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: 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
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
ERK kinase inhibition stabilizes the aryl hydrocarbon receptor: implications for transcriptional activation and protein degradation.	2005 Feb 11	15572374
Inactivation of the mitogen-activated protein kinase pathway as a potential target-based therapy in ovarian serous tumors with KRAS or BRAF mutations.	2005 Mar 1	15753399
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
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
An in vivo platform for translational drug development in pancreatic cancer.	2006 Aug 1	16899615
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
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
Blockade of the ERK pathway markedly sensitizes tumor cells to HDAC inhibitor-induced cell death.	2006 Jan 27	16338224
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
MEK1 inhibition sensitizes primary acute myelogenous leukemia to arsenic trioxide-induced apoptosis.	2006 Jun 1	16467208
Bidirectional cross talk between ERalpha and EGFR signalling pathways regulates tamoxifen-resistant growth.	2006 Mar	16261397
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
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
Mitogen-activated protein kinase inhibition induces translocation of Bmf to promote apoptosis in melanoma.	2009 Mar 1	19244105
MEK inhibitors potentiate dexamethasone lethality in acute lymphoblastic leukemia cells through the pro-apoptotic molecule BIM.	2009 Oct	19404317
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

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 `Fri Dec 15 15:47:41 GMT 2023` Edited by `admin` on `Fri Dec 15 15:47:41 GMT 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