Proteolysis Targeting Chimeras for the Selective Degradation of Mcl-1/Bcl-2 Derived from Nonselective Target Binding Ligands
Abstract
Proteolysis targeting chimera (PROTAC) recruits an E3 ligase to a target protein to induce its ubiquitination and subsequent degradation. We reported success in the development of two PROTACs ( C3 and C5 ) that potently and selectively induce the degradation of Mcl-1 and Bcl-2 (DC 50 = 0.7 and 3.0 μM), respectively, by introducing the E3 ligase cereblon-binding ligand pomalidomide to Mcl-1/Bcl-2 dual inhibitors S1-6 and Nap-1 with micromolar-range affinity. C3 -induced Mcl-1 ubiquitination translated into much more lethality in Mcl-1-dependent H23 cells than the most potent Mcl-1 occupancy-based inhibitor A-1210477 with nanomolar-range affinity. Moreover, structure–activity relationship analysis and molecular dynamic simulations discovered the structural basis for turning nonselective or promiscuous Bcl-2 family ligands into selective PROTACs. C3 and C5 exhibited reversible depletion in living cells, which provides a new potent toolkit for gain-of-function studies to probe the dynamic roles of Bcl-2 and Mcl-1 in apoptosis networks.
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dMCL1-2 degrades Mcl-1 in OPM2 and MM.1S multiple myeloma cell lines.
“There are reported Mcl-1 PROTACs [45, 58], dMCL1-2 as a representative, which degrades Mcl-1 in OPM2 and MM.1S MM cell lines.”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [58]
Cites
Phthalimide conjugation as a strategy for in vivo target protein degradation
Winter, G. E., Buckley, D. L., Paulk, J., Roberts, J. M., Souza, A., Dhe-Paganon, S., & Bradner, J. E. (2015) · Science · doi:10.1126/science.aab1433 · Cited by 1,760 · see citing works
Induced protein degradation: an emerging drug discovery paradigm
Lai, A. C., & Crews, C. M. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.211 · Cited by 1,486 · see citing works
Catalytic in vivo protein knockdown by small-molecule PROTACs
Bondeson, D. P., Mares, A., Smith, I. E. D., Ko, E., Campos, S., Miah, A. H., Mulholland, K. E., Routly, N., Buckley, D. L., Gustafson, J. L., et al. (2015) · Nature Chemical Biology · doi:10.1038/nchembio.1858 · Cited by 1,356 · see citing works
Structural basis of PROTAC cooperative recognition for selective protein degradation
Gadd, M. S., Testa, A., Lucas, X., Chan, K.-H., Chen, W., Lamont, D. J., Zengerle, M., & Ciulli, A. (2017) · Nature Chemical Biology · doi:10.1038/nchembio.2329 · Cited by 1,242 · 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
Selective Small Molecule Induced Degradation of the BET Bromodomain Protein BRD4
Zengerle, M., Chan, K.-H., & Ciulli, A. (2015) · ACS Chemical Biology · doi:10.1021/acschembio.5b00216 · Cited by 1,056 · see citing works
Lessons in PROTAC Design from Selective Degradation with a Promiscuous Warhead
Bondeson, D. P., Smith, B. E., Burslem, G. M., Buhimschi, A. D., Hines, J., Jaime-Figueroa, S., Wang, J., Hamman, B. D., Ishchenko, A., & Crews, C. M. (2018) · Cell Chemical Biology · doi:10.1016/j.chembiol.2017.09.010 · Cited by 923 · 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
Inhibition of α-helix-mediated protein–protein interactions using designed molecules
Azzarito, V., Long, K., Murphy, N. S., & Wilson, A. J. (2013) · Nature Chemistry · doi:10.1038/nchem.1568 · Cited by 727 · see citing works
Pelay‐Gimeno, M., Glas, A., Koch, O., & Grossmann, T. N. (2015) · Angewandte Chemie International Edition · doi:10.1002/anie.201412070 · Cited by 718 · see citing works
The Advantages of Targeted Protein Degradation Over Inhibition: An RTK Case Study
Burslem, G. M., Smith, B. E., Lai, A. C., Jaime-Figueroa, S., McQuaid, D. C., Bondeson, D. P., Toure, M., Dong, H., Qian, Y., Wang, J., et al. (2018) · Cell Chemical Biology · doi:10.1016/j.chembiol.2017.09.009 · Cited by 686 · see citing works
Small‐Molecule PROTACS: New Approaches to Protein Degradation
Toure, M., & Crews, C. M. (2016) · Angewandte Chemie International Edition · doi:10.1002/anie.201507978 · Cited by 674 · see citing works
Pharmacological perturbation of CDK9 using selective CDK9 inhibition or degradation
Olson, C. M., Jiang, B., Erb, M. A., Liang, Y., Doctor, Z. M., Zhang, Z., Zhang, T., Kwiatkowski, N., Boukhali, M., Green, J. L., et al. (2018) · Nature Chemical Biology · doi:10.1038/nchembio.2538 · Cited by 552 · see citing works
Self-citationChamberlain, P. P., Lopez-Girona, A., Miller, K., Carmel, G., Pagarigan, B., Chie-Leon, B., Rychak, E., Corral, L. G., Ren, Y. J., Wang, M., et al. (2014) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2874 · Cited by 531 · see citing works
Modulators of Protein–Protein Interactions
Milroy, L.-G., Grossmann, T. N., Hennig, S., Brunsveld, L., & Ottmann, C. (2014) · Chemical Reviews · doi:10.1021/cr400698c · Cited by 497 · see citing works
Protac-Induced Protein Degradation in Drug Discovery: Breaking the Rules or Just Making New Ones?
Churcher, I. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.7b01272 · Cited by 491 · see citing works
A Chemoproteomic Approach to Query the Degradable Kinome Using a Multi-kinase Degrader
Huang, H.-T., Dobrovolsky, D., Paulk, J., Yang, G., Weisberg, E. L., Doctor, Z. M., Buckley, D. L., Cho, J.-H., Ko, E., Jang, J., et al. (2018) · Cell Chemical Biology · doi:10.1016/j.chembiol.2017.10.005 · Cited by 437 · see citing works
Targeted Protein Degradation: from Chemical Biology to Drug Discovery
Cromm, P. M., & Crews, C. M. (2017) · Cell chemical biology · doi:10.1016/j.chembiol.2017.05.024 · Cited by 423 · 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
Protein–protein interactions in human disease
Ryan, D., & Matthews, J. M. (2005) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2005.06.001 · Cited by 370 · see citing works
Zoppi, V., Hughes, S. J., Maniaci, C., Testa, A., Gmaschitz, T., Wieshofer, C., Koegl, M., Riching, K. M., Daniels, D. L., Spallarossa, A., et al. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b01413 · Cited by 336 · see citing works
Li, Y., Yang, J., Aguilar, A., McEachern, D., Przybranowski, S., Liu, L., Yang, C.-Y., Wang, M., Han, X., & Wang, S. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b00909 · Cited by 312 · see citing works
Ku, B., Liang, C., Jung, J. U., & Oh, B. (2010) · Cell Research · doi:10.1038/cr.2010.149 · Cited by 304 · see citing works
Degradation of the BAF Complex Factor BRD9 by Heterobifunctional Ligands
Remillard, D., Buckley, D. L., Paulk, J., Brien, G. L., Sonnett, M., Seo, H., Dastjerdi, S., Wühr, M., Dhe‐Paganon, S., Armstrong, S. A., et al. (2017) · Angewandte Chemie International Edition · doi:10.1002/anie.201611281 · Cited by 294 · see citing works
Chemically induced degradation of CDK9 by a proteolysis targeting chimera (PROTAC)
Robb, C. M., Contreras, J. I., Kour, S., Taylor, M., Abid, M., Sonawane, Y. A., Zahid, M., Murry, D. J., Natarajan, A., & Rana, S. (2017) · Chemical Communications · doi:10.1039/c7cc03879h · Cited by 221 · see citing works
Hines, J. F., Gough, J. D., Corson, T. W., & Crews, C. M. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1217206110 · Cited by 177 · see citing works
Structure-Guided Design of a Series of MCL-1 Inhibitors with High Affinity and Selectivity
Bruncko, M., Wang, L., Sheppard, G. S., Phillips, D. C., Tahir, S. K., Xue, J., Erickson, S., Fidanze, S., Fry, E., Hasvold, L., et al. (2015) · Journal of Medicinal Chemistry · doi:10.1021/jm501258m · Cited by 164 · see citing works
Deshaies, R. J. (2015) · Nature Chemical Biology · doi:10.1038/nchembio.1887 · Cited by 162 · see citing works
Homo-PROTACs for the Chemical Knockdown of Cereblon
Steinebach, C., Lindner, S., Udeshi, N. D., Mani, D. R., Kehm, H., Köpff, S., Carr, S. A., Gütschow, M., & Krönke, J. (2018) · ACS Chemical Biology · doi:10.1021/acschembio.8b00693 · Cited by 160 · see citing works
Patch, R. J., Searle, L. L., Kim, A. J., De, D., Zhu, X., Askari, H. B., O’Neill, J. C., Abad, M. C., Rentzeperis, D., Liu, J., et al. (2011) · Journal of Medicinal Chemistry · doi:10.1021/jm101063h · Cited by 141 · see citing works
McCoull, W., Cheung, T., Anderson, E., Barton, P., Burgess, J., Byth, K., Cao, Q., Castaldi, M. P., Chen, H., Chiarparin, E., et al. (2018) · ACS Chemical Biology · doi:10.1021/acschembio.8b00698 · Cited by 139 · see citing works
Evolution of Bcl-2 homology motifs: homology versus homoplasy
Aouacheria, A., Rech de Laval, V., Combet, C., & Hardwick, J. M. (2013) · Trends in Cell Biology · doi:10.1016/j.tcb.2012.10.010 · Cited by 103 · see citing works
From Inhibition to Degradation: Targeting the Antiapoptotic Protein Myeloid Cell Leukemia 1 (MCL1)
Papatzimas, J. W., Gorobets, E., Maity, R., Muniyat, M. I., MacCallum, J. L., Neri, P., Bahlis, N. J., & Derksen, D. J. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b00455 · Cited by 103 · see citing works
Mcl‐1–Bim complexes accommodate surprising point mutations via minor structural changes
Fire, E., Gullà, S. V., Grant, R. A., et al. (2010) · Protein Science · doi:10.1002/pro.329 · Cited by 102 · see citing works
Yap, J. L., Chen, L., Lanning, M. E., & Fletcher, S. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b01888 · Cited by 99 · see citing works
Lucas, X., & Ciulli, A. (2017) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2016.12.015 · Cited by 92 · see citing works
Zhang, Z., Wu, G., Xie, F., et al. (2011) · Journal of Medicinal Chemistry · doi:10.1021/jm101181u · Cited by 86 · see citing works
Self-citationRedefining the BH3 Death Domain as a ‘Short Linear Motif’
Aouacheria, A., Combet, C., Tompa, P., & Hardwick, J. M. (2015) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2015.09.007 · Cited by 59 · see citing works
Song, T., Wang, Z., Ji, F., et al. (2016) · Angewandte Chemie International Edition · doi:10.1002/anie.201606543 · Cited by 49 · see citing works
Self-citationTan, L., & Gray, N. S. (2018) · Chinese Journal of Chemistry · doi:10.1002/cjoc.201800293 · Cited by 33 · see citing works
BCL2: a 30-year tale of life, death and much more to come
Pentimalli, F. (2017) · Cell Death and Differentiation · doi:10.1038/cdd.2017.189 · Cited by 24 · see citing works
Bcl-2/MDM2 Dual Inhibitors Based on Universal Pyramid-Like α-Helical Mimetics
Wang, Z., Song, T., Feng, Y., Guo, Z., Fan, Y., Xu, W., Liu, L., Wang, A., & Zhang, Z. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b01913 · Cited by 23 · see citing works
Self-citationWang, Z., Guo, Z., Song, T., Zhang, X., He, N., Liu, P., Wang, P., & Zhang, Z. (2018) · ChemBioChem · doi:10.1002/cbic.201800380 · Cited by 16 · see citing works
Self-citationSong, T., Chen, Q., Li, X., et al. (2013) · Journal of Medicinal Chemistry · doi:10.1021/jm401588g · Cited by 12 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Current strategies for the design of PROTAC linkers: a critical review
Troup, R. I., Fallan, C., & Baud, M. G. J. (2020) · Exploration of Targeted Anti-tumor Therapy · doi:10.37349/etat.2020.00018 · Cited by 424 · see citing works
PROTACs: great opportunities for academia and industry (an update from 2020 to 2021)
He, M., Cao, C., Ni, Z., Liu, Y., Song, P., Hao, S., He, Y., Sun, X., & Rao, Y. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-00999-9 · Cited by 283 · see citing works
Harnessing the Power of Proteolysis for Targeted Protein Inactivation
Verma, R., Mohl, D., & Deshaies, R. J. (2020) · Molecular Cell · doi:10.1016/j.molcel.2020.01.010 · Cited by 185 · see citing works
Drummond, M. L., Henry, A., Li, H., & Williams, C. I. (2020) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.0c00897 · Cited by 166 · see citing works
Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies
He, Y., Khan, S., Huo, Z., Lv, D., Zhang, X., Liu, X., Yuan, Y., Hromas, R., Xu, M., Zheng, G., et al. (2020) · Journal of Hematology & Oncology · doi:10.1186/s13045-020-00924-z · Cited by 126 · see citing works
Self-citationZhang, X., Thummuri, D., Liu, X., Hu, W., Zhang, P., Khan, S., Yuan, Y., Zhou, D., & Zheng, G. (2020) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.112186 · Cited by 123 · see citing works
“The discovery of PROTAC MCL-1 and BCL-2 degraders (Figure 1) have been reported recently [38,39].”
BackgroundSelf-citationLink-INVENT: Generative Linker Design with Reinforcement Learning
Guo, J., Knuth, F., Margreitter, C., Janet, J. P., Papadopoulos, K., Engkvist, O., & Patronov, A. (2022) · doi:10.26434/chemrxiv-2022-qkx9f · Cited by 101 · see citing works
Zhang, X., Thummuri, D., He, Y., Liu, X., Zhang, P., Zhou, D., & Zheng, G. (2019) · Chemical Communications · doi:10.1039/c9cc07217a · Cited by 86 · see citing works
Self-citationSelective CDK6 degradation mediated by cereblon, VHL, and novel IAP-recruiting PROTACs
Anderson, N. A., Cryan, J., Ahmed, A., Dai, H., McGonagle, G. A., Rozier, C., & Benowitz, A. B. (2020) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2020.127106 · Cited by 69 · see citing works
- Authors
- Wang, Z., He, N., Guo, Z., Niu, C., Song, T., Guo, Y., Cao, K., Wang, A., Zhu, J., Zhang, X., & Zhang, Z.
- Affiliations
- Dalian University of Technology (CN)
- Corresponding author
- Zhang, Zhichao
- ORCID
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2019-08-07
- Volume
- 62
- Issue
- 17
- Pages
- 8152-8163
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2964430254
- Cited by
- 120
- References
- 44
- Citations by year
- 2026: 13 · 2025: 16 · 2024: 13 · 2023: 11 · 2022: 18 · 2021: 20 · 2020: 25 · 2019: 4
- FWCI
- 5.79
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- China Postdoctoral Science Foundation (2018M641694)
- National Natural Science Foundation of China (81430083, 21502015, 81570129)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- PROTACs, Mcl-1 degradation, Bcl-2 family proteins, pomalidomide, E3 ubiquitin ligase, ubiquitination, selective protein degradation, structure-activity relationship, molecular dynamics simulation, apoptosis, H23 cells
- MeSH terms
- Binding Sites, Dose-Response Relationship, Drug, HeLa Cells, Humans, Ligands, Models, Molecular, Structure-Activity Relationship, Thalidomide, Tumor Cells, Cultured, Molecular Structure, Proto-Oncogene Proteins c-bcl-2, Proteolysis, Myeloid Cell Leukemia Sequence 1 Protein
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