Milik Sandra N, Lasheen Deena S, Serya Rabah A T, Abouzid Khaled A M
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo 11566, Egypt.
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo 11566, Egypt.
Eur J Med Chem. 2017 Dec 15;142:131-151. doi: 10.1016/j.ejmech.2017.07.023. Epub 2017 Jul 18.
Epidermal Growth Factor Receptor (EGFR) stands out as a key player in the development of many cancers. Its dysregulation is associated with a vast number of tumors such as non-small-cell lung cancer, colon cancer, head-and-neck cancer, breast and ovarian cancer. Being implicated in the development of a number of the most lethal cancers worldwide, EGFR has long been considered as a focal target for cancer therapies, ever since the FDA approval of "Gefitinib" in 2003 and up to the last FDA approved small molecule EGFR kinase inhibitor "Osimertinib" in 2015. Studies are still going on to find more efficient EGFR inhibitors due to the continuous emergence of resistance to the current inhibitors. Cancerous cells resist EGFR tyrosine kinase inhibitors (TKIs) through various mechanisms, the most commonly reported ones are the T790M mutation and HER2 amplification. Therefore, tackling EGFR TKIs-resistant tumors through a multi-targeting approach comprising a dual EGFR/HER2 inhibitor that is also capable of inhibiting the mutant T790M EGFR is anticipated to overcome drug resistance. In this review, we will survey the structural aspects of EGFR family and the structure-activity relationship of representative dual EGFR/HER2 inhibitors. To follow, we will discuss the structural aspects of the mutation-driven resistance and various design strategies to overcome it. Finally, we will review the SAR of exemplary irreversible dual EGFR/HER2 inhibitors that can overcome the mutation-driven resistance.
表皮生长因子受体（EGFR）在多种癌症的发展过程中起着关键作用。其失调与大量肿瘤相关，如非小细胞肺癌、结肠癌、头颈癌、乳腺癌和卵巢癌。由于EGFR与全球一些最致命癌症的发展有关，自2003年美国食品药品监督管理局（FDA）批准“吉非替尼”以来，一直到2015年FDA批准的最后一种小分子EGFR激酶抑制剂“奥希替尼”，EGFR长期以来一直被视为癌症治疗的重点靶点。由于目前的抑制剂不断出现耐药性，仍在进行研究以寻找更有效的EGFR抑制剂。癌细胞通过多种机制对EGFR酪氨酸激酶抑制剂（TKIs）产生耐药性，最常见的是T790M突变和HER2扩增。因此，预计通过一种多靶点方法来攻克EGFR TKIs耐药肿瘤，该方法包括一种双EGFR/HER2抑制剂，其还能够抑制突变型T790M EGFR，从而克服耐药性。在本综述中，我们将概述EGFR家族的结构方面以及代表性双EGFR/HER2抑制剂的构效关系。接下来，我们将讨论突变驱动的耐药性的结构方面以及克服它的各种设计策略。最后，我们将综述能够克服突变驱动耐药性的示例性不可逆双EGFR/HER2抑制剂的构效关系。
