By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clinical development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC₅₀ of 4.4, 2.4, and 15.7 nM, respectively. In most tumor cell lines tested, 8 exhibits efficient antiproliferative activity with greater potency than vorinostat (SAHA), erlotinib, lapatinib, and combinations of vorinostat/erlotinib and vorinostat/lapatinib. In vivo, 8 promotes tumor regression or inhibition in various cancer xenograft models including nonsmall cell lung cancer (NSCLC), liver, breast, head and neck, colon, and pancreatic cancers. These results suggest that a single compound that simultaneously inhibits HDAC, EGFR, and HER2 may offer greater therapeutic benefits in cancer over single-acting agents through the interference with multiple pathways and potential synergy among HDAC and EGFR/HER2 inhibitors.

中文翻译：

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发现7-（4-（3-乙炔基苯基氨基）-7-甲氧基喹唑啉-6-基氧基）-N-羟基庚酰胺（CUDC-101）作为有效的多效HDAC，EGFR和HER2抑制剂来治疗癌症

通过将组蛋白脱乙酰基酶（HDAC）抑制功能结合到表皮生长因子受体（EGFR）和人类表皮生长因子受体2（HER2）抑制剂的药效团中，我们合成了一系列新型的具有强效多作用HDAC，EGFR和HER2的化合物抑制作用，并确定7-（4-（3-乙炔基苯基氨基）-7-甲氧基喹唑啉-6-酰氧基）-N-羟基庚酰胺8（CUDC-101）为候选药物，目前正在临床开发中。图8显示了对HDAC，EGFR和HER2的有效体外抑制活性，IC _50分别为4.4、2.4和15.7 nM。在测试的大多数肿瘤细胞系中，8与伏立诺他（SAHA），厄洛替尼，拉帕替尼以及伏立诺他/厄洛替尼和伏立诺他/拉帕替尼的组合相比，具有更高的抗增殖活性。在体内，8可促进多种癌症异种移植模型中的肿瘤消退或抑制，包括非小细胞肺癌（NSCLC），肝癌，乳腺癌，头颈癌，结肠癌和胰腺癌。这些结果表明，同时抑制HDAC，EGFR和HER2的单一化合物通过干扰多种途径以及HDAC和EGFR / HER2抑制剂之间的潜在协同作用，可能比单作用剂在癌症中提供更大的治疗益处。