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. 2022 Dec 8;14(1):92–102. doi: 10.1021/acsmedchemlett.2c00446

Discovery of Coumarin-Based MEK1/2 PROTAC Effective in Human Cancer Cells

Chao Wang ⊥,*, Han Wang ‡, Cangxin Zheng ‡, Bingru Li §, Zhenming Liu §, Liangren Zhang §, Lan Yuan ∥,*, Ping Xu ‡,*
PMCID: PMC9841598  PMID: 36655129

Abstract

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The RAF/MEK/ERK pathway is a crucial signal path which is closely associated with the proliferation, differentiation, and apoptosis of tumors. MEK1/2 is a key kinase target in the pathway, with ERK1/2 acting as the main substrate of it. Despite the rapid development of MEK1/2 inhibitors, acquired resistance still happens and remains a significant problem. Most of the inhibitors possess a similar diarylamine scaffold. Here we designed and synthesized a series of MEK1/2 degraders based on a coumarin derivative which was a potent non-diarylamine allosteric MEK1/2 inhibitor. P6b among them showed the most potent degradation effect, with DC50 values of 0.3 μM and 0.2 μM in MEK1 and MEK2 degradation, respectively. An antiproliferation assay showed that it more significantly inhibits the growth of A375 cells (IC50= 2.8 μM) compared to A549 cells (IC50 = 27.3 μM). To sum up, we discovered P6b with a non-diarylamine scaffold for the first time as a potent MEK PROTAC effective in human cancer cells.

Keywords: PROTAC, Degradation, MEK1/2, coumarin, cancer

The RAF/MEK/ERK pathway plays an important role in cell proliferation, differentiation, and apoptosis and is involved in the regulation of cancer progression and other diseases.1 MEK1/2 is a key kinase target in the pathway, with ERK1/2 acting as the main substrate of it. Numerous MEK1/2 inhibitors have been reported in recent years. Most of them bind to the allosteric binding site of the protein without competing against ATP or its substrate ERK1/2, therefore showing high selectivity and low toxicity in drug discovery and cancer therapy.2 Many MEK1/2 inhibitors possessing a diarylamine scaffold entered into different clinical trial stages2 (Figure 1). Four compounds, i.e., Trametinib, Cobimetinib, Binimetinib, and Selumetinib, have been approved by the U.S. FDA to date.3−6 Despite the rapid development of MEK1/2 inhibitors, acquired resistance still happens and remains a significant problem due to the mutation of MEK1/2 or the amplification of its upstream driving oncogene.7−11

Figure 1.

Figure 1

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Chemical structures of four marketed MEK1/2 inhibitors and representative MEK1/2 inhibitors based on coumarin derivatives reported previously.

With the capacities of catalytic degradation, high selectivity, and overcoming drug resistance, proteolysis targeting chimeras (PROTACs) have become widely used in drug discovery strategies.12−23 Three MEK1/2 degraders showing obvious MEK1/2 degradation have been reported to date, with all of them have diarylamine structures as the warheads24−26 (Figure 2). To determine whether a non-diarylamine scaffold such as coumarin can be a proper warhead for MEK1/2 degradation and expand the variety of MEK1/2 degraders, in this paper we report our discovery of P6b as a highly efficacious MEK1/2 degrader based upon a non-diarylamine MEK inhibitor with a coumarin scaffold. Mechanism assays show that P6b induces MEK1/2 degradation in a time- and dose-dependent manner via the ubiquitin-proteasome system (UPS). Studies of inhibition effects on cell growth show that P6b can inhibit the cell growth of A549 and A375 cells effectively and the A375 cell line is more sensitive to P6b than the A549 cell line.

Figure 2.

Figure 2

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Reported MEK1/2 PROTACs.

We have been working on the discovery of new MEK inhibitors for many years. Compound 18 (here 1), which has a coumarin scaffold, was reported by our group in 2013;27 at nearly the same time, RO5126766 (2)28,29 and 14d (here 3),30 which have the same scaffold, were reported (Figure 1). All of them showed excellent MEK binding and inhibition activities. The MEK PROTAC molecules are composed of a MEK ligand and an E3 ligase ligand, connected by a linker. In the current work, 14d was used as the ligand on the MEK protein. Classical ligands of E3 ligases CRBN and VHL, such as 21 and 22, were used as the E3 ligands. To find the appropriate linker connection site, we performed molecular docking using the Schrödinger Maestro package (www.schrodinger.com). The docking study of the complex of MEK1 (PDB: 3WIG) and 14d suggested that the arylamine group of 14d is oriented toward the exterior of the MEK1 protein, making it a potentially suitable tethering site (Figure 3). We next did a docking study for the complex of MEK1 and compound 17 with sulfamide removed. The data showed that although 14d has an H-bond between the sulfamide and Arg190 of the protein with a docking score of −8.85, compound 17 with sulfamide removed has a better docking score of −9.87 (Figure S1) since the carbonyl oxygen of compound 17 forms an additional H-bond with Val212, which is much more important to the binding activity compared to the sulfamide–Arg190 interaction. Moreover, compound 17 is easier to synthesize. Therefore, compound 17 was selected as an optimal warhead in terms of docking score and feasibility of synthesis. Thus, we designed and synthesized a series of MEK degraders using compound 17 as the MEK ligand and CRBN ligand Pomalidomide (21) and VHL ligand (22) as the ligand of E3 ligases, with different linkers tethering them together (see Figure 4 and Schemes 1–4).

Figure 3.

Figure 3

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Binding mode of 14d to the MEK protein (PDB: 3WIG).

Figure 4.

Figure 4

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Graphical representation of MEK1/2 PROTAC structure.

Scheme 1. Synthetic Routes to MEK1/2 Ligand.

Scheme 1

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Conditions and reagents: (a) NBS, dibenzoyl peroxide, CCl4, reflux; (b) ethyl acetoacetate, NaH, THF, 0 °C; (c) resorcinol, strong sulfuric acid, 0 °C; (d) Pd/C, H2, CH3OH; (e) 2-bromopyrimidine, Cs2CO3, DMF, reflux; (f) propargyl bromide, K2CO3, DMF, rt.

Scheme 4. Synthetic Routes to P5a–P5e, P6a–P6e, and P7a–P7d.

Scheme 4

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Conditions and reagents: (a) di-tert-butyl dicarbonate, NaOH, THF/H2O, rt; (b) compound 17 or 18, HATU, DIPEA, DMF, rt, 2 h; (c) TFA, DCM; (d) succinic acid monobenzyl ester, HATU, DIPEA, DMF, rt, 3 h; (e) Pd/C, H2, MeOH, rt; (f) Pomalidomide 21 or compound 22, SOCl2, TEA, DCM/THF, 0 °C → 40 °C.

Scheme 2. Synthetic Routes to P1a–P1d and P2a–P2d.

Scheme 2

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Conditions and reagents: (a) Et3N, pTsCl, DCM, 0 °C; (b) Me3SiN3, KF, dry DMF; (c) PPh3, HCl/EA, RT for 14 h; (d) F-Thalidomide, K2CO3, rt; (e) compound 19 or 20, sodium l-ascorbate, CuSO4·5H2O, DMF, rt.

Scheme 3. Synthetic Routes to P3a–P3d and P4a–P4d.

Scheme 3

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Conditions and reagents: (a) Et3N, pTsCl, DCM, 0 °C; (b) Me3SiN3, KF, dry DMF; (c) compound 22, K2CO3, rt; (d) compound 19 or 20, sodium l-ascorbate, CuSO4·5H2O, DMF, rt.

We first synthesized and evaluated the capacity of compounds P1a–P1d, P2a–P2d with a triazole group and different lengths of PEG linker in inducing MEK1/2 degradation by Western blotting in A549 human lung cancer cells. The data showed that none of the CRBN-recruiting PROTACs (P1a–P1d, P2a–P2d) can effectively reduce MEK1/2 protein at 10 μM concentration (Table 1, Figure S2). We next synthesized a series of VHL-recruiting PROTACs of MEK1/2 using the same PEG linkers (P3a–P3d, P4a–P4d). P3a, which contains a fluorine group and a linker with one ethylene glycol group (n = 1), exhibited a MEK1/2 degradation effect at 10 μM, suggesting that VHL-recruiting PROTACs may have better activity than CRBN-recruiting ones. However, the unremarkable MEK1/2 degradation activity of the VHL series at 1 μM concentration indicated that these compounds are still not potent enough (Table 1, Figure S3).

Table 1. Degradation Activity of MEK1/2 Degraders with a Polyglycol Chain in A549 Cell Lines.

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We next synthesized and evaluated a series of MEK1/2 PROTACs containing linkers with different lengths of alkyl group and an amide bond in replacement of the PEG linker and triazole groups (P5a–P5e, P6a–P6e, P7a–P7d) in expectation of discovering more-potent PROTACs (Scheme 4). These compounds showed better degradation activities than the PEG linker series. Western blot results at 1 μM concentration showed that the VHL-recruiting PROTACs with a fluorine group (P6a–P6e) have the best activities in inducing MEK1/2 degradation compared to the CRBN-recruiting series (P5a–P5e) and the VHL-recruiting PROTACs without a fluorine group (P7a–P7d) (Table 2, Figures S4 and S5), suggesting that the VHL ligand is beneficial to the degradation ability of the PROTACs and the alkyl group linker is better than the PEG linker. Meanwhile, the fluorine substituent on the benzene ring of the MEK ligand plays an important role in improving the degradation activity.

Table 2. Degradation Activity of MEK1/2 Degraders with an Alkyl Chain in the A549 Cell Line.

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Compound P6b, containing an alkyl linker of n = 4, is an optimal MEK degrader which can effectively reduce the MEK1 and MEK2 proteins by 70% and 80%, respectively, at 1 μM concentration with a 24 h treatment in A549 cells. Therefore, it was selected for further biological studies. We evaluated the kinetics of P6b in induction of MEK1/2 degradation at 1 μM in the A549 cell line. Our data showed that P6b effectively reduces the MEK1/2 protein level within 4 h and achieves >70% MEK1/2 degradation with a 24 h treatment (Figure 5a). We further evaluated P6b for its potency in inducing MEK depletion with a 24 h treatment time in the A549 cell line. The data showed that P6b achieves DC50 values of 0.3 μM and 0.2 μM for the degradation of MEK1 and MEK2, respectively, and near-complete MEK2 degradation at 1 μM, suggesting significant selectivity for degrading MEK2 over MEK1 (Figure 5b). The MEK1/2 degradation effect of P6b was also determined in A375 cells, with a DC50 value of 2.8 μM with a 24 h treatment (Figure 5c). Collectively, these data indicate that P6b can induce MEK1/2 degradation rapidly and effectively in a time- and dose-dependent manner.

Figure 5.

Figure 5

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Action of P6b characterized by time and concentration dependence. A549 cells were treated with P6b at the indicated time points for 1 μM (a) or at the indicated concentrations for 24 h (b). A375 cells were treated with P6b at the indicated concentrations for 24 h (c).

We next investigated the mechanism of MEK degradation induced by P6b in A549 cells. The data showed that MEK degradation can be rescued by MEK inhibitor 17, VHL ligand 22, NEDD8-activating E1 enzyme inhibitor MLN4924, and proteasome inhibitor MG132 (Figure 6), suggesting that P6b is a bona fide PROTAC MEK1/2 degrader.

Figure 6.

Figure 6

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Mechanism of MEK1/2 degradation by P6b.

We subsequently evaluated the effect of P6b on downstream signaling of MEK1/2. Western blotting data showed that P6b induced a decrease in the level of p-ERK1/2 but had no effect on that of ERK1/2 (Figure 7), suggesting that this effect could result from the degradation of MEK1/2.

Figure 7.

Figure 7

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Effects of MEK1/2 PROTAC P6b on downstream signaling.

Because the inhibition of MEK can induce cell death, we next investigated the antiproliferation effect of P6b in A549 and A375 cell lines. The data showed that P6b achieves IC50 values of 27.3 μM and 2.8 μM in A549 (Figure 8a) and A375 (Figure 8b) cell lines, respectively, indicating that A375 cells are about 10-fold more sensitive to P6b than A549 cells. In addition, MEK1/2 inhibitor 14d had an IC50 value of 1.9 μM in A375 cells (Figure S6), suggesting that P6b shows antiproliferative activity comparable to that of the inhibitor in A375 cells.

Figure 8.

Figure 8

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Inhibition of cell viability by P6b in A549 (a) and A375 (b) cell lines.

To explore how much the changes to the MEK ligand or the linker affected the affinity for the target, the cell growth inhibition effects of representative compounds P6a, P6b, and P7a at 10 μM were determined in A375 cells for 48 h (Figure S7). The data showed that, compared to P6b (60% inhibition), P6a, with the same MEK warhead and MEK binding affinity but different length of linker, has poor MEK cell growth inhibition (13%). This is consistent with the degradation result in A549 cells, indicating the importance of the linker and the formation of the ternary complex. Both P6a and P7a (21%), with or without a fluorine substituent on the benzene ring of the MEK ligand, have unobvious MEK degradation and cell growth inhibition effects. Above all, the data indicated that the impact of the linker and the formation of the ternary complex are much more important to the activity than the change to MEK ligand.

We have designed and synthesized a series of MEK PROTACs using the non-diarylamine allosteric compound 17 as the warhead of MEK and CRBN or VHL as the E3 ligase. The ability of these PROTACs, with different linker lengths and varieties, in inducing MEK degradation has been evaluated by Western blotting in A549 cells. VHL-based PROTACs are more potent than CRBN-based ones, and the fluorine group on the benzene ring plays an important role in improving the degradation activity. An alkyl group and amide bond in the linker are beneficial to the activity compared to a PEG linker and triazole group.

P6b among the PROTACs studied showed the most potent degradation effect, with DC50 values of 0.3 μM and 0.2 μM in MEK1 and MEK2 degradation, respectively. Therefore, it was selected as the optimal MEK PROTAC. It can induce MEK degradation rapidly and effectively in a time- and dose-dependent manner via the ubiquitin–proteasome system (UPS). The antiproliferation assay showed that it more significantly inhibits the growth of A375 cells (IC50 = 2.8 μM) compared to A549 cells (IC50 = 27.3 μM). Although the antiproliferation activity is similar to that of the inhibitor control and further structure optimization of P6b needs to be done in the future, these data demonstrated that MEK degraders with non-diarylamine scaffold as the warhead are feasible.

The degradation effect in A375 cells (DC50 = 2.8 μM) is consistent with the cell growth inhibition (IC50 = 2.8 μM). However, there is a drop-off from the cellular DC50 of MEK to the effects on proliferation in A549 cells. It is hypothesized that MEK protein may play a more important role in A375 cells than in A549 cells, and thus the proliferation of A375 cells is more sensitive than A549 cells to MEK1/2 degradation.

To sum up, we discovered P6b for the first time as a potent MEK PROTAC with a non-diarylamine scaffold. Given that drug resistance may occur due to long-term using of MEK inhibitors, the development of non-diarylamine MEK degraders may provide a promising approach to overcome acquired resistance of inhibitors.

Acknowledgments

This work was supported by the National Natural Science Foundation of China (Grant No. 21807006), the Peking University Medicine Seed Fund for Interdisciplinary Research and the Fundamental Research Funds for the Central Universities (Grant No. BMU2020MX016), and the Foundation of Peking University Health Science Center (Grant Nos. MU2021ZC010 and BMU2022MX009).

Glossary

Abbreviations

PROTAC

Proteolysis-targeting chimera

MEK1/2

Mitogen-activated protein kinase kinases 1 and 2

ERK1/2

Extracellular signal related kinases

UPS

Ubiquitin-proteasome system

ATP

Adenosine triphosphate

CRBN

Cereblon

VHL

Von Hippel–Lindau

PEG

Polyethylene glycol

DC50

Half-maximal degradation concentration

IC50

Concentration of a drug or inhibitor needed to inhibit a biological process or response by 50% concentration

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.2c00446.

  • Experimental procedures and characterization of key compounds; methods for biological assays; binding model of compound 14d (3) and 17 based on molecular docking (Figure S1); assay of degradation activity of P1a–P2d (Figure S2); assay of degradation activity of P3a–P3d, P4a–P4d (Figure S3); assay of degradation activity of P5a–P5e (Figure S4); assay of degradation activity of P6a–P6e, P7a–P7d (Figure S5); inhibition curve of cell viability by 14d in A375 cells (Figure S6); inhibition of cell viability by P6b, P6a, and P7a at 10 μM in A375 cells (Figure S7) (PDF)

Author Contributions

† C.W. and H.W. contributed equally to this work.

The authors declare no competing financial interest.

Special Issue

Published as part of the ACS Medicinal Chemistry Letters virtual special issue “New Drug Modalities in Medicinal Chemistry, Pharmacology, and Translational Science”.

Supplementary Material

ml2c00446_si_001.pdf (541.1KB, pdf)

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