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
Increased dissolution rate and bioavailability through comicronization with microcrystalline cellulose.	2005	16370174
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
An in vivo platform for translational drug development in pancreatic cancer.	2006 Aug 1	16899615
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 Dec	16940414
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	17145881
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	16891476
Extracellular signal-regulated kinase inhibition slows disease progression in mice with polycystic kidney disease.	2006 Jun	16641154
MEK1 inhibition sensitizes primary acute myelogenous leukemia to arsenic trioxide-induced apoptosis.	2006 Jun 1	16467208
Protein kinases as drug targets in cancer.	2006 Nov	17100568
MEK1/2 inhibition promotes Taxotere lethality in mammary tumors in vivo.	2006 Oct	16957420
New molecular targeted therapies in thyroid cancer.	2006 Sep	16940797
Inhibition of the MAP kinase activity suppresses estrogen-induced breast tumor growth both in vitro and in vivo.	2007 Apr	17332937
ERK1/2-driven and MKP-mediated inhibition of EGF-induced ERK5 signaling in human proximal tubular cells.	2007 Apr	17131384
Requirement for ERK MAP kinase in mouse preimplantation development.	2007 Aug	17611221
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	17911174
Lovastatin inhibits the extracellular-signal-regulated kinase pathway in immortalized rat brain neuroblasts.	2007 Jan 1	16952276
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	17213817
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
MEK blockade converts AML differentiating response to retinoids into extensive apoptosis.	2007 Mar 1	17077328
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
Central role of the MEK/ERK MAP kinase pathway in a mouse model of rheumatoid arthritis: potential proinflammatory mechanisms.	2007 Oct	17907188
4-anilino-5-carboxamido-2-pyridone derivatives as noncompetitive inhibitors of mitogen-activated protein kinase kinase.	2007 Oct 18	17880056
MEK1/2 inhibitors potentiate UCN-01 lethality in human multiple myeloma cells through a Bim-dependent mechanism.	2007 Sep 15	17540843
The INT6 cancer gene and MEK signaling pathways converge during zebrafish development.	2007 Sep 26	17895999
Enzyme kinetics and binding studies on inhibitors of MEK protein kinase.	2008 Apr 29	18393446
Cellular energetic status supervises the synthesis of bis-diphosphoinositol tetrakisphosphate independently of AMP-activated protein kinase.	2008 Aug	18460607
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	18951019
The discovery of the benzhydroxamate MEK inhibitors CI-1040 and PD 0325901.	2008 Dec 15	18952427
K-ras as a target for lung cancer therapy.	2008 Jun	18520303
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
The ground state of embryonic stem cell self-renewal.	2008 May 22	18497825
Reduction of chronic allograft nephropathy by inhibition of extracellular signal-regulated kinase 1 and 2 signaling.	2008 Sep	18614619
Targeting MEK/MAPK signal transduction module potentiates ATO-induced apoptosis in multiple myeloma cells through multiple signaling pathways.	2008 Sep 15	18583568
Inhibition of the growth of papillary thyroid carcinoma cells by CI-1040.	2009 Apr	19380355
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	19500021
LKB1/KRAS mutant lung cancers constitute a genetic subset of NSCLC with increased sensitivity to MAPK and mTOR signalling inhibition.	2009 Jan 27	19165201
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	19458076
Mitogen-activated protein kinase inhibition induces translocation of Bmf to promote apoptosis in melanoma.	2009 Mar 1	19244105
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
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	19288272
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