K-7174-2HCl
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MedKoo CAT#: 406454

CAS#: 191089-60-8 (HCl)

Description: K-7174 is a novel orally active, potent proteasome inhibitor. K-7174 exerts anti-myeloma activity in vitro and in vivo by down-regulating the expression of class I histone deacetylases. K-7174 kills bortezomib-resistant myeloma cells carrying a β5-subunit mutation in vivo and primary cells from a patient resistant to bortezomib. K-7174 is also a GATA-specific inhibitor, which may have potential application in treating anemia of chronic disease.


Chemical Structure

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K-7174-2HCl
CAS# 191089-60-8 (HCl)

Theoretical Analysis

MedKoo Cat#: 406454
Name: K-7174-2HCl
CAS#: 191089-60-8 (HCl)
Chemical Formula: C33H50Cl2N2O6
Exact Mass:
Molecular Weight: 640.3
Elemental Analysis: C, 61.77; H, 7.85; Cl, 11.05; N, 4.37; O, 14.96

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Related CAS #: 191089-60-8 (HCl)   191089-59-5 (free base)  

Synonym: K7174; K 7174; K-7174; K-7174-2HCl; K-7174 dihydrochloride.

IUPAC/Chemical Name: 1,4-bis((E)-5-(3,4,5-trimethoxyphenyl)pent-4-en-1-yl)-1,4-diazepane dihydrochloride.

InChi Key: JKAQFPBRMVEHBD-CHBZAFCASA-N

InChi Code: InChI=1S/C33H48N2O6.2ClH/c1-36-28-22-26(23-29(37-2)32(28)40-5)14-9-7-11-16-34-18-13-19-35(21-20-34)17-12-8-10-15-27-24-30(38-3)33(41-6)31(25-27)39-4;;/h9-10,14-15,22-25H,7-8,11-13,16-21H2,1-6H3;2*1H/b14-9+,15-10+;;

SMILES Code: COC1=C(OC)C(OC)=CC(/C=C/CCCN2CCN(CCC/C=C/C3=CC(OC)=C(OC)C(OC)=C3)CCC2)=C1.[H]Cl.[H]Cl

Appearance: White to off-white 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 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

Biological target: K-7174 dihydrochloride is a novel cell adhesion inhibitor; inhibits the expression of vascular cell adhesion molecule-1 (VCAM-1) induced by either IL-1β or TNF-α.
In vitro activity: First, we examined the cytotoxic effect of K-7174 on MM cell lines using MTT assays. K-7174 significantly inhibited the growth of three MM cell lines in a dose-dependent manner (Fig. 1B). Next, we confirmed the anti-myeloma activity of K-7174 using primary MM cells. CD138-positive cells isolated from bone marrow samples of 6 patients were cultured in the absence or presence of K-7174 for 2 days, followed by annexin-V staining to assess the induction of apoptosis. K-7174 significantly increased the percentage of annexin-V-positive cells in all cases examined (Fig. 1C). Reference: J Biol Chem. 2013 Aug 30;288(35):25593-25602. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23878197/
In vivo activity: The in vivo efficacy was examined using a xenograft mouse model. Either RPMI8226 or U266 cells were inoculated subcutaneously into NOD/SCID mice in the right thigh at 3 × 107 or 1 × 107 cells. When measurable tumors developed (usually after 4 days), either K-7174 (75 mg/kg) or vehicle (3% DMSO in 0.9% NaCl) was intraperitoneally administered once daily for 14 days (n = 3–4 in each group). The tumor volume between vehicle-control and K-7174-treated groups were compared on day 14. The tumor volume was significantly lower in the K-7174-treated group than in the vehicle-control group (Fig. 2, A and B). However, the K-7174-treated group had a significant body weight reduction after 10 days (data not shown). Therefore, the same set of experiments was repeated with reduced doses (30 and 50 mg/kg). Although no body weight reduction was observed, K-7174 failed to inhibit tumor growth at these doses (data not shown). To test the effects of oral administration, either K-7174 (50 mg/kg) or vehicle (3% DMSO in 0.9% NaCl) was orally administered once daily for 14 days (n = 3–4 in each group). The dose of K-7174 was determined to be well tolerated by mice without obvious side effects including weight loss in pilot experiments (data not shown). The tumor volume was compared between vehicle-control and K-7174-treated groups for up to 28 days. As a result, tumor volume was significantly lower in the K-7174-treated group than in the vehicle-control group (Fig. 2, C and D). There were no obvious side effects including body weight reduction, leukocytopenia, thrombocytopenia, anemia and hepatic dysfunction in both vehicle-control and K-7174-treated groups (the data on day 21 are shown in Table 1). To examine the proteasome inhibitory effect of K-7174 in vivo, the accumulation of ubiquitinated proteins was determined in inoculated tumors after oral administration of K-7174. As expected, a 2–4-fold accumulation of ubiquitinated proteins was observed in tumor cells in the K-7174-treated group but not in the vehicle-control group (Fig. 2E). This suggests that K-7174 could effectively inhibit proteasome activity in vivo. Taken together, these data demonstrate the potent anti-myeloma activity of K-7174 in vivo and more importantly, that oral administration is more effective than intraperitoneal injection. Reference: J Biol Chem. 2013 Aug 30;288(35):25593-25602. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23878197/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
Water 15.0 23.38

Preparing Stock Solutions

The following data is based on the product molecular weight 640.3 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.

Recalculate based on batch purity %
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
In vitro protocol: 1. Kikuchi J, Yamada S, Koyama D, Wada T, Nobuyoshi M, Izumi T, Akutsu M, Kano Y, Furukawa Y. The novel orally active proteasome inhibitor K-7174 exerts anti-myeloma activity in vitro and in vivo by down-regulating the expression of class I histone deacetylases. J Biol Chem. 2013 Aug 30;288(35):25593-25602. doi: 10.1074/jbc.M113.480574. Epub 2013 Jul 22. PMID: 23878197; PMCID: PMC3757220. 2. Imagawa S, Nakano Y, Obara N, Suzuki N, Doi T, Kodama T, Nagasawa T, Yamamoto M. A GATA-specific inhibitor (K-7174) rescues anemia induced by IL-1beta, TNF-alpha, or L-NMMA. FASEB J. 2003 Sep;17(12):1742-4. doi: 10.1096/fj.02-1134fje. Epub 2003 Jul 18. PMID: 12958195.
In vivo protocol: 1. Kikuchi J, Yamada S, Koyama D, Wada T, Nobuyoshi M, Izumi T, Akutsu M, Kano Y, Furukawa Y. The novel orally active proteasome inhibitor K-7174 exerts anti-myeloma activity in vitro and in vivo by down-regulating the expression of class I histone deacetylases. J Biol Chem. 2013 Aug 30;288(35):25593-25602. doi: 10.1074/jbc.M113.480574. Epub 2013 Jul 22. PMID: 23878197; PMCID: PMC3757220. 2. Imagawa S, Nakano Y, Obara N, Suzuki N, Doi T, Kodama T, Nagasawa T, Yamamoto M. A GATA-specific inhibitor (K-7174) rescues anemia induced by IL-1beta, TNF-alpha, or L-NMMA. FASEB J. 2003 Sep;17(12):1742-4. doi: 10.1096/fj.02-1134fje. Epub 2003 Jul 18. PMID: 12958195.

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1: Fujiwara T, Ikeda T, Nagasaka Y, Okitsu Y, Katsuoka Y, Fukuhara N, Onishi Y, Ishizawa K, Ichinohasama R, Tomosugi N, Harigae H. A low-molecular-weight compound K7174 represses hepcidin: possible therapeutic strategy against anemia of chronic disease. PLoS One. 2013 Sep 27;8(9):e75568. doi: 10.1371/journal.pone.0075568. eCollection 2013. PubMed PMID: 24086573; PubMed Central PMCID: PMC3785497.

2: Kikuchi J, Yamada S, Koyama D, Wada T, Nobuyoshi M, Izumi T, Akutsu M, Kano Y, Furukawa Y. The novel orally active proteasome inhibitor K-7174 exerts anti-myeloma activity in vitro and in vivo by down-regulating the expression of class I histone deacetylases. J Biol Chem. 2013 Aug 30;288(35):25593-602. doi: 10.1074/jbc.M113.480574. Epub 2013 Jul 22. PubMed PMID: 23878197; PubMed Central PMCID: PMC3757220.

3: Kikuchi J, Shibayama N, Yamada S, Wada T, Nobuyoshi M, Izumi T, Akutsu M, Kano Y, Sugiyama K, Ohki M, Park SY, Furukawa Y. Homopiperazine derivatives as a novel class of proteasome inhibitors with a unique mode of proteasome binding. PLoS One. 2013 Apr 11;8(4):e60649. doi: 10.1371/journal.pone.0060649. Print 2013. PubMed PMID: 23593271; PubMed Central PMCID: PMC3623906.

4: Shimada T, Hiramatsu N, Okamura M, Hayakawa K, Kasai A, Yao J, Kitamura M. Unexpected blockade of adipocyte differentiation by K-7174: implication for endoplasmic reticulum stress. Biochem Biophys Res Commun. 2007 Nov 16;363(2):355-60. Epub 2007 Sep 6. PubMed PMID: 17869220.

5: Takano Y, Hiramatsu N, Okamura M, Hayakawa K, Shimada T, Kasai A, Yokouchi M, Shitamura A, Yao J, Paton AW, Paton JC, Kitamura M. Suppression of cytokine response by GATA inhibitor K-7174 via unfolded protein response. Biochem Biophys Res Commun. 2007 Aug 24;360(2):470-5. Epub 2007 Jun 26. PubMed PMID: 17604001.

6: Nakano Y, Imagawa S, Matsumoto K, Stockmann C, Obara N, Suzuki N, Doi T, Kodama T, Takahashi S, Nagasawa T, Yamamoto M. Oral administration of K-11706 inhibits GATA binding activity, enhances hypoxia-inducible factor 1 binding activity, and restores indicators in an in vivo mouse model of anemia of chronic disease. Blood. 2004 Dec 15;104(13):4300-7. Epub 2004 Aug 24. PubMed PMID: 15328158.

7: Imagawa S, Nakano Y, Obara N, Suzuki N, Doi T, Kodama T, Nagasawa T, Yamamoto M. A GATA-specific inhibitor (K-7174) rescues anemia induced by IL-1beta, TNF-alpha, or L-NMMA. FASEB J. 2003 Sep;17(12):1742-4. Epub 2003 Jul 18. PubMed PMID: 12958195.

8: Umetani M, Nakao H, Doi T, Iwasaki A, Ohtaka M, Nagoya T, Mataki C, Hamakubo T, Kodama T. A novel cell adhesion inhibitor, K-7174, reduces the endothelial VCAM-1 induction by inflammatory cytokines, acting through the regulation of GATA. Biochem Biophys Res Commun. 2000 Jun 7;272(2):370-4. PubMed PMID: 10833420.



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