KRIBB11 - CAS 342639-96-7
Category: Inhibitor
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Molecular Formula:
Molecular Weight:
KRIBB11 is a heat shock factor (HSF) inhibitor (IC50 = 1.2 μM). 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. In vivo, administration of KRIBB11 decreases tumor growth in a mouse HCT116 xenograft model.
Solid powder
N2-(1H-indazole-5-yl)-N6-methyl-3-nitropyridine-2,6-diamine; KRIBB11; KRIBB-11; KRIBB 11.
Store in a cool and dry place (or refer to the Certificate of Analysis).
Boiling Point:
534.9±50.0 °C at 760 Torr
1.531±0.06 g/cm3
Canonical SMILES:
1.ERK-dependent phosphorylation of HSF1 mediates chemotherapeutic resistance to benzimidazole carbamates in colorectal cancer cells.
Wales CT;Taylor FR;Higa AT;McAllister HA;Jacobs AT Anticancer Drugs. 2015 Jul;26(6):657-66. doi: 10.1097/CAD.0000000000000231.
Drugs containing the benzimidazole carbamate scaffold include anthelmintic and antifungal agents, and they are now also recognized as having potential applications in the treatment of colorectal and other cancers. These agents act by binding to β-tubulin, and in doing so they disrupt microtubules, arrest cell division, and promote apoptotic cell death in malignant cells. We have evaluated several commercially available benzimidazole carbamates for cytotoxic activity in colorectal cancer cells. In addition to cytotoxicity, we also observe activation of the transcription factor, heat shock factor-1 (HSF1). HSF1 is well known to mediate a cytoprotective response that promotes tumor cell survival and drug resistance. Here, we show that biochemical inhibition with the HSF1 inhibitor KRIBB11 or siRNA-based silencing of HSF1 results in a significant enhancement of drug potency, causing an approximately two-fold decrease in IC50 values of parbendazole and nocodazole. We also define a mechanism for drug-induced HSF1 activation, which results from a phosphorylation event at Ser326 that is dependent on the activation of the extracellular regulated protein kinase-1/2 (ERK-1/2) mitogen-activated protein kinase pathway.
2.Combined inhibition of AKT and HSF1 suppresses breast cancer stem cells and tumor growth.
Carpenter RL;Sirkisoon S;Zhu D;Rimkus T;Harrison A;Anderson A;Paw I;Qasem S;Xing F;Liu Y;Chan M;Metheny-Barlow L;Pasche BC;Debinski W;Watabe K;Lo HW Oncotarget. 2017 May 22;8(43):73947-73963. doi: 10.18632/oncotarget.18166. eCollection 2017 Sep 26.
Breast cancer is the most common cancer in women and the second leading cause of cancer deaths in women. Over 90% of breast cancer deaths are attributable to metastasis. Our lab has recently reported that AKT activates heat shock factor 1 (HSF1), leading to epithelial-to-mesenchymal transition in HER2-positive breast cancer. However, it is unknown whether the AKT-HSF1 pathway plays an important role in other breast cancer subtypes, breast cancer stem cells, or breast cancer growth and metastasis. Herein, we showed AKT and HSF1 to be frequently co-activated in breast cancer cell lines and specimens across different subtypes. Activated AKT (S473) and HSF1 (S326) are strongly associated with shortened time to metastasis. Inhibition of the AKT-HSF1 signaling axis using small molecule inhibitors, HSF1 knockdown or the dominant-negative HSF1 mutant (S326A) reduced the growth of metastatic breast cancer cells and breast cancer stem cells. The combination of small molecule inhibitors targeting AKT (MK-2206) and HSF1 (KRIBB11) resulted in synergistic killing of breast cancer cells and breast cancer stem cells across different molecular subtypes. Using an orthotopic xenograft mouse model, we found that combined targeting of AKT and HSF1 to significantly reduce tumor growth, induce tumor apoptosis, delay time to metastasis, and prolong host survival.
3.BAG3 Overexpression and Cytoprotective Autophagy Mediate Apoptosis Resistance in Chemoresistant Breast Cancer Cells.
Das CK;Linder B;Bonn F;Rothweiler F;Dikic I;Michaelis M;Cinatl J;Mandal M;Kögel D Neoplasia. 2018 Mar;20(3):263-279. doi: 10.1016/j.neo.2018.01.001. Epub 2018 Feb 22.
Target-specific treatment modalities are currently not available for triple-negative breast cancer (TNBC), and acquired chemotherapy resistance is a primary obstacle for the treatment of these tumors. Here we employed derivatives of BT-549 and MDA-MB-468 TNBC cell lines that were adapted to grow in the presence of either 5-Fluorouracil, Doxorubicin or Docetaxel in an aim to identify molecular pathways involved in the adaptation to drug-induced cell killing. All six drug-adapted BT-549 and MDA-MB-468 cell lines displayed cross resistance to chemotherapy and decreased apoptosis sensitivity. Expression of the anti-apoptotic co-chaperone BAG3 was notably enhanced in two thirds (4/6) of the six resistant lines simultaneously with higher expression of HSP70 in comparison to parental controls. Doxorubicin-resistant BT-549 (BT-549;r;DOX;20;) and 5-Fluorouracil-resistant MDA-MB-468 (MDA-MB-468;r;5-FU;2000;) cells were chosen for further analysis with the autophagy inhibitor Bafilomycin A1 and lentiviral depletion of ATG5, indicating that enhanced cytoprotective autophagy partially contributes to increased drug resistance and cell survival. Stable lentiviral BAG3 depletion was associated with a robust down-regulation of Mcl-1, Bcl-2 and Bcl-xL, restoration of drug-induced apoptosis and reduced cell adhesion in these cells, and these death-sensitizing effects could be mimicked with the BAG3/Hsp70 interaction inhibitor YM-1 and by KRIBB11, a selective transcriptional inhibitor of HSF-1.
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CAS 342639-96-7 KRIBB11

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