CI-1040

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WARNING: This product is for research use only, not for human or veterinary use.

Description:CI-1040, also known as PD184352, 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.

Price and Availability

CI-1040, purity > 98%, is in stock. Current shipping out time is about 2 weeks after order is received. CoA, QC data and MSDS documents are available in one week after order is received.

Chemical Structure

Theoretical Analysis

MedKoo Cat#: 200771Name: CI-1040CAS#: 212631-79-3Chemical Formula: C17H14ClF2IN2O2Exact Mass: 477.97565Molecular Weight: 478.66Elemental Analysis:C, 42.66; H, 2.95; Cl, 7.41; F, 7.94; I, 26.51; N, 5.85; O, 6.69

Synonym:CI1040; CI-1040; CI 1040; PD184352; PD 184352; PD-184352.

IUPAC/Chemical Name:2-(2-Chloro-4-iodophenylamino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide

InChi Key:GFMMXOIFOQCCGU-UHFFFAOYSA-N

InChi Code: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)

SMILES Code:O=C(NOCC1CC1)C2=CC=C(F)C(F)=C2NC3=CC=C(I)C=C3Cl

Technical Data

Additional Information

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.  

References

1: Ou DL, Shen YC, Liang JD, Liou JY, Yu SL,Fan HH, Wang DS, Lu YS, Hsu C, Cheng AL. Induction of Bim expressioncontributes to the antitumor synergy between sorafenib and mitogen-activatedprotein kinase/extracellular signal-regulated kinase kinase inhibitorCI-1040 in hepatocellular carcinoma. Clin Cancer Res. 2009 Sep15;15(18):5820-8. Epub 2009 Sep 8. PubMed PMID: 19737956.

2: Henderson YC, Ahn SH, Clayman GL. Inhibition of the growth ofpapillary thyroid carcinoma cells by CI-1040. Arch Otolaryngol Head NeckSurg. 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-LeopoldJ, Van Becelaere K, Doherty AM, Kennedy RM, Marston D, Howard WA Jr,Smith Y, Warmus JS, Tecle H. The discovery of the benzhydroxamate MEKinhibitors CI-1040 and PD 0325901. Bioorg Med Chem Lett. 2008 Dec15;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 themitogen-activated protein kinase kinase inhibitor CI-1040 on theproliferation and tumor growth of thyroid cancer cells with BRAF or RASmutations. J Clin Endocrinol Metab. 2007 Dec;92(12):4686-95. Epub 2007Oct 2. PubMed PMID: 17911174.

5: Martin L. PD184352 releases the regular hypoxic reversible DNAreplication arrest in T24 cells. J Biochem Mol Biol. 2007 Nov30;40(6):895-8. PubMed PMID: 18047784.

6: Hidalgo M, Amador ML, Jimeno A, Mezzadra H, Patel P, Chan A, NielsenME, Maitra A, Altiok S. Assessment of gefitinib- and CI-1040-mediatedchanges in epidermal growth factor receptor signaling in HuCCT-1 humancholangiocarcinoma 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, NowakJE, Benjamins JA, Tainsky MA, Reiners JJ Jr. The mitogen-activatedprotein kinase/extracellular signal-regulated kinase kinase inhibitorPD184352 (CI-1040) selectively induces apoptosis in malignant schwannomacell lines. J Pharmacol Exp Ther. 2006 Jan;316(1):456-65. Epub 2005 Oct20. 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 studyof the oral MEK inhibitor CI-1040 in patients with advancedmalignancies. J Clin Oncol. 2005 Aug 10;23(23):5281-93. Epub 2005 Jul11. PubMed PMID: 16009947.

9: Wang Y, Van Becelaere K, Jiang P, Przybranowski S, Omer C, Sebolt-LeopoldJ. A role for K-ras in conferring resistance to the MEK inhibitor,CI-1040. Neoplasia. 2005 Apr;7(4):336-47. PubMed PMID: 15967111; PubMedCentral PMCID: PMC1501146.

10: McDaid HM, Lopez-Barcons L, Grossman A, Lia M, Keller S, Pérez-SolerR, Horwitz SB. Enhancement of the therapeutic efficacy of taxol by themitogen-activated protein kinase kinase inhibitor CI-1040 in nude micebearing human heterotransplants. Cancer Res. 2005 Apr 1;65(7):2854-60.PubMed PMID: 15805287.

MedKoo，由化学家和药学家陈清奇博士。北卡罗莱纳州的研究三角区（ResearchTrianglePark,简称RTP)，是一家以研发、生产和销售小分子抗癌化合物为主的医药科技公司，该公司的业务范围主要是为全球所有从事抗癌药物研究和开发的制药公司，高校，研究院所，政府相关机构提供与抗癌药物分子相关的产品、试剂和技术服务。

中文名MedKoo中    文美帝药库医药科技公司创立于2008年总部位于美国东海岸

MedKoo是世界领先的供应商之一的抗癌化学试剂和激酶抑制剂。我们制造、销售和分发高质量的抗癌小分子肿瘤学研究试剂。我们的使命是建立世界上最全面的抗癌小分子的集合。我们也为医药行业提供高质量的研究服务、医学研究机构和学术机构。我们致力于提供优质的服务。

MedKoo是世界领先的供应商之一的抗癌化学试剂和激酶抑制剂。我们制造、销售和分发高质量的抗癌小分子肿瘤学研究试剂。我们的使命是建立世界上最全面的抗癌小分子的集合。我们也为医药行业提供高质量的研究服务、医学研究机构和学术机构。我们致力于提供优质的服务和分子有竞争力的价格。MedKoo是您可靠的合作伙伴采购药物发现和药物分子。

MedKoo是世界的抗癌化学试剂和激酶抑制剂供应商之一。我们制造，销售和分销用于肿瘤学研究的高质量抗癌小分子试剂。我们的使命是建立世界上全面的抗癌小分子集合。我们还为制药行业，医学研究组织和学术机构提供高质量的研究服务。我们致力于以具有竞争力的价格提供服务和分子。MedKoo是您可靠的药物发现和药物分子采购合作伙伴。

CRISPR-Cas9是近年兴起的用于靶向基因组特定位置，进行DNA修饰的重要工具。研究发现CRISPR是细菌为了应对病毒的攻击而演化而来的获得性免疫防御机制。具体来说，在CRISPR和Cas9的作用下，经由小RNA分子的引导，靶向并沉默入侵者遗传物质核酸的关键部分。在该系统中，crRNA（CRISPR-derivedRNA）与tracrRNA（trans-activatingRNA）结合形成的复合物能特异性识别靶基因序列，并引导Cas9核酸内切酶在靶定位点剪切双链DNA，随后，细胞的非同源末端连接修复机制（NHEJ）重新连接断裂处的基因组DNA，并引入插入或缺失突变。另外也可以提供一个外源双链供体DNA（Donor）通过同源重组（HR）整合进断裂处的基因组，从而达到对基因组DNA进行修饰的目的。
目前，CRISPR-Cas9系统的高效基因组编辑功能已被应用于多种生物，包括小鼠、大鼠、斑马鱼、秀丽隐杆线虫，也包含多种细菌和植物，甚至在人体上也有应用。