronization with microcrystalline cellulose.	2005	16370174
A role for K-ras in conferring resistance to the MEK inhibitor, CI-1040.	2005 Apr	15967111
Treating cancer by blocking cell signals.	2005 Aug 10	16091351
Phase I and pharmacodynamic study of the oral MEK inhibitor CI-1040 in patients with advanced malignancies.	2005 Aug 10	16009947
Two targets are better than one. Promising combination therapy to treat breast cancer.	2005 Nov	16322681
Transient exposure of mammary tumors to PD184352 and UCN-01 causes tumor cell death in vivo and prolonged suppression of tumor regrowth.	2005 Nov	16319524
Development of a conditional in vivo model to evaluate the efficacy of small molecule inhibitors for the treatment of Raf-transformed hematopoietic cells.	2005 Nov 1	16267021
Anticancer Drug Discovery and Development - SRI's Seventh Annual Summit.	2005 Oct	16254797
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
Activation of mitogen-activated protein kinase is required for migration and invasion of placental site trophoblastic tumor.	2005 Sep	16127165
Synergistic interactions between MEK1/2 and histone deacetylase inhibitors in BCR/ABL+ human leukemia cells.	2005 Sep	16015388
Quantitative single cell determination of ERK phosphorylation and regulation in relapsed and refractory primary acute myeloid leukemia.	2005 Sep	16001087
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
The mitogen-activated protein kinase/extracellular signal-regulated kinase kinase inhibitor PD184352 (CI-1040) selectively induces apoptosis in malignant schwannoma cell lines.	2006 Jan	16239399
BRAF mutation predicts sensitivity to MEK inhibition.	2006 Jan 19	16273091
Extracellular signal-regulated kinase inhibition slows disease progression in mice with polycystic kidney disease.	2006 Jun	16641154
Bidirectional cross talk between ERalpha and EGFR signalling pathways regulates tamoxifen-resistant growth.	2006 Mar	16261397
Upstream signaling inhibition enhances rapamycin effect on growth of kidney cancer cells.	2007 Mar	17382186
Dual mitogen-activated protein kinase and epidermal growth factor receptor inhibition in biliary and pancreatic cancer.	2007 Mar	17363501
MEK1/2 inhibitors sensitize Bcr/Abl+ human leukemia cells to the dual Abl/Src inhibitor BMS-354/825.	2007 May 1	17218385
Mutations in BRAF and KRAS converge on activation of the mitogen-activated protein kinase pathway in lung cancer mouse models.	2007 May 15	17510423
PD184352 releases the regular hypoxic reversible DNA replication arrest in T24 cells.	2007 Nov 30	18047784
4-anilino-5-carboxamido-2-pyridone derivatives as noncompetitive inhibitors of mitogen-activated protein kinase kinase.	2007 Oct 18	17880056
Cellular energetic status supervises the synthesis of bis-diphosphoinositol tetrakisphosphate independently of AMP-activated protein kinase.	2008 Aug	18460607
Increase of MCP-1 (CCL2) in myelin mutant Schwann cells is mediated by MEK-ERK signaling pathway.	2008 Jun	18383340
Restoration of PTEN expression alters the sensitivity of prostate cancer cells to EGFR inhibitors.	2008 Jun 15	18386291
Reduction of chronic allograft nephropathy by inhibition of extracellular signal-regulated kinase 1 and 2 signaling.	2008 Sep	18614619
Simvastatin inhibits angiotensin II-induced abdominal aortic aneurysm formation in apolipoprotein E-knockout mice: possible role of ERK.	2009 Nov	19729613
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.

Substance Class	Chemical Created by `admin` on `Mon Mar 31 18:08:51 GMT 2025` Edited by `admin` on `Mon Mar 31 18:08:51 GMT 2025`
Record UNII	R3K9Y00J04
Record Status	`Validated (UNII)`
Record Version

Download

Name

Type

Language

CI-1040

Common Name

English

PD-18435

Preferred 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

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

Systematic Name

English

Code System Code Type Description

CAS

212631-79-3