National Pharmaceutical Teaching Laboratory Center, School of Pharmaceutical Sciences, Peking University, Beijing, China.
Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Peking University, Beijing, China.
Eur J Med Chem. 2021 Jun 5;218:113386. doi: 10.1016/j.ejmech.2021.113386. Epub 2021 Mar 19.
Mitogen-activated protein kinase kinases 1 and 2 (MEK1/2) are the crucial part of the RAS-RAF-MEK-ERK pathway (or ERK pathway), which is involved in the regulation of various cellular processes including proliferation, survival, and differentiation et al. Targeting MEK has become an important strategy for cancer therapy, and 4 MEK inhibitors (MEKis) have been approved by FDA to date. However, the application of MEKis is limited due to acquired resistance under long-term treatment. Fortunately, an emerging technology, named proteolysis targeting chimera (PROTAC), could break through this limitation by inducing MEK1/2 degradation. Compared to MEKis, MEK1/2 PROTAC is rarely studied and only three MEK1/2 PROTAC molecules, have been reported until now. This paper will outline the ERK pathway and the mechanism and research progress of MEK1/2 inhibitors, but focus on the development of MEK degraders and their optimization strategies. PAC-1 strategy which can induce MEK degradation indirectly, other PROTACs on ERK pathway, the advantages and challenges of PROTAC technology will be subsequently discussed.
丝裂原活化蛋白激酶激酶 1 和 2（MEK1/2）是 RAS-RAF-MEK-ERK 通路（或 ERK 通路）的关键部分，参与调节包括增殖、存活和分化等各种细胞过程。靶向 MEK 已成为癌症治疗的重要策略，迄今为止，已有 4 种 MEK 抑制剂（MEKi）获得 FDA 批准。然而，由于长期治疗下获得性耐药，MEKi 的应用受到限制。幸运的是，一种新兴技术，称为蛋白水解靶向嵌合体（PROTAC），可以通过诱导 MEK1/2 降解来突破这一限制。与 MEKi 相比，MEK1/2 PROTAC 的研究较少，迄今为止仅报道了三种 MEK1/2 PROTAC 分子。本文将概述 ERK 通路以及 MEK1/2 抑制剂的作用机制和研究进展，但重点介绍 MEK 降解剂的开发及其优化策略。随后将讨论 PAC-1 策略，该策略可以间接诱导 MEK 降解，以及 ERK 通路中的其他 PROTAC，PROTAC 技术的优势和挑战。
