Hamed Mostafa M, Darwish Sarah S, Herrmann Jennifer, Abadi Ashraf H, Engel Matthias
Pharmaceutical and Medicinal Chemistry, Campus C2.3, and Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Saarland University , Campus E8.1, D-66123 Saarbrücken, Germany.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo , Cairo 11835, Egypt.
J Med Chem. 2017 Apr 13;60(7):2853-2868. doi: 10.1021/acs.jmedchem.6b01774. Epub 2017 Mar 28.
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 IC for NF-κB inhibition of 0.3 μM while retaining a potent EGFR kinase inhibition (IC = 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.
NF-κB转录因子的激活是用表皮生长因子受体（EGFR）激酶抑制剂治疗后诱导的一种主要适应性反应，导致非小细胞肺癌和其他肿瘤类型产生耐药性。为了抑制这种存活机制，我们开发了新的硫脲喹唑啉衍生物，它们是EGFR激酶和NF-κB活性的双重抑制剂。在NF-κB报告基因检测中鉴定出的活性化合物经过优化，得到了化合物9b，其对NF-κB抑制的细胞半数抑制浓度（IC）为0.3 μM，同时保留了对EGFR激酶的强效抑制作用（IC = 60 nM）。这些双重抑制剂在体外和体内异种移植模型中显示出比吉非替尼更高的抑制EGFR过表达肿瘤细胞系生长的效力，同时未观察到毒性迹象。对NF-κB抑制分子机制的研究表明，双重抑制剂使细胞核中NF-κB复合物的转录共激活因子CREB结合蛋白减少。
