Potent and Selective Mitogen-Activated Protein Kinase Kinase 1/2 (MEK1/2) Heterobifunctional Small-molecule Degraders

Abstract

Previously, we reported a first-in-class von Hippel–Lindau (VHL)-recruiting mitogen-activated protein kinase kinases 1 and 2 (MEK1/2) degrader, MS432. To date, only two MEK1/2 degrader papers have been published and very limited structure–activity relationships (SAR) have been reported. Here, we describe our extensive SAR studies exploring both von Hippel–Lindau (VHL) and cereblon (CRBN) E3 ligase ligands and a variety of linkers, which resulted in two novel, improved VHL-recruiting MEK1/2 degraders, 24 (MS928) and 27 (MS934), and the first CRBN-recruiting MEK1/2 degrader 50 (MS910). These compounds potently and selectively degraded MEK1/2 by hijacking the ubiquitin-proteasome system, inhibited downstream signaling, and suppressed cancer cell proliferation. Furthermore, concurrent inhibition of BRAF or PI3K significantly potentiated the antitumor activity of degrader 27, suggesting that the combination of MEK1/2 degradation with BRAF or PI3K inhibition may provide potential therapeutic benefits. Finally, besides being more potent, degrader 27 displayed improved plasma exposure levels in mice, representing the best MEK1/2 degrader to date for in vivo studies.

MDR1 Drug Efflux Pump Promotes Intrinsic and Acquired Resistance to PROTACs in Cancer Cells

“…4F ) improved the degradation efficiency, resulting in a greater reduction in BET proteins or CDK9 at lower concentrations of the PROTACs. Additionally, co-treatment of DLD-1 cells with FAK degrader (FAK-degrader-1) ( 29 ) or MEK1/2 degrader (MS432) ( 30 ) and tariquidar improved the protein reduction relative to single agent therapies ( Fig. S4E-F ), suggesting overexpression of MDR1 promotes resistance to degrader therapies, independent of protein target.…”

“…K-ras mutations occur in nearly 40% of colorectal cancer (CRC) patients, supporting therapies that target K-ras effectors such as the MEK-ERK signaling pathway ( 35 ). Recently, MEK1/2 degraders have been developed that show potent anti-growth properties in RAS-RAF altered cancers ( 30 ). Notably, the majority of K-ras mutant CRC cell lines exhibit elevated ABCB1 expression ( 28 ), suggesting concomitant blockade of MDR1 may be required to achieve therapeutic efficacy with MEK1/2 degraders ( Fig.…”

“…6M ). Next, we explored the efficacy of combining MEK degraders and lapatinib in vivo using LS513 xenograft models and the recently published MEK degrader MS934, which has optimal bioavailability for animal studies ( 30 ). Similar to MS432, combining MS934 and lapatinib enhanced MEK1/2 degradation in LS513 cells, exhibited drug synergy, and distinctly induced apoptosis ( Fig.…”

Small-Molecule Inhibitors and Degraders Targeting KRAS-Driven Cancers

“…PAC-1 has shown to directly activate procaspase-3 to caspase-3 and consequently induce MEK1/2 degradation. [57] In this article, the authors showed the combination effect of PAC-1 with In 2020, the same group reported the result of an extensive structure-activity relationship study of MS432 [53]. They optimized the types and length of the linkers to obtain two improved MEK1/2 PROTACs, MS928 and MS934 (Figure 10), by maintaining the MEK1/2 binder and VHL E3 ligase binder.…”

“…The use of MEK inhibitors is limited due to the acquired resistance towards them in patients undergoing long-term treatment. However, since mutations in MEK1/2 induce resistance to MEK inhibitors, the opportunity to overcome resistance should be investigated via MEK1/2 degradation and PROTAC technology [52][53][54].…”