KRIBB11
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MedKoo CAT#: 407439

CAS#: 342639-96-7

Description: KRIBB11 is a HSP70 inhibitor. 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.

Chemical Structure

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KRIBB11
CAS# 342639-96-7
Product data Instruction

Theoretical Analysis

MedKoo Cat#: 407439
Name: KRIBB11
CAS#: 342639-96-7
Chemical Formula: C13H12N6O2
Exact Mass: 284.10
Molecular Weight: 284.279
Elemental Analysis: C, 54.93; H, 4.25; N, 29.56; O, 11.26

Price and Availability

Size Price Availability Quantity
10mg USD 110 Ready to ship
25mg USD 250 Ready to ship
50mg USD 450 Ready to ship
100mg USD 800 Ready to ship
200mg USD 1450 Ready to ship
500mg USD 2150 Ready to ship
1g USD 3250 2 weeks
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Synonym: KRIBB11; KRIBB-11; KRIBB 11.

IUPAC/Chemical Name: N2-(1H-indazole-5-yl)-N6-methyl-3-nitropyridine-2,6-diamine

InChi Key: NDJJEQIMIJJCLL-UHFFFAOYSA-N

InChi Code: 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)

SMILES Code: O=[N+](C1=CC=C(NC)N=C1NC2=CC3=C(NN=C3)C=C2)[O-]

Appearance: 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

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

More Info:

Biological target: KRIBB11 is an inhibitor of Heat shock factor 1 (HSF1), with IC50 of 1.2 μM.
In vitro activity: The inhibitory effect of KRIBB11 on the endogenous hsp70, hsp47, and hsp27 promoter activities was investigated. For this purpose, HCT-116 cells were subjected to heat shock at 43 °C for 1 h in the presence or absence of KRIBB11 and incubated further at 37 °C for 1 h to allow recovery. After isolation of total RNA, hsp70 mRNA expression was evaluated by quantitative real time reverse transcription-PCR. As shown in Fig. 1C, heat shock treatment caused a 13-fold increase in hsp70 mRNA expression relative to the non-heat shock condition. Pretreatment of HCT-116 cells with KRIBB11 blocked heat shock-induced hsp70 mRNA expression in a concentration-dependent manner, with 70% inhibition at 10 μmol/liter. Similarly, KRIBB11 inhibited hsp47 and hsp27 mRNA expression in a concentration-dependent manner (Fig. 1, D and E). In accordance with its effect on mRNA expression, KRIBB11 also significantly down-regulated HSF1 downstream target proteins such as HSP70 and HSP27 in a concentration-dependent manner (Fig. 1F). Heat shock induces hyperphosphorylation of HSF1, resulting in a shift in its mobility on SDS gels. To exclude the possible nonspecific transcriptional inhibitory activity of KRIBB11, its effect on NF-κB activity was tested. NF-κB regulates the transcription of various inflammatory cytokines as well as anti-apoptotic genes. A pNF-κB-Luc plasmid for an NF-κB luciferase reporter assay was obtained from Stratagene (La Jolla, CA) and used as described previously. As shown in Fig. 1G, NF-κB reporter activity was stimulated by treating cells with 20 ng/ml TNF-α. However, pretreatment with high concentrations of KRIBB11 weakly inhibited TNF-α-dependent NF-κB reporter activity. This result suggests that KRIBB11 is not a general transcription inhibitor. The inhibition of HSF1 activity by KRIBB11 and the consequent down-regulation of HSP70 and HSP27 led to the speculation that KRIBB11 could inhibit the proliferation of cancer cells. To evaluate the effect of KRIBB11 on the growth of cancer cells, HCT-116 cells were treated with different concentrations of KRIBB11 (0–50 μmol/liter) for 48 h (Fig. 2A). KRIBB11 exhibited a dose-dependent inhibition of HCT-116 cell growth over a broad range of concentrations, with an IC50 of 5 μmol/liter, where IC50 is the inhibitor concentration at which a 50% inhibition of cell growth is observed. The effect of KRIBB11 on the proliferation of various other tumor cell lines was also analyzed; these cell lines and the IC50 value for each are as follows: HCT-15 (5 μmol/liter), Mia-PaCa-2 (3 μmol/liter), SW-620 (4 μmol/liter), HT-29 (3 μmol/liter), A549 (5 μmol/liter), and MDA-MB-231 (8 μmol/liter). Reference: J Biol Chem. 2011 Jan 21;286(3):1737-47. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21078672/
In vivo activity: HCT-116 tumor xenografts in nude mice were used to investigate the inhibitory activity of KRIBB11 on tumor growth in vivo. HCT-116 cells were implanted subcutaneously into the right flank of nude mice. When the tumor volume reached 72.2 mm3 (13 days after implantation), the indicated compounds were administered intraperitoneally at a dose of 50 mg/kg of KRIBB11 or 2 mg/kg of adriamycin per day. Because there is no available anticancer drug that specifically targets HSF1, adriamycin was used as a positive control compound. Adriamycin interacts with DNA by intercalation and is commonly used in the treatment of a wide range of cancers. To determine the toxicity of the compound, the body weight of tumor-bearing mice was measured. On day 18, the mice were sacrificed, and the tumors were removed and weighed. Mice treated with KRIBB11 showed a 47.4% (p < 0.05) decrease in tumor volume compared with control mice (Fig. 6A). Similarly, when adriamycin was used as a positive control compound, tumor volume was decreased by 31.7%. There was no change in body weight when KRIBB11 was used at 50 mg/kg (Fig. 6B). However, when adriamycin was used at 2 mg/kg, a loss of 13.2% (p < 0.001) of body weight was observed. To confirm that KRIBB11 suppressed the growth of HCT-116 tumors through the inhibition of HSF1 activity in vivo, HSP70 protein levels were measured in tumor tissues from both KRIBB11- and control-treated mice. As shown in Fig. 6C, HSP70 protein levels were significantly decreased in tumors from mice treated with KRIBB11, as compared with mice treated with vehicle. Reference: J Biol Chem. 2011 Jan 21;286(3):1737-47. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21078672/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 27.0 94.98

Preparing Stock Solutions

The following data is based on the product molecular weight 284.28 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
Formulation protocol:
In vitro protocol: 1. Yoon YJ, Kim JA, Shin KD, Shin DS, Han YM, Lee YJ, Lee JS, Kwon BM, Han DC. 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. J Biol Chem. 2011 Jan 21;286(3):1737-47. doi: 10.1074/jbc.M110.179440. Epub 2010 Nov 15. PMID: 21078672; PMCID: PMC3023468.
In vivo protocol: 1. Yoon YJ, Kim JA, Shin KD, Shin DS, Han YM, Lee YJ, Lee JS, Kwon BM, Han DC. 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. J Biol Chem. 2011 Jan 21;286(3):1737-47. doi: 10.1074/jbc.M110.179440. Epub 2010 Nov 15. PMID: 21078672; PMCID: PMC3023468.

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1: Yoon YJ, Kim JA, Shin KD, Shin DS, Han YM, Lee YJ, Lee JS, Kwon BM, Han DC. 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. J Biol Chem. 2011 Jan 21;286(3):1737-47. doi: 10.1074/jbc.M110.179440. Epub 2010 Nov 15. PubMed PMID: 21078672; PubMed Central PMCID: PMC3023468.

2: Antonietti P, Linder B, Hehlgans S, Mildenberger IC, Burger MC, Fulda S, Steinbach JP, Gessler F, Rödel F, Mittelbronn M, Kögel D. Interference with the HSF1/HSP70/BAG3 Pathway Primes Glioma Cells to Matrix Detachment and BH3 Mimetic-Induced Apoptosis. Mol Cancer Ther. 2017 Jan;16(1):156-168. doi: 10.1158/1535-7163.MCT-16-0262. Epub 2016 Oct 24. PubMed PMID: 27777286.

3: Huang C, Lu X, Tong L, Wang J, Zhang W, Jiang B, Yang R. Requirement for endogenous heat shock factor 1 in inducible nitric oxide synthase induction in murine microglia. J Neuroinflammation. 2015 Oct 14;12:189. doi: 10.1186/s12974-015-0406-5. PubMed PMID: 26467650; PubMed Central PMCID: PMC4607096.

4: Mani J, Antonietti P, Rakel S, Blaheta R, Bartsch G, Haferkamp A, Kögel D. Knockdown of BAG3 sensitizes bladder cancer cells to treatment with the BH3 mimetic ABT-737. World J Urol. 2016 Feb;34(2):197-205. doi: 10.1007/s00345-015-1616-2. Epub 2015 Jun 23. PubMed PMID: 26100943.

5: Wales CT, Taylor FR, Higa AT, McAllister HA, Jacobs AT. ERK-dependent phosphorylation of HSF1 mediates chemotherapeutic resistance to benzimidazole carbamates in colorectal cancer cells. Anticancer Drugs. 2015 Jul;26(6):657-66. doi: 10.1097/CAD.0000000000000231. PubMed PMID: 25811962.

6: Samarasinghe B, Wales CT, Taylor FR, Jacobs AT. Heat shock factor 1 confers resistance to Hsp90 inhibitors through p62/SQSTM1 expression and promotion of autophagic flux. Biochem Pharmacol. 2014 Feb 1;87(3):445-55. doi: 10.1016/j.bcp.2013.11.014. Epub 2013 Nov 28. PubMed PMID: 24291777; PubMed Central PMCID: PMC3934577.