KRIBB11 (Cat No.:I003247) is a small molecule inhibitor that targets the heat shock factor 1 (HSF1) pathway. It acts by disrupting the binding of HSF1 to heat shock response elements (HSEs) in the promoter regions of target genes, thereby inhibiting the transcriptional activity of HSF1. KRIBB11 has been shown to suppress the expression of heat shock proteins (HSPs) and inhibit the activation of the HSF1 pathway. It has demonstrated promising anticancer activity in preclinical studies, making it a potential candidate for the development of novel cancer therapeutics. Additionally, KRIBB11 has shown potential in other disease areas, including neurodegenerative disorders and viral infections, through its modulation of the HSF1 pathway.
| Catalog Number | I003247 |
| CAS Number | 342639-96-7 |
| Molecular Formula | C₁₃H₁₂N₆O₂ |
| Purity | ≥95% |
| Target | 1.2 μM (HSF) |
| Solubility | DMSO: ≥ 27 mg/mL |
| Storage | Store at -20°C |
| IUPAC Name | 2-N-(1H-indazol-5-yl)-6-N-methyl-3-nitropyridine-2,6-diamine |
| InChI | InChI=1S/C13H12N6O2/c1-14-12-5-4-11(19(20)21)13(17-12)16-9-2-3-10-8(6-9)7-15-18-10/h2-7H,1H3,(H,15,18)(H2,14,16,17) |
| InChIKey | NDJJEQIMIJJCLL-UHFFFAOYSA-N |
| SMILES | CNC1=NC(=C(C=C1)[N+](=O)[O-])NC2=CC3=C(C=C2)NN=C3 |
| Reference | 1:J Biol Chem. 2011 Jan 21;286(3):1737-47. doi: 10.1074/jbc.M110.179440. Epub 2010 Nov 15. KRIBB11 inhibits HSP70 synthesis through inhibition of heat shock factor 1 function by impairing the recruitment of positive transcription elongation factor b to the hsp70 promoter.Yoon YJ,Kim JA,Shin KD,Shin DS,Han YM,Lee YJ,Lee JS,Kwon BM,Han DC, PMID: 21078672 PMCID: PMC3023468 DOI: 10.1074/jbc.M110.179440 </br><span>Abstract:</span> Heat shock factor 1 (HSF1) is the master switch for heat shock protein (HSP) expression in eukaryotes. A synthetic chemical library was screened to identify inhibitors of HSF1 using a luciferase reporter under the control of a heat shock element. A compound named KRIBB11 (N(2)-(1H-indazole-5-yl)-N(6)-methyl-3-nitropyridine-2,6-diamine) was identified for its activity in abolishing the heat shock-induced luciferase activity with an IC(50) of 1.2 μmol/liter. When the cells were exposed to heat shock in the presence of KRIBB11, the induction of HSF1 downstream target proteins such as HSP27 and HSP70 was blocked. In addition, treatment of HCT-116 cells with KRIBB11 induced growth arrest and apoptosis. Markers of apoptosis, such as cleaved poly(ADP-ribose) polymerase, were detected after KRIBB11 treatment. Biotinyl-KRIBB11 was synthesized as an affinity probe for the identification of KRIBB11 target proteins. Using affinity chromatography and competition assays, KRIBB11 was shown to associate with HSF1 in vitro. Chromatin immunoprecipitation analysis showed that KRIBB11 inhibited HSF1-dependent recruitment of p-TEFb (positive transcription elongation factor b) to the hsp70 promoter. Finally, intraperitoneal treatment of nude mice with KRIBB11 at 50 mg/kg resulted in a 47.4% (p < 0.05) inhibition of tumor growth without body weight loss. Immunoblotting assays showed that the expression of HSP70 was lower in KRIBB11-treated tumor tissue than in control tissues. Because HSPs are expressed at high levels in a wide range of tumors, these results strengthen the rationale for targeting HSF1 in cancer therapy. |
