WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 401535
CAS#: 934593-90-5
Description: CAY10585, also known as LW6, was first identified and reported by a group scientists from Korea. LW8 was found to inhibits the accumulation of HIF-1alpha. LW6 decreased HIF-1alpha protein expression without affecting HIF-1beta expression. It was further found that LW8 promoted the degradation of wild type HIF-1alpha, but not of a DM-HIF-1alpha with modifications of P402A and P564A, at hydroxylation sites in the oxygen-dependent degradation domain (ODDD). LW6 did not affect the activity of prolyl hydroxylase (PHD), but induced the expression of von Hippel-Lindau (VHL), which interacts with prolyl-hydroxylated HIF-1alpha for proteasomal degradation. In the presence of LW8, knockdown of VHL did not abolish HIF-1alpha protein accumulation, indicating that LW8 degraded HIF-1alpha via regulation of VHL expression. In mice carrying xenografts of human colon cancer HCT116 cells, LW8 demonstrated strong anti-tumor efficacy in vivo and caused a decrease in HIF-1alpha expression in frozen-tissue immunohistochemical staining. These data suggest that LW8 may be valuable in the development of a HIF-1alpha inhibitor for cancer treatment. (source: Biochem Pharmacol. 2010 Oct 1;80(7):982-9.)
MedKoo Cat#: 401535
Name: CAY10585
CAS#: 934593-90-5
Chemical Formula: C26H29NO5
Exact Mass: 435.20457
Molecular Weight: 435.51216
Elemental Analysis: C, 71.70; H, 6.71; N, 3.22; O, 18.37
Synonym: CAY10585; CAY-10585; CAY 10585; LW6; LW-6; LW 6
IUPAC/Chemical Name: methyl 3-(2-(4-(adamantan-1-yl)phenoxy)acetamido)-4-hydroxybenzoate
InChi Key: BJRPPNOJYFZSLY-UHFFFAOYSA-N
InChi Code: InChI=1S/C26H29NO5/c1-31-25(30)19-2-7-23(28)22(11-19)27-24(29)15-32-21-5-3-20(4-6-21)26-12-16-8-17(13-26)10-18(9-16)14-26/h2-7,11,16-18,28H,8-10,12-15H2,1H3,(H,27,29)
SMILES Code: O=C(OC)C1=CC=C(O)C(NC(COC2=CC=C(C34CC5CC(C4)CC(C5)C3)C=C2)=O)=C1
Appearance: 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 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
| Biological target: | LW6 (HIF-1α inhibitor) is a novel HIF-1 inhibitor with an IC50 of 4.4 μM. |
| In vitro activity: | To clarify, if hypoxia is necessary to investigate the anti-cancer effects of LW6, 6606PDA and MIA PaCa-2 cells were cultured under normoxic and hypoxic conditions. Surprisingly, the inhibition of cell proliferation by LW6 was not influenced by the oxygen supply (Fig. 1). Thus, the following experiments were performed under normoxic conditions. To investigate the anti-cancer effects of LW6, the proliferation and cell death of 6606PDA and MIA PaCa-2 cells were analyzed. In both cell lines, LW6 inhibited proliferation (Fig. 2A and 2B) and induced cell death (Fig. 2C and D) in a dose-dependent manner. In 6606PDA and MIA PaCa-2 cells, the application of 80 µM and 160 µM LW6 significantly inhibited cell proliferation compared to Sham-treated or 40 µM LW6-treated cells, respectively (Fig. 2A and B). In 6606PDA cells, these concentrations of LW6 also significantly increased cell death (Fig. 2C). In addition, LW6 had more efficient cytotoxic effects on MIA PaCa-2 cells than on 6606PDA cells. A dose of 80 µM LW6 killed almost 84% of the MIA PaCa-2 cells within 48 h (Fig. 2D). In order to evaluate, if and how LW6 influences the autophagic flux, the accumulation of LC3II and p62 was analyzed. It was observed that 80 µM LW6 induced the accumulation of LC3II in a timedependent manner in 6606PDA cells as well as MIA PaCa-2 cells, with the strongest induction at 12 h (Fig. 7A and B). Moreover, LW6 also induced the accumulation of LC3II in a dose-dependent manner in both cell lines (Fig. 7C and D). Similar to LC3II, p62 also accumulated after treating the cells with LW6 (Fig. 7E and F). LW6 inhibited the accumulation of LC3II and p62 in a similar manner to CQ, a traditional inhibitor of autophagic flux after 6 h (Fig. 8A) as well as 12 h (Fig. 8B). In addition, CQ in combination with LW6 failed to increase the accumulation of LC3II and p62, when compared to cells treated by LW6 monotherapy (Fig. 8). These data demonstrate that 80 µM LW6 completely blocks autophagic flux leading to increased accumulation of LC3II and p62. J Adv Res. 2019 Nov; 20: 9–21. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6514270/ |
| In vivo activity: | The objective of this study was to investigate the pharmacokinetics and metabolism of LW6 in male ICR mice to support its preclinical development as an antitumor agent. After i.v. administration of LW6 at a dose of 5 mg/kg, the plasma concentration declined rapidly in an apparent polyexponential fashion. The plasma level of LW6 was below the quantitation limit beyond 4 h (Figure 1A). An apparent terminal phase was defined in the plasma concentration-time curve of LW6 between 1 to 4 h postadministration with a t1/2 of 0.6 ± 0.1 h (Figure 1 and Table 1); the volume of distribution at steady state (Vss) was 0.5 ± 0.1 L/kg, close to the total body water volume (0.7 L/kg), indicating that LW6 was distributed outside the vasculature. The systemic clearance (CL) of LW6 was 1.7 ± 0.1 L/hr/kg (Table 1), lower than the hepatic blood flow of the mouse (Table 1). LW6 (1 µM) was incubated with pooled mouse liver microsomes (0.5 mg/mL) in the absence or presence of NADPH (1 mM) to determine its conversion to APA. LW6 was degraded slowly in the absence or presence of NADPH, with 63% or 65% remaining after 60 min microsomal incubations, respectively (Figure 3A). LW6 was converted slowly to APA (t1/2 > 60 min) in a quantitative manner in liver microsomes (Figure 3A). APA, following its formation, gradually disappeared from the microsomal incubation media only in the presence of NAPDH (Figure 3A). To determine whether APA was metabolized by cytochrome P450 (CYP450), APA (1 µM) also was incubated with pooled male mouse liver microsomes (0.5 mg/mL) in the absence or presence of NADPH (1 mM). As shown in Figure 4, APA was progressively decreased when incubated with mouse liver microsomes in the presence of NADPH. These results suggested that LW6 was metabolized to APA, which was further metabolized by CYP450. In the case of mouse serum, LW6 was also converted slowly to APA (Figure 3B). These results suggested that LW6 as an anticancer drug is highly likely to work as its active metabolite APA in the body. Molecules. 2021 Apr; 26(8): 2226. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070284/ |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 17.5 | 40.18 | |
| DMF | 25.6 | 58.8 |
The following data is based on the product molecular weight 435.51216 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. Zhang X, Kumstel S, Jiang K, Meng S, Gong P, Vollmar B, Zechner D. LW6 enhances chemosensitivity to gemcitabine and inhibits autophagic flux in pancreatic cancer. J Adv Res. 2019 Apr 24;20:9-21. doi: 10.1016/j.jare.2019.04.006. PMID: 31193017; PMCID: PMC6514270. 2. Sato M, Hirose K, Kashiwakura I, Aoki M, Kawaguchi H, Hatayama Y, Akimoto H, Narita Y, Takai Y. LW6, a hypoxia-inducible factor 1 inhibitor, selectively induces apoptosis in hypoxic cells through depolarization of mitochondria in A549 human lung cancer cells. Mol Med Rep. 2015 Sep;12(3):3462-3468. doi: 10.3892/mmr.2015.3862. Epub 2015 May 27. PMID: 26017562; PMCID: PMC4526100. 3. Lee K, Kang JE, Park SK, Jin Y, Chung KS, Kim HM, Lee K, Kang MR, Lee MK, Song KB, Yang EG, Lee JJ, Won M. LW6, a novel HIF-1 inhibitor, promotes proteasomal degradation of HIF-1alpha via upregulation of VHL in a colon cancer cell line. Biochem Pharmacol. 2010 Oct 1;80(7):982-9. doi: 10.1016/j.bcp.2010.06.018. Epub 2010 Jun 23. PMID: 20599784. 4. Lee JY, Lee K, Lee K, Kang JS, Kim MJ, Yoo DG, Kim JA, Shin EJ, Oh SJ. Pharmacokinetic Characterization of LW6, a Novel Hypoxia-Inducible Factor-1α (HIF-1α) Inhibitor in Mice. Molecules. 2021 Apr 12;26(8):2226. doi: 10.3390/molecules26082226. PMID: 33921487; PMCID: PMC8070284. |
| In vitro protocol: | 1. Zhang X, Kumstel S, Jiang K, Meng S, Gong P, Vollmar B, Zechner D. LW6 enhances chemosensitivity to gemcitabine and inhibits autophagic flux in pancreatic cancer. J Adv Res. 2019 Apr 24;20:9-21. doi: 10.1016/j.jare.2019.04.006. PMID: 31193017; PMCID: PMC6514270. 2. Sato M, Hirose K, Kashiwakura I, Aoki M, Kawaguchi H, Hatayama Y, Akimoto H, Narita Y, Takai Y. LW6, a hypoxia-inducible factor 1 inhibitor, selectively induces apoptosis in hypoxic cells through depolarization of mitochondria in A549 human lung cancer cells. Mol Med Rep. 2015 Sep;12(3):3462-3468. doi: 10.3892/mmr.2015.3862. Epub 2015 May 27. PMID: 26017562; PMCID: PMC4526100. |
| In vivo protocol: | 1. Lee K, Kang JE, Park SK, Jin Y, Chung KS, Kim HM, Lee K, Kang MR, Lee MK, Song KB, Yang EG, Lee JJ, Won M. LW6, a novel HIF-1 inhibitor, promotes proteasomal degradation of HIF-1alpha via upregulation of VHL in a colon cancer cell line. Biochem Pharmacol. 2010 Oct 1;80(7):982-9. doi: 10.1016/j.bcp.2010.06.018. Epub 2010 Jun 23. PMID: 20599784. 2. Lee JY, Lee K, Lee K, Kang JS, Kim MJ, Yoo DG, Kim JA, Shin EJ, Oh SJ. Pharmacokinetic Characterization of LW6, a Novel Hypoxia-Inducible Factor-1α (HIF-1α) Inhibitor in Mice. Molecules. 2021 Apr 12;26(8):2226. doi: 10.3390/molecules26082226. PMID: 33921487; PMCID: PMC8070284. |
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