Research progress of MEK1/2 inhibitors and degraders in the treatment of cancer.

Abstract 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.