College of Pharmacy, Chung-Ang University, Seoul, 06974, Republic of Korea.
Department of Global Innovative Drugs, Graduate School of Chung-Ang University, Seoul, 06974, Republic of Korea.
Arch Pharm Res. 2022 Mar;45(3):123-141. doi: 10.1007/s12272-022-01376-4. Epub 2022 Mar 21.
The gene amplification of human epidermal growth factor receptor 2 (HER2) plays an essential role in the proliferation and progression of several cancers. However, HER2 inhibitors such as lapatinib strongly suppress wild-type EGFR, resulting in severe adverse effects. Therefore, there is an unmet need for highly selective HER2 inhibitors. In this study, we describe the design and synthesis of novel quinazoline derivatives that exhibit enhanced selectivity for HER2 over wild-type EGFR. Structure-activity relationship analysis indicated that the selectivity for HER2 over EGFR depends on the aniline moiety at C-4 and the substituents at C-6 in the quinazoline derivatives. Compound 7c with an IC of 8 nM for HER2 exhibited significantly higher selectivity for HER2 over EGFR, with a 240-fold improvement over lapatinib. In addition, the synthesized compounds exhibited anti-proliferative activity in the nanomolar range against SKBR3, a human breast cancer cell line that overexpresses HER2.
人类表皮生长因子受体 2（HER2）的基因扩增在几种癌症的增殖和进展中起着至关重要的作用。然而，HER2 抑制剂如拉帕替尼强烈抑制野生型 EGFR，导致严重的不良反应。因此，非常需要高度选择性的 HER2 抑制剂。在这项研究中，我们描述了设计和合成新型喹唑啉衍生物，这些衍生物对 HER2 表现出增强的选择性，超过野生型 EGFR。结构-活性关系分析表明，喹唑啉衍生物中 C-4 位的苯胺部分和 C-6 位的取代基决定了对 HER2 的选择性高于 EGFR。化合物 7c 对 HER2 的 IC 为 8 nM，对 HER2 表现出显著的选择性，比拉帕替尼高 240 倍。此外，所合成的化合物对 SKBR3（一种过表达 HER2 的人乳腺癌细胞系）具有纳摩尔范围内的抗增殖活性。
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