| Identification | Back Directory | [Name]
N-(12-Cyanindolizino[2,3-b]quinoxalin-2-yl)-2-thiophenecarboxaMide | [CAS]
487020-03-1 | [Synonyms]
HI-TOPK-32
HI-TOPK-032
HI-TOPK-032
(HI TOPK 032
N-(12-Cyanindolizino[2,3-b]quinoxalin-2-yl)-2-thiophenecarboxaMide
N-(12-Cyanoindolizino[2,3-b]quinoxalin-2-yl)-2-thiophenecarboxamide
2-Thiophenecarboxamide, N-(12-cyanoindolizino[2,3-b]quinoxalin-2-yl)- | [Molecular Formula]
C20H11N5OS | [MDL Number]
MFCD03286313 | [MOL File]
487020-03-1.mol | [Molecular Weight]
369.4 |
| Chemical Properties | Back Directory | [Boiling point ]
415.3±45.0 °C(Predicted) | [density ]
1.50±0.1 g/cm3(Predicted) | [storage temp. ]
2-8°C | [solubility ]
DMSO: soluble3mg/mL, clear (warmed) | [form ]
powder | [pka]
9.32±0.46(Predicted) | [color ]
orange-brown | [InChI]
1S/C20H11N5OS/c21-11-13-16-10-12(22-20(26)17-6-3-9-27-17)7-8-25(16)19-18(13)23-14-4-1-2-5-15(14)24-19/h1-10H,(H,22,26) | [InChIKey]
BCSBXWKRZUPFHW-UHFFFAOYSA-N | [SMILES]
[s]1c(ccc1)C(=O)Nc2cc3[n](c4nc5c(nc4c3C#N)cccc5)cc2 |
| Hazard Information | Back Directory | [Description]
HI TOPK 032 is an inhibitor of lymphokine-activated killer T cell-originated protein kinase (TOPK), blocking phosphorylation of the substrate histone H2AX with an IC50 value of ~2 μM and providing complete inhibition at 5 μM. It also inhibits checkpoint kinase 1 (Chk1; IC50 = 9.6 μM). In addition, HI TOPK 032 inhibits MEK1, achieving 40% inhibition at 5 μM, but it does not alter the activities of ERK1, JNK1, or p38 MAPK at 2 μM. HI TOPK 032 decreases the growth of colon cancer and glioma initiating cells in vitro and suppresses tumor growth in vivo. | [Uses]
N-(12-Cyanindolizino[2,3-b]quinoxalin-2-yl)-2-thiophenecarboxamide is a novel TOPK inhibitor that was shown to effectively suppress colon cancer growth. | [Biological Activity]
HI-TOPK-032 is a potent and specific inhibitor of TOPK. HI-TOPK-032 also reduces ERK-RSK phosphorylation, modulates the abundance of p53, cleaved caspase-7, and cleaved PARP, and induces apoptosis in cancer cells. | [Biochem/physiol Actions]
HI-TOPK-032 is a specific TOPK (T-LAK cell–originated protein kinase) inhibitor both in vitro and in vivo. HI-TOPK-032 suppressed tumor growth in a colon cancer xenograft model. | [in vitro]
HI-TOPK-032 strongly suppresses TOPK kinase activity but has little effect on extracellular signal-regulated kinase 1 (ERK1), c-jun-NH2-kinase 1, or p38 kinase activities. HI-TOPK-032 occupies the ATP-binding site of TOPK and fits the binding site very well. The compound forms hydrogen bonds with GLY83 and ASP151 and has a hydrophobic interaction with LYS30. However, HI-TOPK-032 at the highest concentration (5 μM) also inhibits MEK1 activity by 40%. HI-TOPK-032 also inhibits anchorage-dependent and -independent colon cancer cell growth by reducing ERK-RSK phosphorylation as well as increasing colon cancer cell apoptosis through regulation of the abundance of p53, cleaved caspase-7, and cleaved PARP. | [in vivo]
Treatment of mice with 1 or 10 mg/kg of HI-TOPK-032 significantly inhibits HCT-116 tumor growth by more than 60% relative to the vehicle-treated group. Mice are well tolerated with HI-TOPK-032 treatment. The expression of p53 is strongly induced, and phosphorylation of ERK and RSK, a direct downstream protein of ERK, is markedly inhibited in the HI-TOPK-032-treated group. | [References]
[1] DONG JOON KIM. Novel TOPK inhibitor HI-TOPK-032 effectively suppresses colon cancer growth.[J]. Cancer research, 2012: 3060-3068. DOI: 10.1158/0008-5472.can-11-3851
[2] YAN LI. Discovery of Novel Checkpoint Kinase 1 Inhibitors by Virtual Screening Based on Multiple Crystal Structures[J]. Journal of Chemical Information and Modeling , 2011, 51 11: 2904-2914. DOI: 10.1021/ci200257b
[3] MRINAL JOEL. Targeting PBK/TOPK decreases growth and survival of glioma initiating cells in vitro and attenuates tumor growth in vivo.[J]. Molecular Cancer, 2015: 121. DOI: 10.1186/s12943-015-0398-x |
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