MRK003

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

Description:MRK003 is a γ-secretase inhibitor exhibits promising in vitro pre-clinical activity in multiple myeloma and non-Hodgkin's lymphoma. MRK003 treatment induced caspase-dependent apoptosis and inhibited proliferation of MM and NHL cell lines and patient cells. Examination of signaling events after treatment showed time-dependent decrease in levels of the notch intracellular domain, Hes1 and c-Myc. MRK003 downregulated cyclin D1, Bcl-Xl and Xiap levels in NHL cells and p21, Bcl-2 and Bcl-Xl in MM cells. In addition, MRK003 caused an upregulation of pAkt, indicating crosstalk with the PI3K/Akt pathway.

Price and Availability

MRK003 is not in stock, but may be available through custom synthesis. For cost-effective reason, minimum 1 gram order is requested. The product will be characterized by NMR, HPLC and MS analysis. Purity (HPLC) is usually >98%. CoA, QC data, MSDS will be provided when product is successfully made. The estimated lead time is 2-3 months. Please send email to sales@medkoo.com to inquire quote.

Chemical Structure

Theoretical Analysis

MedKoo Cat#: 205885Name: MRK003CAS#: 623165-93-5Chemical Formula: C25H31F6N3O2SExact Mass: 551.20412Molecular Weight: 551.59Elemental Analysis:C, 54.44; H, 5.66; F, 20.67; N, 7.62; O, 5.80; S, 5.81

Synonym:MRK003; MRK 003; MRK-003.

IUPAC/Chemical Name:(3'R,6R,9R)-5'-(2,2,2-trifluoroethyl)-2-((E)-3-(4-(trifluoromethyl)piperidin-1-yl)prop-1-en-1-yl)-5,6,7,8,9,10-hexahydrospiro[6,9-methanobenzo[8]annulene-11,3'-[1,2,5]thiadiazolidine] 1',1'-dioxide.

InChi Key:NKHUILHBYOOZDF-RWIQBJEJSA-N

InChi Code:InChI=1S/C25H31F6N3O2S/c26-24(27,28)16-34-15-23(32-37(34,35)36)21-5-6-22(23)14-19-12-17(3-4-18(19)13-21)2-1-9-33-10-7-20(8-11-33)25(29,30)31/h1-4,12,20-22,32H,5-11,13-16H2/b2-1+/t21-,22-,23-/m1/s1

SMILES Code:FC(C1CCN(C/C=C/C2=CC=C3C(C[C@@]4([H])CC[C@]([C@@]4(CN5CC(F)(F)F)NS5(=O)=O)([H])C3)=C2)CC1)(F)F

Technical Data

Additional Information

  Highlights of recent research using this agent MRK-003 inhibits Notch3 signaling, growth, and apoptosis of lung cancer cell lines in vitro and in vivo using mouse xenograft models  (Cancer Res 2007;67(17):8051–7, http://cancerres.aacrjournals.org/content/67/17/8051.full).   

References

1: Tanaka S, Nakada M, Yamada D, Nakano I, Todo T,Ino Y, Hoshii T, Tadokoro Y, Ohta K, Ali MA, Hayashi Y, Hamada J, HiraoA. Strong therapeutic potential of γ-secretase inhibitor MRK003 forCD44-high and CD133-low glioblastoma initiating cells. J Neurooncol.2015 Jan;121(2):239-50. doi: 10.1007/s11060-014-1630-z. Epub 2014 Oct 8.PubMed PMID: 25293440.

2: Stoeck A, Lejnine S, Truong A, Pan L, Wang H, Zang C, Yuan J, Ware C,MacLean J, Garrett-Engele PW, Kluk M, Laskey J, Haines BB, Moskaluk C,Zawel L, Fawell S, Gilliland G, Zhang T, Kremer BE, Knoechel B,Bernstein BE, Pear WS, Liu XS, Aster JC, Sathyanarayanan S. Discovery ofbiomarkers predictive of GSI response in triple-negative breast cancerand adenoid cystic carcinoma. Cancer Discov. 2014 Oct;4(10):1154-67. doi:10.1158/2159-8290.CD-13-0830. Epub 2014 Aug 7. PubMed PMID: 25104330;PubMed Central PMCID: PMC4184927.

3: Groeneweg JW, DiGloria CM, Yuan J, Richardson WS, Growdon WB,Sathyanarayanan S, Foster R, Rueda BR. Inhibition of notch signaling incombination with Paclitaxel reduces platinum-resistant ovarian tumorgrowth. Front Oncol. 2014 Jul 7;4:171. doi: 10.3389/fonc.2014.00171.eCollection 2014. PubMed PMID: 25072022; PubMed Central PMCID:PMC4083224.

4: Samore WR, Gondi CS. Brief overview of selected approaches intargeting pancreatic adenocarcinoma. Expert Opin Investig Drugs. 2014Jun;23(6):793-807. doi: 10.1517/13543784.2014.902933. Epub 2014 Mar 27.Review. PubMed PMID: 24673265.

5: Groeneweg JW, Hall TR, Zhang L, Kim M, Byron VF, Tambouret R,Sathayanrayanan S, Foster R, Rueda BR, Growdon WB. Inhibition of gamma-secretaseactivity impedes uterine serous carcinoma growth in a human xenograftmodel. Gynecol Oncol. 2014 Jun;133(3):607-15. doi:10.1016/j.ygyno.2014.03.560. Epub 2014 Mar 22. PubMed PMID: 24667249.

6: Liu QQ, Liu JL, Guo DM, Teng QL. [Inhibitory effects of gammasecretase inhibitor on human multiple myeloma xenograft mouse model].Zhonghua Xue Ye Xue Za Zhi. 2013 Sep;34(9):794-7. doi:10.3760/cma.j.issn.0253-2727.2013.09.012. Chinese. PubMed PMID:24103879.

7: Timme CR, Gruidl M, Yeatman TJ. Gamma-secretase inhibition attenuatesoxaliplatin-induced apoptosis through increased Mcl-1 and/or Bcl-xL inhuman colon cancer cells. Apoptosis. 2013 Oct;18(10):1163-74. doi:10.1007/s10495-013-0883-x. PubMed PMID: 23887890.

8: Chu Q, Orr BA, Semenkow S, Bar EE, Eberhart CG. Prolonged inhibitionof glioblastoma xenograft initiation and clonogenic growth following invivo Notch blockade. Clin Cancer Res. 2013 Jun 15;19(12):3224-33. doi:10.1158/1078-0432.CCR-12-2119. Epub 2013 Apr 29. PubMed PMID: 23630166;PubMed Central PMCID: PMC3686970.

9: Hassan KA, Wang L, Korkaya H, Chen G, Maillard I, Beer DG,Kalemkerian GP, Wicha MS. Notch pathway activity identifies cells withcancer stem cell-like properties and correlates with worse survival inlung adenocarcinoma. Clin Cancer Res. 2013 Apr 15;19(8):1972-80. doi:10.1158/1078-0432.CCR-12-0370. Epub 2013 Feb 26. PubMed PMID: 23444212;PubMed Central PMCID: PMC3630232.

10: Jin R, Nakada M, Teng L, Furuta T, Sabit H, Hayashi Y, Demuth T,Hirao A, Sato H, Zhao G, Hamada J. Combination therapy using Notch andAkt inhibitors is effective for suppressing invasion but notproliferation in glioma cells. Neurosci Lett. 2013 Feb 8;534:316-21. doi:10.1016/j.neulet.2012.12.008. Epub 2012 Dec 20. PubMed PMID: 23262078.

11: Liang S, Galluzzo P, Sobol A, Skucha S, Rambo B, Bocchetta M.Multimodality Approaches to Treat Hypoxic Non-Small Cell Lung Cancer(NSCLC) Microenvironment. Genes Cancer. 2012 Feb;3(2):141-51. doi:10.1177/1947601912457025. PubMed PMID: 23050046; PubMed Central PMCID:PMC3463922.

12: Mizuma M, Rasheed ZA, Yabuuchi S, Omura N, Campbell NR, de Wilde RF,De Oliveira E, Zhang Q, Puig O, Matsui W, Hidalgo M, Maitra A,Rajeshkumar NV. The gamma secretase inhibitor MRK-003 attenuatespancreatic cancer growth in preclinical models. Mol Cancer Ther. 2012Sep;11(9):1999-2009. doi: 10.1158/1535-7163.MCT-12-0017. Epub 2012 Jul2. PubMed PMID: 22752426; PubMed Central PMCID: PMC3438318.

13: Cook N, Frese KK, Bapiro TE, Jacobetz MA, Gopinathan A, Miller JL,Rao SS, Demuth T, Howat WJ, Jodrell DI, Tuveson DA. Gamma secretaseinhibition promotes hypoxic necrosis in mouse pancreatic ductaladenocarcinoma. J Exp Med. 2012 Mar 12;209(3):437-44. doi:10.1084/jem.20111923. Epub 2012 Feb 20. PubMed PMID: 22351932; PubMedCentral PMCID: PMC3302221.

14: Asnaghi L, Ebrahimi KB, Schreck KC, Bar EE, Coonfield ML, Bell WR,Handa J, Merbs SL, Harbour JW, Eberhart CG. Notch signaling promotesgrowth and invasion in uveal melanoma. Clin Cancer Res. 2012 Feb1;18(3):654-65. doi: 10.1158/1078-0432.CCR-11-1406. Epub 2012 Jan 6.PubMed PMID: 22228632.

15: Osanyingbemi-Obidi J, Dobromilskaya I, Illei PB, Hann CL, Rudin CM.Notch signaling contributes to lung cancer clonogenic capacity in vitrobut may be circumvented in tumorigenesis in vivo. Mol Cancer Res. 2011Dec;9(12):1746-54. doi: 10.1158/1541-7786.MCR-11-0286. Epub 2011 Oct 12.PubMed PMID: 21994468; PubMed Central PMCID: PMC3243765.

16: Pandya K, Meeke K, Clementz AG, Rogowski A, Roberts J, Miele L,Albain KS, Osipo C. Targeting both Notch and ErbB-2 signalling pathwaysis required for prevention of ErbB-2-positive breast tumour recurrence.Br J Cancer. 2011 Sep 6;105(6):796-806. doi: 10.1038/bjc.2011.321. Epub2011 Aug 16. PubMed PMID: 21847123; PubMed Central PMCID: PMC3171020.

17: Ramakrishnan V, Ansell S, Haug J, Grote D, Kimlinger T, Stenson M,Timm M, Wellik L, Halling T, Rajkumar SV, Kumar S. MRK003, a γ-secretaseinhibitor exhibits promising in vitro pre-clinical activity in multiplemyeloma and non-Hodgkin"s lymphoma. Leukemia. 2012 Feb;26(2):340-8. doi:10.1038/leu.2011.192. Epub 2011 Aug 9. PubMed PMID: 21826062.

18: Lin H, Xiong W, Zhang X, Liu B, Zhang W, Zhang Y, Cheng J, Huang H.Notch-1 activation-dependent p53 restoration contributes to resveratrol-inducedapoptosis in glioblastoma cells. Oncol Rep. 2011 Oct;26(4):925-30. doi:10.3892/or.2011.1380. Epub 2011 Jul 4. PubMed PMID: 21743969.

19: Clementz AG, Rogowski A, Pandya K, Miele L, Osipo C. NOTCH-1 andNOTCH-4 are novel gene targets of PEA3 in breast cancer: noveltherapeutic implications. Breast Cancer Res. 2011 Jun 14;13(3):R63. doi:10.1186/bcr2900. PubMed PMID: 21679465; PubMed Central PMCID:PMC3218952.

20: Cao L, Zhou Y, Zhai B, Liao J, Xu W, Zhang R, Li J, Zhang Y, Chen L,Qian H, Wu M, Yin Z. Sphere-forming cell subpopulations with cancer stemcell properties in human hepatoma cell lines. BMC Gastroenterol. 2011Jun 14;11:71. doi: 10.1186/1471-230X-11-71. PubMed PMID: 21669008;PubMed Central PMCID: PMC3136412.

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。