Discovery of IAP-recruiting BCL-XL PROTACs as potent degraders across multiple cancer cell lines
Open accessAbstract
Targeting BCL-X L via PROTACs is a promising strategy in reducing BCL-X L inhibition associated platelet toxicity. Recently, we reported potent BCL-X L PROTAC degraders that recruit VHL or CRBN E3 ligase. However, low protein expression or mutation of the responsible E3 ligase has been known to result in decreased protein degradation efficiency of the corresponding PROTACs. To overcome these mechanisms of resistance, PROTACs based on recruiting alternative E3 ligases could be generated. Thus, we designed and synthesized a series of PROTACs that recruit IAP E3 ligases for BCL-X L degradation. Among those PROTACs, compound 8a efficiently degrades BCL-X L in malignant T-cell lymphoma cell line MyLa 1929 while CRBN-based PROTACs that have high potency in other cancer cell lines show compromised potency, likely due to the low CRBN expression. Moreover, compared with the parent compound ABT-263, PROTAC 8a shows comparable cell killing effects in MyLa 1929 cells whereas the on-target platelet toxicity is significantly reduced. Our findings expand the anti-tumor spectra of BCL-X L degraders and further highlight the importance of selecting suitable E3 members to achieve effective cellular activity.
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BIRC3 is highly expressed in T cell lymphoma (TCL) cells compared to other IAP proteins.
“We also found that BIRC3 is highly expressed in T cell lymphoma (TCL) cells compared to other IAP proteins [61].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [61]
Bcl-xL PROTACs are an example of targeting a POI to a tissue- and/or tumor-selective E3 ligase to limit on-target toxicity.
“Bcl-xL PROTACs discussed above are an example of this approach [4, 61–63].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [61]
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Cites
Hallmarks of Cancer: The Next Generation
Hanahan, D., & Weinberg, R. A. (2011) · Cell · doi:10.1016/j.cell.2011.02.013 · Cited by 66,590 · see citing works
ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets
Souers, A. J., Leverson, J. D., Boghaert, E. R., Ackler, S. L., Catron, N. D., Chen, J., Dayton, B. D., Ding, H., Enschede, S. H., Fairbrother, W. J., et al. (2013) · Nature Medicine · doi:10.1038/nm.3048 · Cited by 3,058 · see citing works
Regulation of apoptosis in health and disease: the balancing act of BCL-2 family proteins
Singh, R., Letai, A., & Sarosiek, K. (2019) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-018-0089-8 · Cited by 2,111 · 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
Programmed Anuclear Cell Death Delimits Platelet Life Span
Mason, K. D., Carpinelli, M. R., Fletcher, J. I., Collinge, J. E., Hilton, A. A., Ellis, S., Kelly, P. N., Ekert, P. G., Metcalf, D., Roberts, A. W., et al. (2007) · Cell · doi:10.1016/j.cell.2007.01.037 · Cited by 1,031 · 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
A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity
Khan, S., Zhang, X., Lv, D., Zhang, Q., He, Y., Zhang, P., Liu, X., Thummuri, D., Yuan, Y., Wiegand, J. S., et al. (2019) · Nature Medicine · doi:10.1038/s41591-019-0668-z · Cited by 688 · see citing works
Self-citationBCL-2 family antagonists for cancer therapy
Lessène, G., Czabotar, P. E., & Colman, P. M. (2008) · Nature Reviews Drug Discovery · doi:10.1038/nrd2658 · Cited by 623 · 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
Bcl-2 family proteins are essential for platelet survival
Zhang, H., Nimmer, P. M., Tahir, S. K., Chen, J., Fryer, R. M., Hahn, K. R., Iciek, L. A., Morgan, S. J., Nasarre, M. C., Nelson, R., et al. (2007) · Cell Death & Differentiation · doi:10.1038/sj.cdd.4402081 · Cited by 427 · see citing works
An informatics approach identifying markers of chemosensitivity in human cancer cell lines.
Amundson, S. A., Myers, T. G., Scudiero, D. A., Kitada, S., Reed, J. C., & Fornace, A. J. (2000) · PubMed · Cited by 399 · see citing works
Zhang, L., Riley-Gillis, B., Vijay, P., & Shen, Y. (2019) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-18-1129 · Cited by 365 · see citing works
The PROTAC technology in drug development
Zou, Y., Ma, D., & Wang, Y. (2019) · Cell Biochemistry and Function · doi:10.1002/cbf.3369 · Cited by 307 · see citing works
He, Y., Zhang, X., Chang, J., Kim, H.-N., Zhang, P., Wang, Y., Khan, S., Liu, X., Zhang, X., Lv, D., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-15838-0 · Cited by 280 · see citing works
Self-citationCai, Q., Sun, H., Peng, Y., Lü, J., Nikolovska‐Coleska, Z., McEachern, D., Liu, L., Qiu, S., Yang, C., Miller, R. S., et al. (2011) · Journal of Medicinal Chemistry · doi:10.1021/jm101505d · Cited by 274 · see citing works
Flygare, J. A., Beresini, M., Budha, N., Chan, H., Chan, I. T., Cheeti, S., Cohen, F., Deshayes, K., Doerner, K., Eckhardt, S. G., et al. (2012) · Journal of Medicinal Chemistry · doi:10.1021/jm300060k · Cited by 252 · see citing works
Ohoka, N., Okuhira, K., Ito, M., Nagai, K., Shibata, N., Hattori, T., Ujikawa, O., Shimokawa, K., Sano, O., Koyama, R., et al. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.768853 · Cited by 240 · see citing works
Infante, J. R., Dees, E. C., Olszanski, A. J., Dhuria, S. V., Sen, S., Cameron, S., & Cohen, R. B. (2014) · Journal of Clinical Oncology · doi:10.1200/jco.2013.52.3993 · Cited by 210 · see citing works
SNIPERs—Hijacking IAP activity to induce protein degradation
Naito, M., Ohoka, N., & Shibata, N. (2019) · Drug Discovery Today Technologies · doi:10.1016/j.ddtec.2018.12.002 · Cited by 167 · see citing works
A Phase I Study of the SMAC-Mimetic Birinapant in Adults with Refractory Solid Tumors or Lymphoma
Amaravadi, R. K., Schilder, R. J., Martin, L. P., Levin, M. J., Graham, M. A., Weng, D. E., & Adjei, A. A. (2015) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-15-0475 · Cited by 131 · see citing works
Small-molecule PROTAC degraders of the Bromodomain and Extra Terminal (BET) proteins — A review
Yang, C., Qin, C., Bai, L., & Wang, S. (2019) · Drug Discovery Today Technologies · doi:10.1016/j.ddtec.2019.04.001 · Cited by 125 · see citing works
Zhang, 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
Self-citationTargeting BCL2-Proteins for the Treatment of Solid Tumours
Vogler, M. (2014) · Advances in Medicine · doi:10.1155/2014/943648 · Cited by 118 · see citing works
Ohoka, N., Morita, Y., Nagai, K., Shimokawa, K., Ujikawa, O., Fujimori, I., Ito, M., Hayase, Y., Okuhira, K., Shibata, N., et al. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra117.001091 · Cited by 105 · 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-citationLv, D., Zhang, K., & Li, R. (2018) · PLoS Pathogens · doi:10.1371/journal.ppat.1006868 · Cited by 53 · see citing works
Self-citationTargeting Anti-Apoptotic BCL-2 Family Proteins for Cancer Treatment
Zhang, X., Liu, X., Zhou, D., & Zheng, G. (2020) · Future Medicinal Chemistry · doi:10.4155/fmc-2020-0004 · Cited by 40 · see citing works
Self-citationVamos, M., Welsh, K., Finlay, D., et al. (2013) · ACS Chemical Biology · doi:10.1021/cb3005512 · Cited by 32 · see citing works
Wu, Y., Lakhani, N. J., Boyer, M. J., et al. (2018) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2018.10.022 · Cited by 4 · see citing works
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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
Self-citationProteolysis 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-citationSnapshots and ensembles of BTK and cIAP1 protein degrader ternary complexes
Schiemer, J., Horst, R., Meng, Y., Montgomery, J. I., Xu, Y., Feng, X., Borzilleri, K., Uccello, D. P., Leverett, C., Brown, S., et al. (2021) · Nature Chemical Biology · doi:10.1038/s41589-020-00686-2 · Cited by 113 · see citing works
Discovery of a Novel BCL-X<sub>L</sub> PROTAC Degrader with Enhanced BCL-2 Inhibition
Pal, P., Thummuri, D., Lv, D., Liu, X., Zhang, P., Hu, W., Poddar, S. K., Hua, N., Khan, S., Yuan, Y., et al. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c00517 · Cited by 60 · see citing works
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- Authors
- Zhang, X., He, Y., Zhang, P., Budamagunta, V., Lv, D., Thummuri, D., Yang, Y., Pei, J., Yuan, Y., Zhou, D., & Zheng, G.
- Affiliations
- University of Florida (US)
- University of Florida Health (US)
- Corresponding author
- Zhou, Daohong
- Zheng, Guangrong
- ORCID
- Venue
- European Journal of Medicinal Chemistry
- Publisher
- Elsevier BV
- Published
- 2020-08
- Volume
- 199
- Pages
- 112397
- ISSN
- 0223-5234 (ISSN-L)
- PMC
- PMC7325632
- OpenAlex
- W3023706389
- Cited by
- 71
- References
- 29
- Citations by year
- 2026: 11 · 2025: 11 · 2024: 10 · 2023: 6 · 2022: 17 · 2021: 11 · 2020: 5
- FWCI
- 3.41
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- European Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (R01CA219836, R01CA242003, R21CA223371)
- 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 › Chemical Synthesis and Analysis
- Keywords
- platelet toxicity, T-cell lymphoma, navitoclax, BCL-XL inhibition, cancer cell lines
- MeSH terms
- Antineoplastic Agents, Cell Survival, Cells, Cultured, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Humans, Structure-Activity Relationship, Molecular Structure, Ubiquitin-Protein Ligases, Cell Proliferation, bcl-X Protein, Inhibitor of Apoptosis Proteins, Drug Discovery, Proteolysis
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