A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity
Open accessAbstract
B-cell lymphoma extra large (BCL-X L) is a well-validated cancer target. However, the on-target and dose-limiting thrombocytopenia limits the use of BCL-X L inhibitors, such as ABT263, as safe and effective anticancer agents. To reduce the toxicity of ABT263, we converted it into DT2216, a BCL-X L proteolysis-targeting chimera (PROTAC), that targets BCL-X L to the Von Hippel-Lindau (VHL) E3 ligase for degradation. We found that DT2216 was more potent against various BCL-X L-dependent leukemia and cancer cells but considerably less toxic to platelets than ABT263 in vitro because VHL is poorly expressed in platelets. In vivo, DT2216 effectively inhibits the growth of several xenograft tumors as a single agent or in combination with other chemotherapeutic agents, without causing appreciable thrombocytopenia. These findings demonstrate the potential to use PROTAC technology to reduce on-target drug toxicities and rescue the therapeutic potential of previously undruggable targets. Furthermore, DT2216 may be developed as a safe first-in-class anticancer agent targeting BCL-X L.
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A navitoclax PROTAC rapidly and specifically degraded BCL-2, causing apoptosis of cancer cells with less off-target lysis.
“The use of a navitoclax PROTAC facilitated the rapid and specific degradation of BCL-2, resulting in apoptosis of cancer cells with less off-target lysis.”
From Senolytic Drugs: Reducing Senescent Cell Viability to Extend Health Span (2021) · cites this paper as [76]
The Discussion states that DT2216, the PROTAC derived from navitoclax, is specific for BCL-XL and does not induce BCL-2 degradation. The Abstract supports reduced platelet toxicity and antitumor activity, but explicitly says DT2216 does not degrade BCL-2—the central target named in the claim. (LLM, conf=0.94)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredThe therapeutic window of navitoclax is improved by degrading certain BCL-2 family members rather than only inhibiting their function.
“the therapeutic window of navitoclax is improved by utilizing an approach that degrades certain BCL-2 family members instead of just inhibiting their function (76).”
From Senolytic Drugs: Reducing Senescent Cell Viability to Extend Health Span (2021) · cites this paper as [76]
DT2216 has shown promising antitumor activities in BCL-XL-dependent hematologic cancers as a single agent and in multiple solid tumors when combined with conventional chemotherapy.
“DT2216 has shown promising antitumor activities in BCL-XL-dependent hematologic cancers as a single agent therapy and in multiple solid tumors when combined with conventional chemotherapy [8–10].”
From BCL-XL PROTAC degrader DT2216 synergizes with sotorasib in preclinical models of KRASG12C-mutated cancers (2022) · cites this paper as [8]
DT2216 is a platelet-sparing BCL-XL PROTAC reported by our group.
“Recently, our group has reported platelet-sparing targeting of BCL-XL by proteolysis targeting chimeras (PROTACs) exemplified by DT2216.”
From BCL-XL PROTAC degrader DT2216 synergizes with sotorasib in preclinical models of KRASG12C-mutated cancers (2022) · cites this paper as [8]
This modification potentiates the antitumour activity of ABT263 while suppressing its side effects on platelets in which VHL is poorly expressed.
“This potentiates the antitumour activity of ABT263 while suppressing its side effects on platelets in which VHL is poorly expressed [120].”
From The role of cellular senescence and SASP in tumour microenvironment (2023) · cites this paper as [120]
Linkage of ABT263 to a VHL E3 ligase-targeting moiety results in degradation rather than inhibition of BCL-XL activity itself.
“Linkage of ABT263 to a von Hippel -Lindau (VHL) E3 ligasetargeting moiety results in degradation rather than inhibition of BCL-XL activity itself.”
From The role of cellular senescence and SASP in tumour microenvironment (2023) · cites this paper as [120]
DT2216 (200) is the first selective Bcl-xL degrader based on ABT263 (navitoclax), linking ABT263 to VHL ligands.
“In 2019, Zhou’s team identified DT2216 (200), the first selective Bcl-xL degrader based on ABT263 (navitoclax), by linking ABT263 to VHL ligands (Table 4).”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [492]
In vivo, DT2216 effectively inhibits growth of multiple xenograft tumors without causing significant thrombocytopenia.
“In vivo, DT2216 effectively inhibited the growth of multiple xenograft tumors without causing significant thrombocytopenia.492”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [492]
DT2216 exhibits high potency against various Bcl-xL-dependent leukemia and cancer cells while demonstrating lower platelet toxicity than ABT263.
“DT2216 exhibited high potency against various Bcl-xL-dependent leukemia and cancer cells while demonstrating lower platelet toxicity than ABT263.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [492]
A PROTAC that co-opts VHL to induce degradation of BCL-XL can spare thrombocytopenia associated with systemic BCL-XL inhibition.
“For instance, it was shown that a PROTAC that co-opts the E3 ligase VHL to induce the degradation of BCL-XL can spare the thrombocytopenia associated with systemic BCL-XL inhibition.72”
From Advancing Targeted Protein Degradation via Multiomics Profiling and Artificial Intelligence (2023) · cites this paper as [72]
VHL has low expression in platelets.
“A remarkable example is the low expression of VHL in platelets”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [152]
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 [152]
A number of PROTACs have been developed to target various proteins of interest involved in the tumorigenesis and progression of hematologic malignancies, including ALK, Bcl-xL, BCR-ABL, BTK, BRD4, CDK-6, FLT-3, HDAC6, and STAT3.
“A number of PROTACs have been developed to target various POIs that are involved in the tumorigenesis and progression of hematologic malignancies, such as anaplastic lymphoma kinase (ALK) [5], Bcl-xL [4], BCR-ABL [6], Bruton’s tyrosine kinase (BTK) [7], BRD4 [8], CDK-6 [9], FMS-like tyrosine kinase-3 (FLT-3) [10], HDAC6 [11], and signal transducer and activator of transcription 3 (STAT3) [3].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [4]
DT2216 potently degraded Bcl-xL protein and inhibited MOLT-4 T-ALL in vitro and in vivo.
“Moreover, DT2216 potently degraded Bcl-xL protein and inhibited MOLT-4 T-ALL in vitro and in vivo.”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [4]
DT2216 is more potent against Bcl-xL-dependent tumor cells and less toxic against platelets in comparison to conventional Bcl-xL inhibitors.
“DT2216, a representative PROTAC that hijacks the VHL E3 ligase to achieve tissue/cell-selective degradation of Bcl-xL, was found to be more potent against Bcl-xL-dependent tumor cells and less toxic against platelets in comparison to conventional Bcl-xL inhibitors.”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [4]
Tumor-specific or selective degradation of a protein of interest with PROTACs is possible by using ligands for cell type- and/or tumor-specific or selective E3 ligases.
“Fourth, it is possible to achieve tumor-specific/selective degradation of a POI with PROTACs by using ligands for cell type- and/or tumor-specific/selective E3 ligases [2, 4].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [4]
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 [4]
Prolonged depletion of a target by PROTACs may cause on-target toxicities if a POI is indispensable for normal functions.
“The prolonged depletion of a target by PROTACs may cause on-target toxicities if a POI is indispensable for normal functions [4].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [4]
Profiling changes in global protein expression by proteomics will be helpful to appreciate potential off-target toxicities of PROTACs.
“Therefore, profiling the changes in global protein expression by proteomics will be helpful to appreciate the potential off-target toxicities of PROTACs [3, 4, 43].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [4]
Several PROTACs have shown promising preclinical results in the treatment of hematologic malignancies.
“several PROTACs have shown promising preclinical results in the treatment of hematologic malignancies [3, 4, 44]”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [4]
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 [4]
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 [35]
In the case of the authors' BCL-XL PROTACs, prolonged degradation of BCL-XL may be advantageous because BCL-XL exhibits functional redundancy in normal tissues except platelets, and therefore its prolonged depletion accounts for better therapeutic efficacy.
“in the case of our BCL-XL PROTACs the prolonged degradation of BCL-XL may be advantageous because BCL-XL exhibits functional redundancy in normal tissues except platelets, and therefore its prolonged depletion accounts for better therapeutic efficacy [35, 80, 81].”
From PROteolysis TArgeting Chimeras (PROTACs) as emerging anticancer therapeutics (2020) · cites this paper as [35]
The authors converted a dual inhibitor of BCL-XL and BCL-2, ABT263, into selective VHL-based BCL-XL PROTACs, providing evidence that promiscuous inhibitors can be converted into target-specific PROTACs.
“Recently, we converted a dual inhibitor of BCL-XL and BCL-2, named ABT263 (or navitoclax), into selective VHL-based BCL-XL PROTACs, which provides further evidence that promiscuous inhibitors can be converted into target-specific PROTACs [35, 36].”
From PROteolysis TArgeting Chimeras (PROTACs) as emerging anticancer therapeutics (2020) · cites this paper as [35]
VHL is differentially expressed between tumor cells and platelets, which helped design platelet-sparing BCL-XL PROTACs.
“we have shown that VHL is differentially expressed between tumor cells and platelets, which helped us to design platelet-sparing BCL-XL PROTACs [35, 36].”
From PROteolysis TArgeting Chimeras (PROTACs) as emerging anticancer therapeutics (2020) · cites this paper as [35]
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 [35]
Several other PROTAC drug candidates with promising preclinical data can potentially be tested in clinical trials in the near future.
“In addition, there are several other PROTAC drug candidates with promising preclinical data that can potentially be tested in clinical trials in the near future [1, 35, 40].”
From PROteolysis TArgeting Chimeras (PROTACs) as emerging anticancer therapeutics (2020) · cites this paper as [35]
The development of PROTACs based on tissue-specific and tumor-selective E3 ligases could be a potential strategy that can revolutionize the field of PROTACs as cancer therapeutics.
“The development of PROTACs based on tissue-specific and tumor-selective E3 ligases could be one such potential strategy that can revolutionize the field of PROTACs as cancer therapeutics, as we recently demonstrated [35, 36].”
From PROteolysis TArgeting Chimeras (PROTACs) as emerging anticancer therapeutics (2020) · cites this paper as [35]
PROTACs targeting BCL-XL and ALK have broad-spectrum antitumor activities, effectively killing leukemia and solid tumor cells in vitro and in xenograft models.
“Some of the PROTACs, such as PROTACs targeting BCL-XL and ALK [35, 105], have broad-spectrum antitumor activities, which can effectively kill leukemia and solid tumor cells in vitro and in xenograft models.”
From PROteolysis TArgeting Chimeras (PROTACs) as emerging anticancer therapeutics (2020) · cites this paper as [35]
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PROTAC targeted protein degraders: the past is prologue
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Protein degraders enter the clinic — a new approach to cancer therapy
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Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials
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Proteolysis-targeting chimeras (PROTACs) in cancer therapy
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The manipulation of apoptosis for cancer therapy using BH3-mimetic drugs
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The flavonoid procyanidin C1 has senotherapeutic activity and increases lifespan in mice
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Self-citationSenolytic Drugs: Reducing Senescent Cell Viability to Extend Health Span
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“However, the therapeutic window of navitoclax is improved by utilizing an approach that degrades certain BCL-2 family members instead of just inhibiting their function (76).”
BackgroundTargeted protein degradation: advances in drug discovery and clinical practice
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Target and tissue selectivity of PROTAC degraders
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Chemistries of bifunctional PROTAC degraders
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PROTAC: An Effective Targeted Protein Degradation Strategy for Cancer Therapy
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Self-citationPROTACs: great opportunities for academia and industry (an update from 2020 to 2021)
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Self-citationMajor advances in targeted protein degradation: PROTACs, LYTACs, and MADTACs
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PROteolysis TArgeting Chimeras (PROTACs) as emerging anticancer therapeutics
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Proteolysis‐targeting chimeras in drug development: A safety perspective
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Targeted protein degradation for cancer therapy
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Self-citationThe Cancer SENESCopedia: A delineation of cancer cell senescence
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Co-targeting of BAX and BCL-XL proteins broadly overcomes resistance to apoptosis in cancer
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Expanding PROTACtable genome universe of E3 ligases
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PROTACs to address the challenges facing small molecule inhibitors
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Reduced Mitochondrial Apoptotic Priming Drives Resistance to BH3 Mimetics in Acute Myeloid Leukemia
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Apoptosis in Cancer Biology and Therapy
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PROTAC technology: A new drug design for chemical biology with many challenges in drug discovery
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Discovery of SHP2-D26 as a First, Potent, and Effective PROTAC Degrader of SHP2 Protein
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INK4 Tumor Suppressor Proteins Mediate Resistance to CDK4/6 Kinase Inhibitors
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Development of a BCL-xL and BCL-2 dual degrader with improved anti-leukemic activity,
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COVID-19 and cellular senescence
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Expanding the arsenal of E3 ubiquitin ligases for proximity-induced protein degradation
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The role of cellular senescence and SASP in tumour microenvironment
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Bioorthogonal PROTAC Prodrugs Enabled by On-Target Activation
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The peptide PROTAC modality: a novel strategy for targeted protein ubiquitination
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Self-citationCharacteristic roadmap of linker governs the rational design of PROTACs
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DT2216—a Bcl-xL-specific degrader is highly active against Bcl-xL-dependent T cell lymphomas
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Self-citationOvercoming Cancer Drug Resistance Utilizing PROTAC Technology
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Self-citationSenolytics for Cancer Therapy: Is All that Glitters Really Gold?
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Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies
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“Similar to DT2216 (1e) [34], none of these VHL-based PROTACs were able to degrade BCL-2 in MOLT-4 cells (Figure 3), further demonstrated the feasibility of achieving target specificity through conversion of non-selective inhibitors to PROTACs.”
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Self-citationStrategies for designing proteolysis targeting chimaeras (PROTACs)
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Targeted degradation via direct 26S proteasome recruitment
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Recent Advances in Pro-PROTAC Development to Address On-Target Off-Tumor Toxicity
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Self-citationPeptide-based PROTAC degrader of FOXM1 suppresses cancer and decreases GLUT1 and PD-L1 expression
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PROTAC’ing oncoproteins: targeted protein degradation for cancer therapy
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Expanding Chemical Probe Space: Quality Criteria for Covalent and Degrader Probes
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Gastrointestinal Stromal Tumor: Challenges and Opportunities for a New Decade
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Self-citation
- Authors
- Khan, S., Zhang, X., Lv, D., Zhang, Q., He, Y., Zhang, P., Liu, X., Thummuri, D., Yuan, Y., Wiegand, J. S., Pei, J., Zhang, W., Sharma, A., McCurdy, C. R., Kuruvilla, V. M., Baran, N., Ferrando, A. A., Kim, Y.-M., Rogojina, A., Houghton, P. J., Huang, G., Hromas, R., Konopleva, M., Zheng, G., & Zhou, D.
- Affiliations
- University of Florida (US)
- The University of Texas MD Anderson Cancer Center (US)
- Columbia University (US)
- Children's Hospital Los Angeles (US)
- The University of Texas at San Antonio Health Science Center (US)
- Corresponding author
- Zheng, Guangrong
- Zhou, Daohong
- ORCID
- Khan, Sajid
- Zhang, Xuan
- Lv, Dongwen
- Zhang, Qi
- He, Yonghan
- Zhang, Peiyi
- Liu, Xingui
- Thummuri, Dinesh
- Yuan, Yaxia
- Pei, Jing
- Zhang, Weizhou
- Sharma, Abhisheak
- McCurdy, Christopher R.
- Kuruvilla, Vinitha M.
- Baran, Natalia
- Ferrando, Adolfo A.
- Kim, Yong-mi
- Houghton, Peter J.
- Huang, Guangcun
- Hromas, Robert
- Konopleva, Marina
- Zheng, Guangrong
- Zhou, Daohong
- Venue
- Nature Medicine
- Published
- 2019-12
- Volume
- 25
- Issue
- 12
- Pages
- 1938-1947
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC6898785
- OpenAlex
- W2990669650
- Cited by
- 688
- References
- 63
- Citations by year
- 2026: 98 · 2025: 127 · 2024: 116 · 2023: 103 · 2022: 105 · 2021: 83 · 2020: 55
- FWCI
- 20.26
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH
- CPRIT
- 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
- Bcl-xL, PROTACs, VHL E3 ubiquitin ligase, thrombocytopenia, navitoclax, platelet toxicity, leukemia, tumor xenografts, BCL-2 inhibitor, on-target toxicity
- MeSH terms
- Aniline Compounds, Animals, Antineoplastic Agents, Blood Platelets, Humans, Sulfonamides, Thrombocytopenia, Gene Expression Regulation, Neoplastic, bcl-X Protein, Mice, Von Hippel-Lindau Tumor Suppressor Protein, Proteolysis, Heterografts
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