1474030-72-2Relevant academic research and scientific papers
First Bispecific Inhibitors of the Epidermal Growth Factor Receptor Kinase and the NF-κB Activity As Novel Anticancer Agents
Hamed, Mostafa M.,Darwish, Sarah S.,Herrmann, Jennifer,Abadi, Ashraf H.,Engel, Matthias
, p. 2853 - 2868 (2017/04/21)
The 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.
Quinazoline and tetrahydropyridothieno[2,3-d]pyrimidine derivatives as irreversible EGFR tyrosine kinase inhibitors: Influence of the position 4 substituent
Hamed, Mostafa M.,Abou El Ella, Dalal A.,Keeton, Adam B.,Piazza, Gary A.,Engel, Matthias,Hartmann, Rolf W.,Abadi, Ashraf H.
, p. 1202 - 1207 (2013/08/23)
Herein, we describe new quinazoline and tetrahydropyridothieno[2,3-d] pyrimidine derivatives with an acrylamido group at positions 6 and 7 respectively, and with variable anilino, sulfonamido and cycloalkylamino substituents at position 4. The lipophilic and steric properties of the position 4 substituent seem crucial for activity. Several compounds were more active than gefitinib in inhibiting the wild type EGFR enzyme, the autophosphorylation of the mutant EGFR expressing cell line (H1975), and the growth of cell lines with wild type and mutant EGFR tyrosine kinase. Moreover, a novel synthesis of the quinazoline nucleus from a formimidate derivative is described.
