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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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“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]
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Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“DT2216, a VHL-recruiting BCL-xL PROTAC that achieved potent antitumor activity without the severe thrombocytopenia observed with navitoclax87”
From Emerging strategies in senotherapeutics: from broad-spectrum senolysis to precision reprogramming (2026) · cites this paper as [87]
In the citing paper
“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 the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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 citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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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Metadata
- 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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