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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 of CI-1040

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
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

Curator's Comment: In June 2000, Warner Lambert merged with Pfizer and the resulting company retained the Pfizer name. Parke Davis was integrated into Pfizer Global Research and Development.

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
11700 ng/mL
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
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
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

AUC

ValueDoseCo-administeredAnalytePopulation
114000 ng × h/mL
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
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
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
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
20.9 h
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

Overview

OverviewOther

Drug as perpetrator​Drug as victim
PubMed

PubMed

TitleDatePubMed
Increased dissolution rate and bioavailability through comicronization with microcrystalline cellulose.
2005
Transient exposure of mammary tumors to PD184352 and UCN-01 causes tumor cell death in vivo and prolonged suppression of tumor regrowth.
2005 Nov
Anticancer Drug Discovery and Development - SRI's Seventh Annual Summit.
2005 Oct
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
A novel BH3 mimetic reveals a mitogen-activated protein kinase-dependent mechanism of melanoma cell death controlled by p53 and reactive oxygen species.
2006 Dec 1
The mitogen-activated protein kinase/extracellular signal-regulated kinase kinase inhibitor PD184352 (CI-1040) selectively induces apoptosis in malignant schwannoma cell lines.
2006 Jan
BRAF mutation predicts sensitivity to MEK inhibition.
2006 Jan 19
Blockade of the ERK pathway markedly sensitizes tumor cells to HDAC inhibitor-induced cell death.
2006 Jan 27
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 Jul
Extracellular signal-regulated kinase inhibition slows disease progression in mice with polycystic kidney disease.
2006 Jun
Bidirectional cross talk between ERalpha and EGFR signalling pathways regulates tamoxifen-resistant growth.
2006 Mar
Protein kinases as drug targets in cancer.
2006 Nov
Inhibition of the MAP kinase activity suppresses estrogen-induced breast tumor growth both in vitro and in vivo.
2007 Apr
ERK1/2-driven and MKP-mediated inhibition of EGF-induced ERK5 signaling in human proximal tubular cells.
2007 Apr
Requirement for ERK MAP kinase in mouse preimplantation development.
2007 Aug
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 Dec
Lovastatin inhibits the extracellular-signal-regulated kinase pathway in immortalized rat brain neuroblasts.
2007 Jan 1
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 Jun 7
Upstream signaling inhibition enhances rapamycin effect on growth of kidney cancer cells.
2007 Mar
Dual mitogen-activated protein kinase and epidermal growth factor receptor inhibition in biliary and pancreatic cancer.
2007 Mar
MEK1/2 inhibitors sensitize Bcr/Abl+ human leukemia cells to the dual Abl/Src inhibitor BMS-354/825.
2007 May 1
Mutations in BRAF and KRAS converge on activation of the mitogen-activated protein kinase pathway in lung cancer mouse models.
2007 May 15
PD184352 releases the regular hypoxic reversible DNA replication arrest in T24 cells.
2007 Nov 30
Central role of the MEK/ERK MAP kinase pathway in a mouse model of rheumatoid arthritis: potential proinflammatory mechanisms.
2007 Oct
4-anilino-5-carboxamido-2-pyridone derivatives as noncompetitive inhibitors of mitogen-activated protein kinase kinase.
2007 Oct 18
MEK1/2 inhibitors potentiate UCN-01 lethality in human multiple myeloma cells through a Bim-dependent mechanism.
2007 Sep 15
The INT6 cancer gene and MEK signaling pathways converge during zebrafish development.
2007 Sep 26
Enzyme kinetics and binding studies on inhibitors of MEK protein kinase.
2008 Apr 29
Cellular energetic status supervises the synthesis of bis-diphosphoinositol tetrakisphosphate independently of AMP-activated protein kinase.
2008 Aug
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 Dec 1
The discovery of the benzhydroxamate MEK inhibitors CI-1040 and PD 0325901.
2008 Dec 15
K-ras as a target for lung cancer therapy.
2008 Jun
Increase of MCP-1 (CCL2) in myelin mutant Schwann cells is mediated by MEK-ERK signaling pathway.
2008 Jun
Restoration of PTEN expression alters the sensitivity of prostate cancer cells to EGFR inhibitors.
2008 Jun 15
The ground state of embryonic stem cell self-renewal.
2008 May 22
Reduction of chronic allograft nephropathy by inhibition of extracellular signal-regulated kinase 1 and 2 signaling.
2008 Sep
Targeting MEK/MAPK signal transduction module potentiates ATO-induced apoptosis in multiple myeloma cells through multiple signaling pathways.
2008 Sep 15
Inhibition of the growth of papillary thyroid carcinoma cells by CI-1040.
2009 Apr
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 Aug
LKB1/KRAS mutant lung cancers constitute a genetic subset of NSCLC with increased sensitivity to MAPK and mTOR signalling inhibition.
2009 Jan 27
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 Jun 1
Mitogen-activated protein kinase inhibition induces translocation of Bmf to promote apoptosis in melanoma.
2009 Mar 1
Simvastatin inhibits angiotensin II-induced abdominal aortic aneurysm formation in apolipoprotein E-knockout mice: possible role of ERK.
2009 Nov
Suppression of Erk signalling promotes ground state pluripotency in the mouse embryo.
2009 Oct
MEK inhibitors potentiate dexamethasone lethality in acute lymphoblastic leukemia cells through the pro-apoptotic molecule BIM.
2009 Oct
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
Response and resistance to MEK inhibition in leukaemias initiated by hyperactive Ras.
2009 Sep 17
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 Feb
Three-dimensional overlay culture models of human breast cancer reveal a critical sensitivity to mitogen-activated protein kinase kinase inhibitors.
2010 Mar
Hepatitis C virus RNA replication is regulated by Ras-Erk signalling.
2010 Mar
Patents

Sample Use Guides

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
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 Fri Dec 15 15:47:41 UTC 2023
Edited
by admin
on Fri Dec 15 15:47:41 UTC 2023
Record UNII
R3K9Y00J04
Record Status Validated (UNII)
Record Version
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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
Created by admin on Fri Dec 15 15:47:41 UTC 2023 , Edited by admin on Fri Dec 15 15:47:41 UTC 2023
PRIMARY
FDA UNII
R3K9Y00J04
Created by admin on Fri Dec 15 15:47:41 UTC 2023 , Edited by admin on Fri Dec 15 15:47:41 UTC 2023
PRIMARY
ChEMBL
CHEMBL105442
Created by admin on Fri Dec 15 15:47:41 UTC 2023 , Edited by admin on Fri Dec 15 15:47:41 UTC 2023
PRIMARY
EPA CompTox
DTXSID8048945
Created by admin on Fri Dec 15 15:47:41 UTC 2023 , Edited by admin on Fri Dec 15 15:47:41 UTC 2023
PRIMARY
DRUG BANK
DB12429
Created by admin on Fri Dec 15 15:47:41 UTC 2023 , Edited by admin on Fri Dec 15 15:47:41 UTC 2023
PRIMARY
PUBCHEM
6918454
Created by admin on Fri Dec 15 15:47:41 UTC 2023 , Edited by admin on Fri Dec 15 15:47:41 UTC 2023
PRIMARY
NCI_THESAURUS
C2670
Created by admin on Fri Dec 15 15:47:41 UTC 2023 , Edited by admin on Fri Dec 15 15:47:41 UTC 2023
PRIMARY
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