WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 205885
CAS#: 623165-93-5
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.
MedKoo Cat#: 205885
Name: MRK003
CAS#: 623165-93-5
Chemical Formula: C25H31F6N3O2S
Exact Mass: 551.20412
Molecular Weight: 551.59
Elemental Analysis: C, 54.44; H, 5.66; F, 20.67; N, 7.62; O, 5.80; S, 5.81
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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
Appearance: Solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO, not in water
Shelf Life: >2 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
The following data is based on the product molecular weight 551.59 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass | 1 mg | 5 mg | 10 mg |
|---|---|---|---|
| 1 mM | 1.15 mL | 5.76 mL | 11.51 mL |
| 5 mM | 0.23 mL | 1.15 mL | 2.3 mL |
| 10 mM | 0.12 mL | 0.58 mL | 1.15 mL |
| 50 mM | 0.02 mL | 0.12 mL | 0.23 mL |
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, Hirao A. Strong therapeutic potential of γ-secretase inhibitor MRK003 for CD44-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 of biomarkers predictive of GSI response in triple-negative breast cancer and 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 in combination with Paclitaxel reduces platinum-resistant ovarian tumor growth. 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 in targeting pancreatic adenocarcinoma. Expert Opin Investig Drugs. 2014 Jun;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-secretase activity impedes uterine serous carcinoma growth in a human xenograft model. 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 gamma secretase 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 attenuates oxaliplatin-induced apoptosis through increased Mcl-1 and/or Bcl-xL in human 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 inhibition of glioblastoma xenograft initiation and clonogenic growth following in vivo 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 with cancer stem cell-like properties and correlates with worse survival in lung 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 and Akt inhibitors is effective for suppressing invasion but not proliferation 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 attenuates pancreatic cancer growth in preclinical models. Mol Cancer Ther. 2012 Sep;11(9):1999-2009. doi: 10.1158/1535-7163.MCT-12-0017. Epub 2012 Jul 2. 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 secretase inhibition promotes hypoxic necrosis in mouse pancreatic ductal adenocarcinoma. J Exp Med. 2012 Mar 12;209(3):437-44. doi: 10.1084/jem.20111923. Epub 2012 Feb 20. PubMed PMID: 22351932; PubMed Central 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 promotes growth and invasion in uveal melanoma. Clin Cancer Res. 2012 Feb 1;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 vitro but may be circumvented in tumorigenesis in vivo. Mol Cancer Res. 2011 Dec;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 pathways is 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. Epub 2011 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-secretase inhibitor exhibits promising in vitro pre-clinical activity in multiple myeloma 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-induced apoptosis 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 and NOTCH-4 are novel gene targets of PEA3 in breast cancer: novel therapeutic 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 stem cell properties in human hepatoma cell lines. BMC Gastroenterol. 2011 Jun 14;11:71. doi: 10.1186/1471-230X-11-71. PubMed PMID: 21669008; PubMed Central PMCID: PMC3136412.
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).
