Targeting of the FOXM1 Oncoprotein by E3 Ligase-Assisted Degradation
Abstract
The transcription factor FOXM1 that regulates multiple proliferation-related genes through selective protein-DNA and protein-protein interactions is now considered an attractive oncotarget. There are several small-molecule inhibitors that indirectly suppress the expression of FOXM1 or block its DNA binding domain (FOXM1-DBD). However, insufficient specificity or/and efficacy are two potential drawbacks. Here, we employed in silico modeling of FOXM1-DBD with inhibitors to enable the design of an effective CRBN-recruiting molecule that induced significant FOXM1 protein degradation and exerted promising in vivo antitumor activity against TNBC xenograft models. This study is the first of its kind showcasing the use of an approach described in the literature as protein-targeting chimeras to degrade the elusive FOXM1, providing an alternative strategy to counter the pathological effects resulting from the increased transcriptional activity of FOXM1 observed in cancer cells.
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Compound 216 is the first PROTAC degrader targeting FOXM1 and is the most potent FOXM1 degrader with a DC50 of 1.96 μM in TNBC MDA-MB-231 cells.
“In 2021, Xiang’s research team pioneered the discovery of the first set of PROTAC degraders targeting FOXM1, including compound 216 (Table 4). Among them, 216 emerged as the most potent FOXM1 degrader, exhibiting a DC50 value of 1.96 μM in TNBC MDA-MB-231 cells.514”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [514]
Cites
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
Proteolysis-Targeting Chimeras as Therapeutics and Tools for Biological Discovery
Burslem, G. M., & Crews, C. M. (2020) · Cell · doi:10.1016/j.cell.2019.11.031 · Cited by 1,079 · see citing works
The emerging roles of forkhead box (Fox) proteins in cancer
Myatt, S. S., & Lam, E. W. ‐. (2007) · Nature reviews. Cancer · doi:10.1038/nrc2223 · Cited by 1,065 · see citing works
FoxM1 is required for execution of the mitotic programme and chromosome stability
Laoukili, J., Kooistra, M. R. H., Brás, A., Kauw, J. J. W., Kerkhoven, R. M., Morrison, A. J., Clevers, H. C., & Medema, R. H. (2005) · Nature Cell Biology · doi:10.1038/ncb1217 · Cited by 808 · see citing works
A Potent and Selective Small-Molecule Degrader of STAT3 Achieves Complete Tumor Regression In Vivo
Bai, L., Zhou, H., Xu, R., Zhao, Y., Chinnaswamy, K., McEachern, D., Chen, J., Yang, C.-Y., Liu, Z., Wang, M., et al. (2019) · Cancer Cell · doi:10.1016/j.ccell.2019.10.002 · Cited by 652 · see citing works
Zhang, N., Wei, P., Gong, A., Chiu, W., Lee, H., Colman, H., Huang, H., Xue, J., Liu, M., Wang, Y., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.08.016 · Cited by 584 · 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
FOXM1: From cancer initiation to progression and treatment
Koo, C.-Y., Muir, K., & Lam, E. W. ‐. (2011) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2011.09.004 · Cited by 406 · see citing works
Wonsey, D. R., & Follettie, M. T. (2005) · Cancer Research · doi:10.1158/0008-5472.can-04-4059 · Cited by 346 · see citing works
FoxM1: A Master Regulator of Tumor Metastasis
Raychaudhuri, P., & Park, H. J. (2011) · Cancer Research · doi:10.1158/0008-5472.can-11-0640 · Cited by 308 · see citing works
Hu, J., Hu, B., Wang, M., Xu, F., Miao, B., Yang, C., Wang, M., Liu, Z., Hayes, D. F., Chinnaswamy, K., et al. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b01572 · Cited by 286 · see citing works
FOXM1 in Cancer: Interactions and Vulnerabilities
Gartel, A. L. (2017) · Cancer Research · doi:10.1158/0008-5472.can-16-3566 · Cited by 236 · see citing works
Identification of a Chemical Inhibitor of the Oncogenic Transcription Factor Forkhead Box M1
Radhakrishnan, S. K., Bhat, U. G., Hughes, D. E., Wang, I., Costa, R. H., & Gartel, A. L. (2006) · Cancer Research · doi:10.1158/0008-5472.can-06-1576 · Cited by 235 · see citing works
Chen, X. X., Müller, G. A., Quaas, M., Fischer, M., Han, N., Stutchbury, B., Sharrocks, A. D., & Engeland, K. (2012) · Molecular and Cellular Biology · doi:10.1128/mcb.00881-12 · Cited by 226 · see citing works
Suppression of the FOXM1 transcriptional programme via novel small molecule inhibition
Gormally, M. V., Dexheimer, T. S., Marsico, G., Sanders, D. A., Lowe, C. E., Matak‐Vinković, D., Michael, S., Jadhav, A., Rai, G., Maloney, D. J., et al. (2014) · Nature Communications · doi:10.1038/ncomms6165 · Cited by 223 · see citing works
Halasi, M., & Gartel, A. L. (2013) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-12-0712 · Cited by 210 · see citing works
Pan-Cancer Analyses Reveal Genomic Features of FOXM1 Overexpression in Cancer
Barger, C. J., Branick, C., Chee, L., & Karpf, A. R. (2019) · Cancers · doi:10.3390/cancers11020251 · Cited by 209 · see citing works
Costa, R. H. (2005) · Nature Cell Biology · doi:10.1038/ncb0205-108 · Cited by 187 · see citing works
FoxM1 Is a General Target for Proteasome Inhibitors
Bhat, U. G., Halasi, M., & Gartel, A. L. (2009) · PLoS ONE · doi:10.1371/journal.pone.0006593 · Cited by 185 · see citing works
FOXM1 (Forkhead box M1) in Tumorigenesis
Wierstra, I. (2013) · Advances in cancer research · doi:10.1016/b978-0-12-407190-2.00016-2 · Cited by 183 · see citing works
FoxM1 Mediates Resistance to Herceptin and Paclitaxel
Carr, J. R., Park, H. J., Wang, Z., Kiefer, M. M., & Raychaudhuri, P. (2010) · Cancer Research · doi:10.1158/0008-5472.can-10-0545 · Cited by 180 · see citing works
Sustained activation of SMAD3/SMAD4 by FOXM1 promotes TGF-β–dependent cancer metastasis
Xue, J., Lin, X., Chiu, W., et al. (2014) · Journal of Clinical Investigation · doi:10.1172/jci71104 · Cited by 169 · see citing works
Self-citationPROTACs– a game-changing technology
Konstantinidou, M., Li, J., Zhang, B., Wang, Z., Shaabani, S., ter Brake, F., Essa, K., & Dömling, A. S. S. (2019) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2019.1659242 · Cited by 167 · see citing works
Structure of the FoxM1 DNA-recognition domain bound to a promoter sequence
Littler, D. R., Álvarez‐Fernández, M., Stein, A., Hibbert, R. G., Heidebrecht, T., Aloy, P., Medema, R. H., & Anastassis Perrakis, A. (2010) · Nucleic Acids Research · doi:10.1093/nar/gkq194 · Cited by 157 · see citing works
Liao, H., Li, X., Zhao, L., Wang, Y., Wang, X., Wu, Y., Zhou, X., Fu, W., Liu, L., Hu, H.-G., et al. (2020) · Cell Discovery · doi:10.1038/s41421-020-0171-1 · Cited by 156 · see citing works
Bergamaschi, A., Madak‐Erdogan, Z., Kim, Y. J., Choi, Y., Lu, H., & Katzenellenbogen, B. S. (2014) · Breast Cancer Research · doi:10.1186/s13058-014-0436-4 · Cited by 130 · see citing works
A novel mode of FoxM1 regulation: Positive auto-regulatory loop
Halasi, M., & Gartel, A. L. (2009) · Cell Cycle · doi:10.4161/cc.8.12.8708 · Cited by 122 · see citing works
Shao, J., Yan, Y., Ding, D., Wang, D., He, Y., Pan, Y., Yan, W., Kharbanda, A., Li, H., & Huang, H. (2021) · Advanced Science · doi:10.1002/advs.202102555 · Cited by 120 · see citing works
Liao, M., Zhang, J. C., Wang, G., Wang, L., Liu, J., Ouyang, L., & Liu, B. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c01180 · Cited by 119 · see citing works
FOXM1: a potential therapeutic target in human solid cancers
Borhani, S., & Gartel, A. L. (2020) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2020.1727888 · Cited by 105 · see citing works
Lee, G. T., Nagaya, N., Desantis, J., Madura, K., Sabaawy, H. E., Kim, W.-J., Vaz, R. J., Cruciani, G., & Kim, I. Y. (2020) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-20-0417 · Cited by 96 · see citing works
Wang, Y., Wen, L., Zhao, S., et al. (2012) · Lung Cancer · doi:10.1016/j.lungcan.2012.10.019 · Cited by 90 · see citing works
Ziegler, Y., Laws, M. J., Guillen, V. S., et al. (2019) · npj Breast Cancer · doi:10.1038/s41523-019-0141-7 · Cited by 89 · see citing works
Fontaine, F. R., Overman, J. P., & François, M. (2015) · Cell Regeneration · doi:10.1186/s13619-015-0015-x · Cited by 86 · see citing works
Luo, G., Li, Z., Lin, X., Li, X., Chen, Y., Xi, K., Xiao, M., Wei, H., Zhu, L., & Xiang, H. (2020) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2020.11.001 · Cited by 83 · see citing works
Self-citationPrognostic value of FOXM1 in solid tumors: a systematic review and meta-analysis
Li, L., Yu, Q., Yu, Q., Li, L., & Wu, P. (2017) · Oncotarget · doi:10.18632/oncotarget.15764 · Cited by 81 · see citing works
The FOXM1 Inhibitor RCM-1 Decreases Carcinogenesis and Nuclear β-Catenin
Shukla, S., Milewski, D., Pradhan, A., et al. (2019) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-18-0709 · Cited by 64 · see citing works
Identification of FOXM1 as a specific marker for triple‑negative breast cancer
Tan, Y., Wang, Q., Xie, Y., Qiao, X., Zhang, S., Wang, Y., Yang, Y., & Zhang, B. (2018) · International Journal of Oncology · doi:10.3892/ijo.2018.4598 · Cited by 61 · see citing works
Suppression of FOXM1 Transcriptional Activities via a Single-Stranded DNA Aptamer Generated by SELEX
Qin, X., Tan, G., Jiang, X., et al. (2017) · Scientific Reports · doi:10.1038/srep45377 · Cited by 57 · see citing works
Honokiol is a FOXM1 antagonist
Halasi, M., Hitchinson, B., Shah, B. N., et al. (2018) · Cell Death and Disease · doi:10.1038/s41419-017-0156-7 · Cited by 57 · see citing works
Thiostrepton, proteasome inhibitors and FOXM1
Gartel, A. L. (2011) · Cell Cycle · doi:10.4161/cc.10.24.18544 · Cited by 48 · see citing works
Roles of FoxM1 in cell regulation and breast cancer targeting therapy
Song, X., Kenston, S. S. F., Zhao, J., Yang, D., & Gu, Y. (2017) · Medical Oncology · doi:10.1007/s12032-017-0888-3 · Cited by 45 · see citing works
PROTACs: New method to degrade transcription regulating proteins
Hu, B.-C., Zhou, Y., Sun, D., Yang, Y., Liu, Y., Li, X., Li, H., & Chen, L. (2020) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.112698 · Cited by 43 · see citing works
Dey, P., Wang, A. Z., Ziegler, Y., et al. (2020) · Cancers · doi:10.3390/cancers12092677 · Cited by 43 · see citing works
Petrovic, V., Costa, R. H., Lau, L. F., Raychaudhuri, P., & Tyner, A. L. (2010) · Cancer Biology & Therapy · doi:10.4161/cbt.9.12.11710 · Cited by 42 · see citing works
Chesnokov, M. S., Halasi, M., Borhani, S., Arbieva, Z. H., Shah, B. N., Oerlemans, R., Khan, I., Camacho, C. J., & Gartel, A. L. (2021) · Cell Death and Disease · doi:10.1038/s41419-021-03978-0 · Cited by 34 · see citing works
Untying the knot of transcription factor druggability: Molecular modeling study of FOXM1 inhibitors
Tabatabaei-Dakhili, S. A., Aguayo‐Ortiz, R., Domı́nguez, L., et al. (2018) · Journal of Molecular Graphics and Modelling · doi:10.1016/j.jmgm.2018.01.009 · Cited by 33 · see citing works
Chen, T., Xiong, J., Yang, C., et al. (2014) · Cancer Gene Therapy · doi:10.1038/cgt.2014.8 · Cited by 28 · see citing works
SP1-independent inhibition of FOXM1 by modified thiazolidinediones
Dakhili, S. A. T., Pérez, D. J., Gopal, K., et al. (2020) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.112902 · Cited by 27 · see citing works
Dakhili, S. A. T., Pérez, D. J., Gopal, K., et al. (2019) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2019.103269 · Cited by 25 · see citing works
Zhang, Z., Bu, H., Yu, J., Chen, Y., Pei, C., Li, Y., Huang, X., Tan, G., & Tan, Y. (2019) · Theranostics · doi:10.7150/thno.32693 · Cited by 17 · see citing works
Henley, M. J., Doyle, S. K., & Koehler, A. N. (2021) · Cell chemical biology · doi:10.1016/j.chembiol.2020.12.014 · Cited by 11 · see citing works
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Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials
Xie, X., Yu, T., Li, X., Zhang, N., Foster, L. J., Peng, C., Huang, W., & He, G. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01589-z · Cited by 396 · see citing works
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- Authors
- Luo, G., Lin, X., Vega-Medina, A., Xiao, M., Li, G., Wei, H., Velázquez-Martínez, C. A., & Xiang, H.
- Affiliations
- China Pharmaceutical University (CN)
- University of Alberta (CA)
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6W1W7, Canada
- Corresponding author
- Xiang, Hua
- ORCID
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2021-11-23
- Volume
- 64
- Issue
- 23
- Pages
- 17098-17114
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W3217741808
- Cited by
- 56
- References
- 53
- Citations by year
- 2026: 11 · 2025: 13 · 2024: 9 · 2023: 15 · 2022: 8
- FWCI
- 2.51
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministry of Education of the People's Republic of China (CPU 2018GY07, CPU 2018PZQ02)
- China Postdoctoral Science Foundation (2019M662007)
- Natural Science Foundation of Jiangsu Province (BK20210423)
- Consejo Nacional de Ciencia y Tecnolog??a (CVU: 686165)
- National Natural Science Foundation of China (82103978)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- FOXM1, protein degradation, E3 ubiquitin ligase, cereblon, small molecule inhibitors, DNA-binding domain, triple-negative breast cancer, anticancer activity, oncotarget
- MeSH terms
- Forkhead Box Protein M1, Humans, Ligands, Ubiquitin-Protein Ligases, Proteolysis
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