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MedKoo product information:
Description of CI-1040:
CI-1040 is a
MEK inhibitor, which demonstrated in vivo activity in
preclinical animal models and subsequently became the first MEK
inhibitor to enter clinical trial.
suffered however from poor exposure due to its poor solubility and
rapid clearance, and as a result, development of the compound was
Current developer: Pfizer
Chemical Formula: C17H14ClF2IN2O2
Exact Mass: 477.97565
Molecular Weight: 478.66
Elemental Analysis: C, 42.66; H, 2.95; Cl,
7.41; F, 7.94; I, 26.51; N, 5.85; O, 6.69
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Information about this agent
CI-1040 (PD184352) is an orally active, highly
specific, small-molecule inhibitor of one of the key components of this
pathway (MEK1/MEK2), and thereby effectively blocks the phosphorylation
of ERK and continued signal transduction through this pathway. Antitumor
activity has been seen in preclinical models with this compound,
particularly for pancreas, colon, and breast cancers, which has been
shown to correlate with its inhibition of pERK. Clinically, CI-1040 has
been shown to be well tolerated in phase I studies, with safety and
pharmacokinetic profiles that permit continuous daily dosing. Biomarker
studies have shown target inhibition in patients, and antitumor activity
has also been observed with a partial response in one patient with
pancreatic cancer and stable disease in approximately 25% of phase I
patients. Given the central role of the ERK/mitogen-activated protein
kinase pathway in mediating growth-promoting signals for a diverse group
of upstream stimuli, inhibitors of MEK, as a key central mediator, could
have significant clinical benefit in the treatment of breast and other
However, in Phase II trials, CI-1040 demonstrated
insufficient antitumor activity to warrant further development in the
four tumors tested. PD 0325901, a second generation MEK inhibitor, has
recently entered clinical development and, with significantly improved
pharmacologic and pharmaceutical properties compared with CI-1040, it
may better test the therapeutic potential of MEK inhibition in cancer.
1: Ou DL, Shen YC, Liang JD, Liou JY, Yu SL,
Fan HH, Wang DS, Lu YS, Hsu C, Cheng AL. 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. Clin Cancer Res. 2009 Sep
15;15(18):5820-8. Epub 2009 Sep 8. PubMed PMID: 19737956.
2: Henderson YC, Ahn SH, Clayman GL. Inhibition of the growth of
papillary thyroid carcinoma cells by CI-1040. Arch Otolaryngol Head Neck
Surg. 2009 Apr;135(4):347-54. PubMed PMID: 19380355.
3: Barrett SD, Bridges AJ, Dudley DT, Saltiel AR, Fergus JH, Flamme CM,
Delaney AM, Kaufman M, LePage S, Leopold WR, Przybranowski SA, Sebolt-Leopold
J, Van Becelaere K, Doherty AM, Kennedy RM, Marston D, Howard WA Jr,
Smith Y, Warmus JS, Tecle H. The discovery of the benzhydroxamate MEK
inhibitors CI-1040 and PD 0325901. Bioorg Med Chem Lett. 2008 Dec
15;18(24):6501-4. Epub 2008 Oct 15. PubMed PMID: 18952427.
4: Liu D, Liu Z, Jiang D, Dackiw AP, Xing M. 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. J Clin Endocrinol Metab. 2007 Dec;92(12):4686-95. Epub 2007
Oct 2. PubMed PMID: 17911174.
5: Martin L. PD184352 releases the regular hypoxic reversible DNA
replication arrest in T24 cells. J Biochem Mol Biol. 2007 Nov
30;40(6):895-8. PubMed PMID: 18047784.
6: Hidalgo M, Amador ML, Jimeno A, Mezzadra H, Patel P, Chan A, Nielsen
ME, Maitra A, Altiok S. Assessment of gefitinib- and CI-1040-mediated
changes in epidermal growth factor receptor signaling in HuCCT-1 human
cholangiocarcinoma by serial fine needle aspiration. Mol Cancer Ther.
2006 Jul;5(7):1895-903. PubMed PMID: 16891476.
7: Mattingly RR, Kraniak JM, Dilworth JT, Mathieu P, Bealmear B, Nowak
JE, Benjamins JA, Tainsky MA, Reiners JJ Jr. The mitogen-activated
protein kinase/extracellular signal-regulated kinase kinase inhibitor
PD184352 (CI-1040) selectively induces apoptosis in malignant schwannoma
cell lines. J Pharmacol Exp Ther. 2006 Jan;316(1):456-65. Epub 2005 Oct
20. PubMed PMID: 16239399.
8: Lorusso PM, Adjei AA, Varterasian M, Gadgeel S, Reid J, Mitchell DY,
Hanson L, DeLuca P, Bruzek L, Piens J, Asbury P, Van Becelaere K,
Herrera R, Sebolt-Leopold J, Meyer MB. Phase I and pharmacodynamic study
of the oral MEK inhibitor CI-1040 in patients with advanced
malignancies. J Clin Oncol. 2005 Aug 10;23(23):5281-93. Epub 2005 Jul
11. PubMed PMID: 16009947.
9: Wang Y, Van Becelaere K, Jiang P, Przybranowski S, Omer C, Sebolt-Leopold
J. A role for K-ras in conferring resistance to the MEK inhibitor,
CI-1040. Neoplasia. 2005 Apr;7(4):336-47. PubMed PMID: 15967111; PubMed
Central PMCID: PMC1501146.
10: McDaid HM, Lopez-Barcons L, Grossman A, Lia M, Keller S, Pérez-Soler
R, Horwitz SB. Enhancement of the therapeutic efficacy of taxol by the
mitogen-activated protein kinase kinase inhibitor CI-1040 in nude mice
bearing human heterotransplants. Cancer Res. 2005 Apr 1;65(7):2854-60.
PubMed PMID: 15805287.
11: Wabnitz PA, Mitchell D, Wabnitz DA. In vitro and in vivo metabolism
of the anti-cancer agent CI-1040, a MEK inhibitor, in rat, monkey, and
human. Pharm Res. 2004 Sep;21(9):1670-9. PubMed PMID: 15497695.
12: Rinehart J, Adjei AA, Lorusso PM, Waterhouse D, Hecht JR, Natale RB,
Hamid O, Varterasian M, Asbury P, Kaldjian EP, Gulyas S, Mitchell DY,
Herrera R, Sebolt-Leopold JS, Meyer MB. Multicenter phase II study of
the oral MEK inhibitor, CI-1040, in patients with advanced
non-small-cell lung, breast, colon, and pancreatic cancer. J Clin Oncol.
2004 Nov 15;22(22):4456-62. Epub 2004 Oct 13. PubMed PMID: 15483017.
13: Kramer BW, Götz R, Rapp UR. Use of mitogenic cascade blockers for
treatment of C-Raf induced lung adenoma in vivo: CI-1040 strongly
reduces growth and improves lung structure. BMC Cancer. 2004 Jun 1;4:24.
PubMed PMID: 15171791; PubMed Central PMCID: PMC436059.
14: Allen LF, Sebolt-Leopold J, Meyer MB. CI-1040 (PD184352), a targeted
signal transduction inhibitor of MEK (MAPKK). Semin Oncol. 2003 Oct;30(5
Suppl 16):105-16. Review. PubMed PMID: 14613031.
15: Steensma DP, Mesa RA, Reeder TL, Tefferi A, Kaufmann SH. Effects of
the MEK inhibitor CI-1040 (PD 184352) on progenitor growth from normal
and myelodysplastic marrow. Haematologica. 2003 Sep;88(9):1072-4. PubMed
16: Meng XW, Chandra J, Loegering D, Van Becelaere K, Kottke TJ, Gore
SD, Karp JE, Sebolt-Leopold J, Kaufmann SH. Central role of Fas-associated
death domain protein in apoptosis induction by the mitogen-activated
protein kinase kinase inhibitor CI-1040 (PD184352) in acute lymphocytic
leukemia cells in vitro. J Biol Chem. 2003 Nov 21;278(47):47326-39. Epub
2003 Sep 8. PubMed PMID: 12963734.
17: Hawkins W, Mitchell C, McKinstry R, Gilfor D, Starkey J, Dai Y,
Dawson K, Ramakrishnan V, Roberts JD, Yacoub A, Grant S, Dent P.
Transient exposure of mammary tumors to PD184352 and UCN-01 causes tumor
cell death in vivo and prolonged suppression of tumor regrowth. Cancer
Biol Ther. 2005 Nov;4(11):1275-84. Epub 2005 Dec 1. PubMed PMID:
18: Delaney AM, Printen JA, Chen H, Fauman EB, Dudley DT. Identification
of a novel mitogen-activated protein kinase kinase activation domain
recognized by the inhibitor PD 184352. Mol Cell Biol. 2002
Nov;22(21):7593-602. PubMed PMID: 12370306; PubMed Central PMCID:
19: Squires MS, Nixon PM, Cook SJ. Cell-cycle arrest by PD184352
requires inhibition of extracellular signal-regulated kinases (ERK) 1/2
but not ERK5/BMK1. Biochem J. 2002 Sep 1;366(Pt 2):673-80. PubMed PMID:
12069688; PubMed Central PMCID: PMC1222809.
(Keyword; CAS#; MedKoo code#)