Development of a BCL-xL and BCL-2 dual degrader with improved anti-leukemic activity,
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PROteolysis-TArgeting Chimeras (PROTACs) have emerged as an innovative drug development platform. However, most PROTACs have been generated empirically because many determinants of PROTAC specificity and activity remain elusive. Through computational modelling of the entire NEDD8-VHL Cullin RING E3 ubiquitin ligase (CRL VHL )/PROTAC/BCL-xL/UbcH5B(E2)-Ub/RBX1 complex, we find that this complex can only ubiquitinate the lysines in a defined band region on BCL-xL. Using this approach to guide our development of a series of ABT263-derived and VHL-recruiting PROTACs, we generate a potent BCL-xL and BCL-2 (BCL-xL/2) dual degrader with significantly improved antitumor activity against BCL-xL/2-dependent leukemia cells. Our results provide experimental evidence that the accessibility of lysines on a target protein plays an important role in determining the selectivity and potency of a PROTAC in inducing protein degradation, which may serve as a conceptual framework to guide the future development of PROTACs.
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753b (203) displays high selectivity for cancer cells over normal platelets and a lower toxicity profile.
“Finally, 753b (203) displayed high selectivity for cancer cells over normal platelets and a lower toxicity profile, making it a promising candidate for future cancer therapy (Table 4).495”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [495]
Some recent studies have shown that only ternary complex models with optimal target-lysine accessibility for E2 could predict target degradation outcomes.
“Moreover, some recent studies have shown that only the ternary complex models with optimal target-lysine accessibility for the E2 could predict target degradation outcomes.[181][182][183]”
From Chasing molecular glue degraders: screening approaches (2022) · cites this paper as [183]
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Venetoclax Resistance in Acute Myeloid Leukemia
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Proteolysis‐Targeting Chimera (PROTAC): Current Applications and Future Directions
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Self-citationTargeted Protein Degradation: Current and Emerging Approaches for E3 Ligase Deconvolution
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Key Considerations in Targeted Protein Degradation Drug Discovery and Development
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Property-based optimisation of PROTACs
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Small-Molecule PROTACs for Cancer Immunotherapy
Liu, Z., Zhang, Y., Xiang, Y., & Kang, X. (2022) · Molecules · doi:10.3390/molecules27175439 · Cited by 29 · see citing works
TACkling Cancer by Targeting Selective Protein Degradation
Noblejas‐López, M. D. M., Tébar-García, D., López‐Rosa, R., Alcaraz-Sanabria, A. L., Cristóbal‐Cueto, P., Pinedo‐Serrano, A., Rivas‐García, L., & Galán‐Moya, E. M. (2023) · Pharmaceutics · doi:10.3390/pharmaceutics15102442 · Cited by 27 · see citing works
PROTAC unleashed: Unveiling the synthetic approaches and potential therapeutic applications
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PROTAC Technology as a New Tool for Modern Pharmacotherapy
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Targeting Apoptosis in AML: Where Do We Stand?
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Recent advances in dual PROTACs degrader strategies for disease treatment
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Navigating PROTACs in Cancer Therapy: Advancements, Challenges, and Future Horizons
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PROTAC-induced protein structural dynamics in targeted protein degradation
Wu, K. Y., Hung, T. I., & Chang, C. A. (2025) · eLife · doi:10.7554/elife.101127.3 · Cited by 23 · see citing works
Rational Proteolysis Targeting Chimera Design Driven by Molecular Modeling and Machine Learning
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Advancing Design Strategy of PROTACs for Cancer Therapy
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Self-citationTherapeutic strategies targeting cellular senescence for cancer and other diseases
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Patent landscape of inhibitors and PROTACs of the anti-apoptotic BCL-2 family proteins
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Self-citationSmall molecule SJ572946 activates BAK to initiate apoptosis
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Self-citationPerspectives of autophagy-tethering compounds (ATTECs) in drug discovery
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The emerging role of targeted protein degradation to treat and study cancer
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Targeting the B cell receptor signaling pathway in chronic lymphocytic leukemia
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PROteolysis‐Targeting Chimeras (PROTACs) in leukemia: overview and future perspectives
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MDM2-BCL-XL PROTACs enable degradation of BCL-XL and stabilization of p53
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Targeting intracellular proteins with cell type-specific functions for cancer immunotherapy
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Thalidomide derivatives degrade BCL-2 by reprogramming the binding surface of CRBN
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Self-citationPrecision oncology revolution: CRISPR-Cas9 and PROTAC technologies unleashed
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Self-citationBcl-x short-isoform is essential for maintaining homeostasis of multiple tissues
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A dual PROTAC nanocarrier amplifies DNA damage and STING activation for cancer immunotherapy
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PROTAC as a novel anti-cancer strategy by targeting aging-related signaling
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Molecular Design of Novel Protein-Degrading Therapeutics Agents Currently in Clinical Trial
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Design, Synthesis, and Evaluation of BCL‐2 Targeting PROTACs
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Self-citationPROTAC-induced protein structural dynamics in targeted protein degradationPreprint
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BCL-2 inhibition in acute myeloid leukemia: resistance and combinations
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Insights into the therapeutic strategies for aging and aging-associated diseases
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Discovery of XZ338, a highly potent BCL-XL degrader
Zhang, X., Thummuri, D., Hu, W., Liu, X., Zhang, P., Zhou, S., Zhou, D., & Zheng, G. (2025) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2025.117624 · Cited by 7 · see citing works
Self-citationDiscovery of PZ671, a highly potent and in vivo active CRBN-recruiting Bcl-xL degrader
Zhang, P., Thummuri, D., Hu, W., Khan, S. U., He, Y., Zhang, X., Pal, P., Lv, D., Zhou, D., & Zheng, G. (2025) · RSC Medicinal Chemistry · doi:10.1039/d5md00119f · Cited by 7 · see citing works
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Developing PROteolysis TArgeting Chimeras (PROTACs) for hematologic malignancies
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Selection of DNA-encoded Chemical Libraries for Compounds that can Induce Protein UbiquitinationPreprint
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Self-citationComputational Modeling of PROTAC Ternary Complexes as Ensembles Using SILCS-xTAC
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PROTACs: Walking through hematological malignancies
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Self-citation
- Authors
- Lv, D., Pal, P., Liu, X., Jia, Y., Thummuri, D., Zhang, P., Hu, W., Pei, J., Zhang, Q., Zhou, S., Khan, S., Zhang, X., Hua, N., Yang, Q., Arango, S., Zhang, W., Nayak, D., Olsen, S. K., Weintraub, S. T., Hromas, R., Konopleva, M., Yuan, Y., Zheng, G., & Zhou, D.
- Affiliations
- University of Florida (US)
- The University of Texas MD Anderson Cancer Center (US)
- The University of Texas at San Antonio Health Science Center (US)
- Corresponding author
- Yuan, Yaxia
- Zheng, Guangrong
- Zhou, Daohong
- ORCID
- Venue
- Nature Communications
- Published
- 2021-11-25
- Volume
- 12
- Issue
- 1
- Pages
- 6896-6896
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC8617031
- OpenAlex
- W3215130076
- Cited by
- 158
- References
- 55
- Citations by year
- 2026: 27 · 2025: 38 · 2024: 41 · 2023: 22 · 2022: 30
- FWCI
- 7.30
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- U.S. Department of Health & Human Services | National Institutes of Health (R01 CA241191, R01 AG063801, R01 CA205224, R01 GM115568, R01 GM128731, R01 CA200673, R01 CA203834)
- Cancer Prevention and Research Institute of Texas (RR200030)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- PROTACs, Bcl-xL, Bcl-2, UbcH5b, RBX1, ubiquitination, navitoclax, leukemia, protein degradation
- MeSH terms
- Antineoplastic Agents, Cell Line, Cell Survival, Humans, Leukemia, Lysine, Models, Molecular, Protein Binding, Protein Conformation, Proto-Oncogene Proteins c-bcl-2, Ubiquitin-Conjugating Enzymes, Ubiquitin-Protein Ligases, Proteasome Endopeptidase Complex, bcl-X Protein, Von Hippel-Lindau Tumor Suppressor Protein, Small Molecule Libraries, Ubiquitination, Proteolysis
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