Synonym
Dofequidar fumarate; MS-209 fumarate; MS 209 fumarate; MS209 fumarate;
IUPAC/Chemical Name
1-[4-(2-Hydroxy-3-quinolin-5-yloxypropyl)piperazin-1-yl]-2,2-diphenylethanone fumarate (2:3)
InChi Key
ZGMJYTYLTJFNCS-VQYXCCSOSA-N
InChi Code
InChI=1S/2C30H31N3O3.3C4H4O4/c2*34-25(22-36-28-15-7-14-27-26(28)13-8-16-31-27)21-32-17-19-33(20-18-32)30(35)29(23-9-3-1-4-10-23)24-11-5-2-6-12-24;3*5-3(6)1-2-4(7)8/h2*1-16,25,29,34H,17-22H2;3*1-2H,(H,5,6)(H,7,8)/b;;3*2-1+
SMILES Code
OC(COC1=C2C=CC=NC2=CC=C1)CN3CCN(C(C(C4=CC=CC=C4)C5=CC=CC=C5)=O)CC3.OC(COC6=C7C=CC=NC7=CC=C6)CN8CCN(C(C(C9=CC=CC=C9)C%10=CC=CC=C%10)=O)CC8.O=C(O)/C=C/C(O)=O.O=C(O)/C=C/C(O)=O.O=C(O)/C=C/C(O)=O
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
Shelf Life
>3 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
2934.99.03.00
Biological target:
Dofequidar fumarate is a potent inhibitor of MDR-1.
In vitro activity:
Because dofequidar could reduce the cell number in the SP fraction that highly expressed ABCG2/BCRP (Figs 3,4), it was hypothesized that dofequidar had the ability to inhibit ABCG2/BCRP in addition to the previously reported ABCB1/P-gp and ABCC1/MRP1. Parental K562 cells or K562 stable transfectants were stained with Hoechst33342 in the presence or absence of ABC-T inhibitors. Dofequidar but not verapamil could increase the intracellular Hoechst33342 concentration in K562/BCRP cells dose dependently (Fig. S1B). Similar results were obtained in KB/BCRP cells (data not shown). To confirm the result, this study carried out an in vitro vesicle transport assay. Membrane vesicles from control or ABCG2/BCRP-overexpressing insect cells were incubated with [3H]MTX in the presence of ATP or AMP. The ATP-dependent uptake of [3H]MTX was observed in ABCG2/BCRP-overexpressing membrane vesicles but not in control vesicles (Fig. 4A). FTC (Fumitremorgin C) and dofequidar, but not verapamil, inhibited [3H]MTX uptake dose dependently (Fig. 5A). These results suggest that dofequidar had the ability to inhibit ABCG2/BCRP in addition to the previously reported ABCB1/P-gp and ABCC1/MRP1.
Reference: Cancer Sci. 2009 Nov;100(11):2060-8. https://onlinelibrary.wiley.com/doi/full/10.1111/j.1349-7006.2009.01288.x
In vivo activity:
FTC is not suitable for clinical studies because of its severe toxicity, but it strongly and specifically inhibits ABCG2/BCRP. On the other hand, dofequidar exhibits low toxicity and has already been approved for clinical trials. To overcome the chemoresistance of cancer stem-like SP cells in vivo, this study evaluated the antitumor activity of CPT-11 plus dofequidar in a clinically relevant model. HeLa-derived SP and NSP cells were transplanted into nude mice, and the xenografted tumors were treated with CPT-11 with or without dofequidar. Dofequidar (200 mg/kg) was orally administrated 30 min before CPT-11 (67 mg/kg) injection. Although xenografted HeLa SP cells showed resistance to CPT-11, co-treatment of the mice with dofequidar drastically decreased the tumor volume (Fig. 6B, left panel), like that seen in CPT-11-treated or CPT-11 plus dofequidar-treated NSP-bearing mice (Fig. 6B, right panel). Dofequidar alone had almost no effect on SP- or NSP-derived tumor growth in vivo. To assess the toxicity, the study measured the bodyweight of the tumor-bearing mice. The mice seemed to be healthy (Fig. 6C), and the change in bodyweight was very small (data not shown). Thus CPT-11 plus dofequidar therapy appeared to have good therapeutic efficacy in vivo by sensitizing cancer stem-like cells to anticancer drugs.
Reference: Cancer Sci. 2009 Nov;100(11):2060-8. https://onlinelibrary.wiley.com/doi/full/10.1111/j.1349-7006.2009.01288.x
Preparing Stock Solutions
The following data is based on the
product
molecular weight
1,311.41
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 |
Formulation protocol:
1. Katayama R, Koike S, Sato S, Sugimoto Y, Tsuruo T, Fujita N. Dofequidar fumarate sensitizes cancer stem-like side population cells to chemotherapeutic drugs by inhibiting ABCG2/BCRP-mediated drug export. Cancer Sci. 2009 Nov;100(11):2060-8. doi: 10.1111/j.1349-7006.2009.01288.x. Epub 2009 Jul 17. PMID: 19673889.
In vitro protocol:
1. Katayama R, Koike S, Sato S, Sugimoto Y, Tsuruo T, Fujita N. Dofequidar fumarate sensitizes cancer stem-like side population cells to chemotherapeutic drugs by inhibiting ABCG2/BCRP-mediated drug export. Cancer Sci. 2009 Nov;100(11):2060-8. doi: 10.1111/j.1349-7006.2009.01288.x. Epub 2009 Jul 17. PMID: 19673889.
In vivo protocol:
1. Katayama R, Koike S, Sato S, Sugimoto Y, Tsuruo T, Fujita N. Dofequidar fumarate sensitizes cancer stem-like side population cells to chemotherapeutic drugs by inhibiting ABCG2/BCRP-mediated drug export. Cancer Sci. 2009 Nov;100(11):2060-8. doi: 10.1111/j.1349-7006.2009.01288.x. Epub 2009 Jul 17. PMID: 19673889.
1: Katayama R, Koike S, Sato S, Sugimoto Y, Tsuruo T, Fujita N. Dofequidar fumarate sensitizes cancer stem-like side population cells to chemotherapeutic drugs by inhibiting ABCG2/BCRP-mediated drug export. Cancer Sci. 2009 Nov;100(11):2060-8. doi: 10.1111/j.1349-7006.2009.01288.x. Epub 2009 Jul 17. PubMed PMID: 19673889.
2: Bayés M, Rabasseda X, Prous JR. Gateways to clinical trials. Methods Find Exp Clin Pharmacol. 2007 Jun;29(5):359-73. PubMed PMID: 17805439.
3: Saeki T, Nomizu T, Toi M, Ito Y, Noguchi S, Kobayashi T, Asaga T, Minami H, Yamamoto N, Aogi K, Ikeda T, Ohashi Y, Sato W, Tsuruo T. Dofequidar fumarate (MS-209) in combination with cyclophosphamide, doxorubicin, and fluorouracil for patients with advanced or recurrent breast cancer. J Clin Oncol. 2007 Feb 1;25(4):411-7. Epub 2006 Dec 18. PubMed PMID: 17179098.
4: Saeki T, Tsuruo T, Sato W, Nishikawsa K. Drug resistance in chemotherapy for breast cancer. Cancer Chemother Pharmacol. 2005 Nov;56 Suppl 1:84-9. PubMed PMID: 16273361.
