HUHS015
目录号 : GC32804A PCA-1 inhibitor
Cas No.:1453097-13-6
Sample solution is provided at 25 µL, 10mM.
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- Purity: >98.50%
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HUHS015 is an inhibitor of prostate cancer antigen-1 (PCA-1; IC50 = 0.67 ?M), also known as α-ketoglutarate-dependent dioxygenase alkB homolog 3 (ALKBH3).1 It inhibits proliferation of DU145 human prostate cancer cells by 54 and 81% in 2D dish and 3D agar assays, respectively when used at a concentration of 10 ?M. HUHS015 (32 mg/kg) reduces tumor growth in a DU145 mouse xenograft model.
1.Nakao, S., Mabuchi, M., Shimizu, T., et al.Design and synthesis of prostate cancer antigen-1 (PCA-1/ALKBH3) inhibitors as anti-prostate cancer drugsBioorg. Med. Chem. Lett.24(4)1071-1074(2014)
Cas No. | 1453097-13-6 | SDF | |
Canonical SMILES | OC1=C(CC2=CC=CC=C2)C(C)=NN1C3=NC4=CC=C(C)C=C4N3 | ||
分子式 | C19H18N4O | 分子量 | 318.37 |
溶解度 | DMSO : ≥ 34 mg/mL (106.79 mM) | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg | |
1 mM | 3.141 mL | 15.705 mL | 31.41 mL |
5 mM | 0.6282 mL | 3.141 mL | 6.282 mL |
10 mM | 0.3141 mL | 1.5705 mL | 3.141 mL |
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2.
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Improving the bioavailability and anticancer effect of the PCA-1/ALKBH3 inhibitor HUHS015 using sodium salt
In Vivo 2015 Jan-Feb;29(1):39-43.PMID:25600528doi
Prostate cancer antigen (PCA)-1/AlkB homologue 3 (ALKBH3) has been identified as a clinically significant factor and siRNA of PCA-1 inhibits DU145 proliferation both in vitro and in vivo. HUHS015 ( 1: ), a previous reported PCA-1 small-molecule inhibitor, was also effective without any obvious side-effects or toxicity. The potency of HUHS015, however, is not satisfying. We thought the reason is poor solubility of HUHS015 because insoluble material remained at the injection site after subcutaneous administration. To improve this inhibitor's solubility, we prepared various salts of HUHS015 and examined their solubility, which resulted in the selection of HUHS015 sodium salt ( 2: ) for further studies in vivo. Next, we compared the pharmacokinetics of 1: and 2: via several administration routes. We observed significant improvements in the pharmacokinetic parameters. For example, subcutaneous administration of 2: increased the area under the curve (AUC)0-24 by 8-fold compared to 1 and increased the suppressive effect on the proliferation of DU145 cells in a xenograft model.
Design and synthesis of prostate cancer antigen-1 (PCA-1/ALKBH3) inhibitors as anti-prostate cancer drugs
Bioorg Med Chem Lett 2014 Feb 15;24(4):1071-4.PMID:24461353DOI:10.1016/j.bmcl.2014.01.008.
A series of 1-aryl-3,4-substituted-1H-pyrazol-5-ol derivatives was synthesized and evaluated as prostate cancer antigen-1 (PCA-1/ALKBH3) inhibitors to obtain a novel anti-prostate cancer drug. After modifying 1-(1H-benzimidazol-2-yl)-3,4-dimethyl-1H-pyrazol-5-ol (1), a hit compound found during random screening using a recombinant PCA-1/ALKBH3, 1-(1H-5-methylbenzimidazol-2-yl)-4-benzyl-3-methyl-1H-pyrazol-5-ol (35, HUHS015), was obtained as a potent PCA-1/ALKBH3 inhibitor both in vitro and in vivo. The bioavailability (BA) of 35 was 7.2% in rats after oral administration. As expected, continuously administering 35 significantly suppressed the growth of DU145 cells, which are human hormone-independent prostate cancer cells, in a mouse xenograft model without untoward effects.
Novel Metabolically Stable PCA-1/ALKBH3 Inhibitor Has Potent Antiproliferative Effects on DU145 Cells In Vivo
Anticancer Res 2018 Jan;38(1):211-218.PMID:29277775DOI:10.21873/anticanres.12210.
Novel potent prostate cancer antigen-1 (PCA-1)/alpha-ketoglutarate-dependent dioxygenase alkB homolog 3 (ALKBH3) inhibitors both in vivo and in vivo were designed and evaluated by a stability assay in an S9 mixture, a mixture of rat liver homogenate and co-factors, and oral absorbability assay in rat, as well as enzyme and cell assays, and resulted in the synthesis of a novel potent PCA-1/ALKBH3 inhibitor in vivo. Among them, compound 7l exhibited potent inhibitory activities in a xenograft model bearing DU145 tumor at 10 mg/kg by subcutaneous administration without negative side-effects. This inhibitory activity in vivo was more potent than that of HUHS015 at 32 mg/kg, a known PCA-1/ALKBH3 inhibitor, or docetaxel at 2.5 mg/kg, the drug clinically used for androgen-independent prostate cancer.