Potent and Selective Mitogen-Activated Protein Kinase Kinase 1/2 (MEK1/2) Heterobifunctional Small-molecule Degraders
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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.
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Recently, MEK1/2 degraders have been developed that show potent anti-growth properties in RAS-RAF altered cancers.
“Recently, MEK1/2 degraders have been developed that show potent anti-growth properties in RAS-RAF altered cancers (33).”
From The drug efflux pump MDR1 promotes intrinsic and acquired resistance to PROTACs in cancer cells (2022) · cites this paper as [33]
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Cites
Mammalian MAP kinase signalling cascades
Chang, L., & Karin, M. (2001) · Nature · doi:10.1038/35065000 · Cited by 5,118 · see citing works
Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer
Roberts, P. J., & Der, C. J. (2007) · Oncogene · doi:10.1038/sj.onc.1210422 · Cited by 2,788 · see citing works
Distinct Sets of Genetic Alterations in Melanoma
Curtin, J. A., Fridlyand, J., Kageshita, T., Patel, H. N., Busam, K. J., Kutzner, H., Cho, K.-H., Aiba, S., Bröcker, E.-B., LeBoit, P. E., et al. (2005) · New England Journal of Medicine · doi:10.1056/nejmoa050092 · Cited by 2,747 · see citing works
Planchard, D., Smit, E. F., Groen, H. J. M., Mazières, J., Besse, B., Helland, Å., Giannone, V., D'amelio, A. M., Zhang, P., Mookerjee, B., et al. (2017) · The Lancet Oncology · doi:10.1016/s1470-2045(17)30679-4 · Cited by 1,360 · see citing works
Structure of the DDB1–CRBN E3 ubiquitin ligase in complex with thalidomide
Fischer, E. S., Böhm, K., Lydeard, J. R., Yang, H., Stadler, M. B., Cavadini, S., Nagel, J., Serluca, F., Acker, V., Lingaraju, G. M., et al. (2014) · Nature · doi:10.1038/nature13527 · Cited by 1,141 · see citing works
Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4
Lu, J., Qian, Y., Altieri, M., Dong, H., Wang, J., Raina, K., Hines, J., Winkler, J. D., Crew, A. P., Coleman, K., et al. (2015) · Chemistry & Biology · doi:10.1016/j.chembiol.2015.05.009 · Cited by 1,140 · see citing works
The dTAG system for immediate and target-specific protein degradation
Nabet, B., Roberts, J. M., Buckley, D. L., Paulk, J., Dastjerdi, S., Yang, A., Leggett, A. L., Erb, M. A., Lawlor, M. A., Souza, A., et al. (2018) · Nature Chemical Biology · doi:10.1038/s41589-018-0021-8 · Cited by 1,118 · see citing works
Targeting the mitogen-activated protein kinase cascade to treat cancer
Sebolt, J. S., & Herrera, R. (2004) · Nature reviews. Cancer · doi:10.1038/nrc1503 · Cited by 1,109 · see citing works
Targeted protein degradation: expanding the toolbox
Schapira, M., Calabrese, M. F., Bullock, A. N., & Crews, C. M. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0047-y · Cited by 960 · see citing works
Planchard, D., Besse, B., Groen, H. J. M., Souquet, P.-J., Quoix, E., Baik, C. S., Barlesi, F., Kim, T. M., Mazieres, J., Novello, S., et al. (2016) · The Lancet Oncology · doi:10.1016/s1470-2045(16)30146-2 · Cited by 888 · see citing works
PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer
Raina, K., Lu, J., Qian, Y., Altieri, M., Gordon, D., Rossi, A. M. K., Wang, J., Chen, X., Dong, H., Siu, K., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1521738113 · Cited by 852 · see citing works
Self-citationJänne, P. A., Shaw, A. T., Pereira, J. R., Jeannin, G., Vansteenkiste, J., Barrios, C., Franke, F. A., Grinsted, L., Zazulina, V., Smith, P., et al. (2013) · The Lancet Oncology · doi:10.1016/s1470-2045(12)70489-8 · Cited by 655 · see citing works
PROTACs: great opportunities for academia and industry
Sun, X., Gao, H., Yang, Y., He, M., Wu, Y., Song, Y.-G., Tong, Y., & Rao, Y. (2019) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-019-0101-6 · Cited by 651 · see citing works
Gilmartin, A. G., Bleam, M. R., Groy, A., Moss, K. G., Minthorn, E. A., Kulkarni, S. G., Rominger, C. M., Erskine, S. G., Fisher, K. E., Yang, J., et al. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-10-2200 · Cited by 591 · see citing works
Dummer, R., Ascierto, P. A., Gogas, H. J., Arance, A. M., Mandalà, M., Liszkay, G., Garbe, C., Schadendorf, D., Krajsová, I., Gutzmer, R., et al. (2018) · The Lancet Oncology · doi:10.1016/s1470-2045(18)30497-2 · Cited by 589 · see citing works
Targeted protein degradation: elements of PROTAC design
Paiva, S.-L., & Crews, C. M. (2019) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2019.02.022 · Cited by 586 · see citing works
Development of targeted protein degradation therapeutics
Chamberlain, P. P., & Hamann, L. G. (2019) · Nature Chemical Biology · doi:10.1038/s41589-019-0362-y · Cited by 489 · see citing works
Kim, K. B., Kefford, R. F., Pavlick, A. C., Infante, J. R., Ribas, A., Sosman, J. A., Fecher, L. A., Millward, M., McArthur, G. A., Hwu, P., et al. (2012) · Journal of Clinical Oncology · doi:10.1200/jco.2012.43.5966 · Cited by 475 · see citing works
Targeted Degradation of Oncogenic KRAS <sup>G12C</sup> by VHL-Recruiting PROTACs
Bond, M. J., Chu, L., Nalawansha, D. A., Li, K., & Crews, C. M. (2020) · ACS Central Science · doi:10.1021/acscentsci.0c00411 · Cited by 450 · see citing works
Delineating the role of cooperativity in the design of potent PROTACs for BTK
Zorba, A., Nguyen, C., Xu, Y., Starr, J., Borzilleri, K., Smith, J., Zhu, H., Farley, K. A., Ding, W., Schiemer, J., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1803662115 · Cited by 419 · see citing works
Protein Degradation by In-Cell Self-Assembly of Proteolysis Targeting Chimeras
Lebraud, H., Wright, D. J., Johnson, C. N., & Heightman, T. D. (2016) · ACS Central Science · doi:10.1021/acscentsci.6b00280 · Cited by 413 · see citing works
LoRusso, P. M., Adjei, A. A., Varterasian, M. L., Gadgeel, S. M., Reid, J. M., Mitchell, D. Y., Hanson, L. J., DeLuca, P., Bruzek, L. M., Piens, J., et al. (2005) · Journal of Clinical Oncology · doi:10.1200/jco.2005.14.415 · Cited by 402 · see citing works
Examination of Mutations in BRAF, NRAS, and PTEN in Primary Cutaneous Melanoma
Goel, V., Lazar, A. J., Warneke, C. L., Redston, M. S., & Haluska, F. G. (2005) · Journal of Investigative Dermatology · doi:10.1038/sj.jid.5700026 · Cited by 393 · see citing works
Long, G. V., Fung, C., Menzies, A. M., Pupo, G. M., Carlino, M. S., Hyman, J., Shahheydari, H., Tembe, V., Thompson, J. F., Saw, R. P., et al. (2014) · Nature Communications · doi:10.1038/ncomms6694 · Cited by 375 · see citing works
Moriceau, G., Hugo, W., Hong, A., Shi, H., Kong, X., Yu, C. C., Koya, R. C., Samatar, A. A., Khanlou, N., Braun, J. G., et al. (2015) · Cancer Cell · doi:10.1016/j.ccell.2014.11.018 · Cited by 345 · see citing works
Combination therapy with BRAF and MEK inhibitors for melanoma: latest evidence and place in therapy
Eroglu, Z., & Ribas, A. (2016) · Therapeutic Advances in Medical Oncology · doi:10.1177/1758834015616934 · Cited by 316 · see citing works
Molina, J. R., & Adjei, A. A. (2006) · Journal of Thoracic Oncology · doi:10.1016/s1556-0864(15)31506-9 · Cited by 307 · see citing works
Regulation of MAP kinase activity by peptide receptor signalling pathway: Paradigms of multiplicity
Liebmann, C. (2001) · Cellular Signalling · doi:10.1016/s0898-6568(01)00192-9 · Cited by 291 · see citing works
Current Development Status of MEK Inhibitors
Cheng, Y., & Tian, H. (2017) · Molecules · doi:10.3390/molecules22101551 · Cited by 291 · see citing works
The discovery of the benzhydroxamate MEK inhibitors CI-1040 and PD 0325901
Barrett, S. D., Bridges, A. J., Dudley, D. T., Saltiel, A. R., Fergus, J. H., Flamme, C. M., Delaney, A. M., Kaufman, M., LePage, S., Leopold, W. R., et al. (2008) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2008.10.054 · Cited by 289 · see citing works
MEK1/2 dual-specificity protein kinases: Structure and regulation
Roskoski, R. J. (2011) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2011.11.145 · Cited by 277 · see citing works
From basic research to clinical development of MEK1/2 inhibitors for cancer therapy
Frémin, C., & Meloche, S. (2010) · Journal of Hematology & Oncology · doi:10.1186/1756-8722-3-8 · Cited by 244 · see citing works
Hoeflich, K. P., Merchant, M., Orr, C., Chan, J., Den Otter, D., Berry, L., Kasman, I., Koeppen, H., Rice, K., Yang, N.-Y., et al. (2012) · Cancer Research · doi:10.1158/0008-5472.can-11-1515 · Cited by 242 · see citing works
AKT and ERK dual inhibitors: The way forward?
Cao, Z., Liao, Q., Su, M., Huang, K., Jin, J., & Cao, D. (2019) · Cancer Letters · doi:10.1016/j.canlet.2019.05.025 · Cited by 234 · see citing works
Self-citationProteolysis Targeting Chimeras (PROTACs) of Anaplastic Lymphoma Kinase (ALK)
Zhang, C., Han, X.-R., Yang, X., Jiang, B., Liu, J., Xiong, Y., & Jin, J. (2018) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2018.03.071 · Cited by 226 · see citing works
Self-citationAdachi, M., Fukuda, M., & Nishida, E. (2000) · The Journal of Cell Biology · doi:10.1083/jcb.148.5.849 · Cited by 218 · see citing works
Extracellular-Regulated Kinases: Signaling From Ras to ERK Substrates to Control Biological Outcomes
Eblen, S. T. (2018) · Advances in cancer research · doi:10.1016/bs.acr.2018.02.004 · Cited by 217 · see citing works
Zheng, C. F., & Guan, K. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(20)80474-8 · Cited by 200 · see citing works
Development of Multifunctional Histone Deacetylase 6 Degraders with Potent Antimyeloma Activity
Wu, H., Yang, K., Zhang, Z., Leisten, E. D., Li, Z., Xie, H., Liu, J., Smith, K. A., Novakova, Z., Barinka, C., et al. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b00516 · Cited by 180 · see citing works
Self-citationA Novel AKT1 Mutant Amplifies an Adaptive Melanoma Response to BRAF Inhibition
Shi, H., Hong, A., Kong, X., Koya, R. C., Song, C., Moriceau, G., Hugo, W., Yu, C. C., Ng, C., Chodon, T., et al. (2013) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0279 · Cited by 174 · see citing works
Clinical experience of MEK inhibitors in cancer therapy
Wang, D., Boerner, S. A., Winkler, J. D., & LoRusso, P. M. (2006) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2006.11.009 · Cited by 173 · see citing works
MEK Guards Proteome Stability and Inhibits Tumor-Suppressive Amyloidogenesis via HSF1
Tang, Z., Dai, S., He, Y., Doty, R. A., Shultz, L. D., Sampson, S. B., & Dai, C. (2015) · Cell · doi:10.1016/j.cell.2015.01.028 · Cited by 168 · see citing works
Burgermeister, E., Chuderland, D., Hanoch, T., Meyer, M., Liscovitch, M., & Seger, R. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.00601-06 · Cited by 162 · see citing works
BRAF-Mutated Colorectal Cancer: Clinical and Molecular Insights
Caputo, F., Santini, C., Bardasi, C., Cerma, K., Gardini, A. C., Spallanzani, A., Andrikou, K., Cascinu, S., & Gelsomino, F. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20215369 · Cited by 162 · see citing works
Mutant-selective degradation by BRAF-targeting PROTACs
Alabi, S., Jaime-Figueroa, S., Yao, Z., Gao, Y., Hines, J., Samarasinghe, K. T. G., Vogt, L., Rosen, N., & Crews, C. M. (2021) · Nature Communications · doi:10.1038/s41467-021-21159-7 · Cited by 152 · see citing works
Functional characterization of a PROTAC directed against BRAF mutant V600E
Posternak, G., Tang, X., Maisonneuve, P., Jin, T., Lavoie, H., Daou, S., Orlicky, S. M., de Rugy, T. G., Caldwell, L., Chan, K., et al. (2020) · Nature Chemical Biology · doi:10.1038/s41589-020-0609-7 · Cited by 128 · see citing works
MEK Inhibitors in the Treatment of Metastatic Melanoma and Solid Tumors
Grimaldi, A., Simeone, E., Festino, L., Vanella, V., Strudel, M., & Ascierto, P. (2017) · American Journal of Clinical Dermatology · doi:10.1007/s40257-017-0292-y · Cited by 124 · see citing works
Activated MEK1 Binds the Nuclear MyoD Transcriptional Complex to Repress Transactivation
Perry, R. L. S., Parker, M. H., & Rudnicki, M. A. (2001) · Molecular Cell · doi:10.1016/s1097-2765(01)00302-1 · Cited by 121 · see citing works
Highly monodisperse water-dispersable iron oxide nanoparticles for biomedical applications
Hofmann, A., Thierbach, S., Semisch, A., Hartwig, A., Taupitz, M., Rühl, E., & Graf, C. M. (2010) · Journal of Materials Chemistry · doi:10.1039/c0jm01169j · Cited by 84 · see citing works
Cassier, E., Gallay, N., Bourquard, T., Claeysen, S., Bockaert, J., Crépieux, P., Anne Poupon, B., Reiter, É., Marin, P., & Vandermoere, F. (2017) · eLife · doi:10.7554/elife.23777 · Cited by 79 · see citing works
A Secondary Mutation in BRAF Confers Resistance to RAF Inhibition in a BRAF V600E-Mutant Brain Tumor
Wang, J., Yao, Z., Jonsson, P., Allen, A. N., Qin, A. C. R., Uddin, S., Dunkel, I. J., Petriccione, M., Manova, K., Haque, S. S., et al. (2018) · Cancer Discovery · doi:10.1158/2159-8290.cd-17-1263 · Cited by 68 · see citing works
Discovery of a First-in-Class Mitogen-Activated Protein Kinase Kinase 1/2 Degrader
Wei, J., Hu, J., Wang, L., Xie, L., Jin, M. S., Chen, X., Liu, J., & Jin, J. J. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b01528 · Cited by 67 · see citing works
Self-citationDiscovery of Selective Small Molecule Degraders of BRAF-V600E
Han, X., Chen, L., Wei, Y., Yu, W., Chen, Y., Zhang, C., Jiao, B., Shi, T., Sun, L., Zhang, C., et al. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b02083 · Cited by 64 · see citing works
Design, Synthesis, and Biological Evaluation of MEK PROTACs
Vollmer, S., Cunoosamy, D. M., Lv, H., Feng, H., Li, X., Nan, Z., Yang, W., & Perry, M. W. D. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b00810 · Cited by 53 · see citing works
Kramer, B. W. W., Götz, R., & Rapp, U. R. (2004) · BMC Cancer · doi:10.1186/1471-2407-4-24 · Cited by 50 · see citing works
Therapeutic Strategies for Targeting BRAF in Human Cancer
Pratilas, C. A., & Solit, D. B. (2007) · Reviews on Recent Clinical Trials · doi:10.2174/157488707780599393 · Cited by 47 · see citing works
Concurrent BRAF/MEK Inhibitors in BRAF V600–Mutant High-Grade Primary Brain Tumors
Schreck, K. C., Guajardo, A., Lin, D. D. M., Eberhart, C. G., & Grossman, S. A. (2018) · Journal of the National Comprehensive Cancer Network · doi:10.6004/jnccn.2017.7052 · Cited by 46 · see citing works
Effective Treatment of Metastatic Melanoma by Combining MAPK and PI3K Signaling Pathway Inhibitors
Aasen, S. N., Parajuli, H., Hoang, T., Feng, Z., Stokke, K., Wang, J., Roy, K., Bjerkvig, R., Knappskog, S., & Thorsen, F. A. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20174235 · Cited by 44 · see citing works
Procaccia, S., Ordan, M., Cohen, I., Bendetz-Nezer, S., & Seger, R. (2017) · Scientific Reports · doi:10.1038/srep43078 · Cited by 39 · see citing works
Abstract 2515: Preclinical Development of ARRY-162, A Potent and Selective MEK 1/2 Inhibitor
Lee, P. A., Wallace, E. M., Marlow, A., Yeh, T. C., Marsh, V., Anderson, D. A., Woessner, R. D., Hurley, B., Lyssikatos, J. P., Poch, G., et al. (2010) · Cancer Research · doi:10.1158/1538-7445.am10-2515 · Cited by 36 · see citing works
Jo, C., Cho, S., & Jo, S. A. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.225128 · Cited by 34 · see citing works
Wabnitz, P. A., Mitchell, D., & Wabnitz, D. A. M. (2004) · Pharmaceutical Research · doi:10.1023/b:pham.0000041464.27579.d0 · Cited by 20 · see citing works
Combination therapy of melanoma using kinase inhibitors
Heppt, M., Tietze, J., Graf, S., & Berking, C. (2015) · Current Opinion in Oncology · doi:10.1097/cco.0000000000000160 · Cited by 20 · see citing works
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- Authors
- Hu, J., Wei, J., Yim, H., Wang, L., Xie, L., Jin, M. S., Kabir, M., Qin, L., Chen, X., Liu, J., & Jin, J.
- Affiliations
- Tisch Cancer Institute (US)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Liu, Jing
- Jin, Jian
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2020-12-07
- Volume
- 63
- Issue
- 24
- Pages
- 15883-15905
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- PMC
- PMC7770057
- OpenAlex
- W3111051161
- Cited by
- 43
- References
- 64
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 7 · 2023: 4 · 2022: 8 · 2021: 6
- FWCI
- 1.62
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (P30CA196521)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Keywords
- heterobifunctional degraders, VHL, cereblon, E3 ubiquitin ligase, structure-activity relationship, ubiquitin-proteasome system, BRAF inhibition, PI3K inhibition, combination therapy, anticancer activity, plasma exposure
- MeSH terms
- Animals, Humans, Neoplasms, Pyrrolidines, Structure-Activity Relationship, Thiazoles, Tissue Distribution, Tumor Cells, Cultured, Signal Transduction, Phosphatidylinositol 3-Kinases, Ubiquitin, Ubiquitin-Protein Ligases, Protein Kinase Inhibitors, MAP Kinase Kinase 1, MAP Kinase Kinase 2, Proto-Oncogene Proteins B-raf, Adaptor Proteins, Signal Transducing, Cell Proliferation, Mice, Von Hippel-Lindau Tumor Suppressor Protein, Small Molecule Libraries, Proteolysis
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