Utilizing PROTAC technology to address the on-target platelet toxicity associated with inhibition of BCL-X L
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A proof-of-concept study demonstrates the potential of utilizing a PROTAC approach to achieve tissue selectivity.
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DT2216 uses VHL as the recruiting ligase and is in phase I trials.
“A notable exception is a BCL-xL degrader known as DT2216 developed by Dialectic Therapeutics that uses VHL as the recruiting ligase77,78, which is in phase I trials (Table 1).”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [78]
Degradation of BCL-xL by the VHL-recruiting PROTAC DT2216 was spared in platelets, resulting in reduced platelet-driven toxicity and an improved therapeutic index compared with a BCL-xL inhibitor.
“degradation of BCL-xL by the VHL-recruiting PROTAC DT2216 (ref.152) was spared in platelets, thus resulting in reduced platelet-driven toxicity and an improved therapeutic index compared with a BCL-xL inhibitor78,153.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [78]
Bcl-xL degraders recruiting CRBN or IAPs showed significantly reduced cytotoxicity against platelets but improved killing of various tumor cells and senescent cells due to differential expression of these E3 ligases.
“These Bcl-xL degraders showed significantly reduced cytotoxicity against platelets but improved killing of various tumor cells and senescent cells due to differential expression of these E3 ligases”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [63]
Only a few PROTACs are tumor-selective to avoid normal tissue toxicity, including platelet sparing Bcl-xL PROTACs reported by us recently by taking advantage of E3 ligases that are barely expressed in platelets.
“Although numerous PROTACs have been generated in the past few years, only a few of them are tumor-selective to avoid normal tissue toxicity, including platelet sparing Bcl-xL PROTACs reported by us recently by taking advantage of the E3 ligases that are barely expressed in platelets [4, 60–63].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [63]
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 [63]
The authors reported the first use of PROTAC technology to selectively target anti-apoptotic BCL-XL protein in tumor cells with reduced platelet toxicity by employing VHL or CRBN E3 ligases that are minimally expressed in platelets.
“Recently, we reported the first use of PROTAC technology to selectively target anti-apoptotic BCL-XL protein in tumor cells with reduced platelet toxicity by employing VHL or CRBN E3 ligases that are minimally expressed in platelets [34, 35, 36].”
From PROteolysis TArgeting Chimeras (PROTACs) as emerging anticancer therapeutics (2020) · cites this paper as [34]
The authors were the first to report tumor-selective and platelet-sparing BCL-XL PROTACs by taking advantage of E3 ligases that are barely expressed in platelets.
“We were the first to report tumor-selective and platelet-sparing BCL-XL PROTACs by taking advantage of the E3 ligases that are barely expressed in platelets [34, 35, 36].”
From PROteolysis TArgeting Chimeras (PROTACs) as emerging anticancer therapeutics (2020) · cites this paper as [34]
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Discovery of a Novel BCL-X<sub>L</sub> PROTAC Degrader with Enhanced BCL-2 Inhibition
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Self-citationTrends in targeting Bcl-2 anti-apoptotic proteins for cancer treatment
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Selectivity through Targeted Protein Degradation (TPD)
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The path to venetoclax resistance is paved with mutations, metabolism, and more
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Cereblon-Recruiting PROTACs: Will New Drugs Have to Face Old Challenges?
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Targeting Anti-Apoptotic BCL-2 Family Proteins for Cancer Treatment
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Self-citationProteolysis‐Targeting Chimera (PROTAC): Current Applications and Future Directions
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Small-Molecule PROTACs for Cancer Immunotherapy
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PROTACs are effective in addressing the platelet toxicity associated with BCL-XL inhibitors
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Self-citationDesign, Synthesis and In Vitro Investigation of Cabozantinib-Based PROTACs to Target c-Met Kinase
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PROteolysis‐Targeting Chimeras (PROTACs) in leukemia: overview and future perspectives
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Cereblon: promise and challenges for combating human diseases
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PROTAC: A Novel Technology for Drug Development**
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Precision oncology revolution: CRISPR-Cas9 and PROTAC technologies unleashed
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Structure-Guided Development of Potent Benzoylurea Inhibitors of BCL-XL and BCL-2
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Ubiquitin recruiting chimera: more than just a PROTAC
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PROTAC as a novel anti-cancer strategy by targeting aging-related signaling
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Design, Synthesis, and Evaluation of BCL‐2 Targeting PROTACs
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Discovery of XZ338, a highly potent BCL-XL degrader
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Self-citationDiscovery of PZ671, a highly potent and in vivo active CRBN-recruiting Bcl-xL degrader
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Developing PROteolysis TArgeting Chimeras (PROTACs) for hematologic malignancies
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Design and optimization of piperlongumine analogs as potent senolytics
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PROTACs in platelets: emerging antithrombotic strategies and future perspectives
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Direct Co-Targeting of Bcl-xL and Mcl-1 Exhibits Synergistic Effects in AR-V7–Expressing CRPC Models
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Targeted Protein Degradation by Proteolysis Targeting Chimeras
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PROTACS- targeted protein degradation as a path to precision cancer therapeutics
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BindingDB Entry 50017954: PROTACs to address the challenges facing small molecule inhibitors.
BindingDB (2023) · UC San Diego · doi:10.7270/q2p55sm1
BindingDB Entry 50015887: Trends in targeting Bcl-2 anti-apoptotic proteins for cancer treatment.
BindingDB (2023) · UC San Diego · doi:10.7270/q2m049dt
BindingDB Entry 50016327: Selectivity through Targeted Protein Degradation (TPD).
BindingDB (2023) · UC San Diego · doi:10.7270/q22n568r
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- Authors
- Zhang, X., Thummuri, D., He, Y., Liu, X., Zhang, P., Zhou, D., & Zheng, G.
- Affiliations
- University of Florida (US)
- Corresponding author
- Zheng, Guangrong
- Venue
- Chemical Communications
- Publisher
- Royal Society of Chemistry (RSC)
- Published
- 2019
- Volume
- 55
- Issue
- 98
- Pages
- 14765-14768
- ISSN
- 1359-7345 (ISSN-L)
- 1364-548X
- PMC
- PMC7057339
- OpenAlex
- W2989708739
- Cited by
- 86
- References
- 49
- Citations by year
- 2026: 6 · 2025: 12 · 2024: 12 · 2023: 8 · 2022: 19 · 2021: 10 · 2020: 18
- FWCI
- 3.89
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Chemical Communications (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Center for Scientific Review (R01CA211963, R01CA219836, R21CA223371, S10OD021758)
- 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
- PROTACs, Bcl-xL, platelet toxicity, Bcl-2 family proteins, MOLT-4 cells, tissue selectivity, anti-apoptotic proteins, cancer therapy
- MeSH terms
- Blood Platelets, Humans, Isoquinolines, Protein Binding, Thalidomide, Apoptosis, Ubiquitin-Protein Ligases, Cell Line, Tumor, Adaptor Proteins, Signal Transducing, bcl-X Protein
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