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CI-1040

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. CI-1040 suffered however from poor exposure due to its poor solubility and rapid clearance, and as a result, development of the compound was terminated.

Current developer: Pfizer

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 cancers.

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 PMID: 12969818.

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: 16319524.

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: PMC135683.

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.