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
Three-dimensional overlay culture models of human breast cancer reveal a critical sensitivity to mitogen-activated protein kinase kinase inhibitors.	2010-03	19952304
Hepatitis C virus RNA replication is regulated by Ras-Erk signalling.	2010-03	19889932
Growth of hormone-dependent MCF-7 breast cancer cells is promoted by constitutive caveolin-1 whose expression is lost in an EGF-R-mediated manner during development of tamoxifen resistance.	2010-02	19288272
Simvastatin inhibits angiotensin II-induced abdominal aortic aneurysm formation in apolipoprotein E-knockout mice: possible role of ERK.	2009-11	19729613
Suppression of Erk signalling promotes ground state pluripotency in the mouse embryo.	2009-10	19710168
MEK inhibitors potentiate dexamethasone lethality in acute lymphoblastic leukemia cells through the pro-apoptotic molecule BIM.	2009-10	19404317
Response and resistance to MEK inhibition in leukaemias initiated by hyperactive Ras.	2009-09-17	19727076
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.	2009-09-15	19737956
Distinct genetic alterations in the mitogen-activated protein kinase pathway dictate sensitivity of thyroid cancer cells to mitogen-activated protein kinase kinase 1/2 inhibition.	2009-08	19500021
Combined inhibition of MEK and mammalian target of rapamycin abolishes phosphorylation of cyclin-dependent kinase 4 in glioblastoma cell lines and prevents their proliferation.	2009-06-01	19458076
Inhibition of the growth of papillary thyroid carcinoma cells by CI-1040.	2009-04	19380355
Mitogen-activated protein kinase inhibition induces translocation of Bmf to promote apoptosis in melanoma.	2009-03-01	19244105
LKB1/KRAS mutant lung cancers constitute a genetic subset of NSCLC with increased sensitivity to MAPK and mTOR signalling inhibition.	2009-01-27	19165201
The discovery of the benzhydroxamate MEK inhibitors CI-1040 and PD 0325901.	2008-12-15	18952427
2-Alkylamino- and alkoxy-substituted 2-amino-1,3,4-oxadiazoles-O-Alkyl benzohydroxamate esters replacements retain the desired inhibition and selectivity against MEK (MAP ERK kinase).	2008-12-01	18951019
Targeting MEK/MAPK signal transduction module potentiates ATO-induced apoptosis in multiple myeloma cells through multiple signaling pathways.	2008-09-15	18583568
Reduction of chronic allograft nephropathy by inhibition of extracellular signal-regulated kinase 1 and 2 signaling.	2008-09	18614619
Cellular energetic status supervises the synthesis of bis-diphosphoinositol tetrakisphosphate independently of AMP-activated protein kinase.	2008-08	18460607
Restoration of PTEN expression alters the sensitivity of prostate cancer cells to EGFR inhibitors.	2008-06-15	18386291
K-ras as a target for lung cancer therapy.	2008-06	18520303
Increase of MCP-1 (CCL2) in myelin mutant Schwann cells is mediated by MEK-ERK signaling pathway.	2008-06	18383340
The ground state of embryonic stem cell self-renewal.	2008-05-22	18497825
Enzyme kinetics and binding studies on inhibitors of MEK protein kinase.	2008-04-29	18393446
Inhibitory effects of the mitogen-activated protein kinase kinase inhibitor CI-1040 on the proliferation and tumor growth of thyroid cancer cells with BRAF or RAS mutations.	2007-12	17911174
PD184352 releases the regular hypoxic reversible DNA replication arrest in T24 cells.	2007-11-30	18047784
4-anilino-5-carboxamido-2-pyridone derivatives as noncompetitive inhibitors of mitogen-activated protein kinase kinase.	2007-10-18	17880056
Central role of the MEK/ERK MAP kinase pathway in a mouse model of rheumatoid arthritis: potential proinflammatory mechanisms.	2007-10	17907188
The INT6 cancer gene and MEK signaling pathways converge during zebrafish development.	2007-09-26	17895999
MEK1/2 inhibitors potentiate UCN-01 lethality in human multiple myeloma cells through a Bim-dependent mechanism.	2007-09-15	17540843
Requirement for ERK MAP kinase in mouse preimplantation development.	2007-08	17611221
Selective inhibition of MEK1/2 reveals a differential requirement for ERK1/2 signalling in the regulation of HIF-1 in response to hypoxia and IGF-1.	2007-06-07	17213817
Mutations in BRAF and KRAS converge on activation of the mitogen-activated protein kinase pathway in lung cancer mouse models.	2007-05-15	17510423
MEK1/2 inhibitors sensitize Bcr/Abl+ human leukemia cells to the dual Abl/Src inhibitor BMS-354/825.	2007-05-01	17218385
Inhibition of the MAP kinase activity suppresses estrogen-induced breast tumor growth both in vitro and in vivo.	2007-04	17332937
ERK1/2-driven and MKP-mediated inhibition of EGF-induced ERK5 signaling in human proximal tubular cells.	2007-04	17131384
MEK blockade converts AML differentiating response to retinoids into extensive apoptosis.	2007-03-01	17077328
Upstream signaling inhibition enhances rapamycin effect on growth of kidney cancer cells.	2007-03	17382186
Dual mitogen-activated protein kinase and epidermal growth factor receptor inhibition in biliary and pancreatic cancer.	2007-03	17363501
Lovastatin inhibits the extracellular-signal-regulated kinase pathway in immortalized rat brain neuroblasts.	2007-01-01	16952276
A novel BH3 mimetic reveals a mitogen-activated protein kinase-dependent mechanism of melanoma cell death controlled by p53 and reactive oxygen species.	2006-12-01	17145881
Dissecting the roles of checkpoint kinase 1/CDC2 and mitogen-activated protein kinase kinase 1/2/extracellular signal-regulated kinase 1/2 in relation to 7-hydroxystaurosporine-induced apoptosis in human multiple myeloma cells.	2006-12	16940414
Protein kinases as drug targets in cancer.	2006-11	17100568
MEK1/2 inhibition promotes Taxotere lethality in mammary tumors in vivo.	2006-10	16957420
New molecular targeted therapies in thyroid cancer.	2006-09	16940797
An in vivo platform for translational drug development in pancreatic cancer.	2006-08-01	16899615
Assessment of gefitinib- and CI-1040-mediated changes in epidermal growth factor receptor signaling in HuCCT-1 human cholangiocarcinoma by serial fine needle aspiration.	2006-07	16891476
MEK1 inhibition sensitizes primary acute myelogenous leukemia to arsenic trioxide-induced apoptosis.	2006-06-01	16467208
Extracellular signal-regulated kinase inhibition slows disease progression in mice with polycystic kidney disease.	2006-06	16641154
Synergistic interactions between DMAG and mitogen-activated protein kinase kinase 1/2 inhibitors in Bcr/abl+ leukemia cells sensitive and resistant to imatinib mesylate.	2006-04-01	16609040
Increased dissolution rate and bioavailability through comicronization with microcrystalline cellulose.	2005	16370174

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

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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