First Bispecific Inhibitors of the Epidermal Growth Factor Receptor Kinase and the NF-κB Activity As Novel Anticancer Agents.
Cast your vote
You can rate an item by clicking the amount of stars they wish to award to this item.
When enough users have cast their vote on this item, the average rating will also be shown.
Your vote was cast
Thank you for your feedback
Thank you for your feedback
MetadataShow full item record
AbstractThe activation of the NF-κB transcription factor is a major adaptive response induced upon treatment with EGFR kinase inhibitors, leading to the emergence of resistance in nonsmall cell lung cancer and other tumor types. To suppress this survival mechanism, we developed new thiourea quinazoline derivatives that are dual inhibitors of both EGFR kinase and the NF-κB activity. Optimization of the hit compound, identified in a NF-κB reporter gene assay, led to compound 9b, exhibiting a cellular IC50 for NF-κB inhibition of 0.3 μM while retaining a potent EGFR kinase inhibition (IC50 = 60 nM). The dual inhibitors showed a higher potency than gefitinib to inhibit cell growth of EGFR-overexpressing tumor cell lines in vitro and in a xenograft model in vivo, while no signs of toxicity were observed. An investigation of the molecular mechanism of NF-κB suppression revealed that the dual inhibitors depleted the transcriptional coactivator CREB-binding protein from the NF-κB complex in the nucleus.
CitationFirst Bispecific Inhibitors of the Epidermal Growth Factor Receptor Kinase and the NF-κB Activity As Novel Anticancer Agents. 2017, 60 (7):2853-2868 J. Med. Chem.
AffiliationHIPS, Helmholtz-Institut für pharmazeutische Forschung Saarland, Universitätscampus E8.1,66123 Saarbrücken, Germany.
JournalJournal of medicinal chemistry
The following license files are associated with this item:
- Creative Commons
Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by-nc-sa/4.0/
- EGFR and NF-κB: partners in cancer.
- Authors: Shostak K, Chariot A
- Issue date: 2015 Jun
- Nuclear factor-kappaB activation: a molecular therapeutic target for estrogen receptor-negative and epidermal growth factor receptor family receptor-positive human breast cancer.
- Authors: Singh S, Shi Q, Bailey ST, Palczewski MJ, Pardee AB, Iglehart JD, Biswas DK
- Issue date: 2007 Jul
- Concurrent inhibition of NF-kappaB, cyclooxygenase-2, and epidermal growth factor receptor leads to greater anti-tumor activity in pancreatic cancer.
- Authors: Ali S, Banerjee S, Schaffert JM, El-Rayes BF, Philip PA, Sarkar FH
- Issue date: 2010 May
- Epidermal growth factor-induced nuclear factor kappa B activation: A major pathway of cell-cycle progression in estrogen-receptor negative breast cancer cells.
- Authors: Biswas DK, Cruz AP, Gansberger E, Pardee AB
- Issue date: 2000 Jul 18
- Genistein enhances the effect of epidermal growth factor receptor tyrosine kinase inhibitors and inhibits nuclear factor kappa B in nonsmall cell lung cancer cell lines.
- Authors: Gadgeel SM, Ali S, Philip PA, Wozniak A, Sarkar FH
- Issue date: 2009 May 15