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DT2216-a Bcl-xL-specific degrader is highly active against Bcl-xL-dependent T cell lymphomas
Yonghan He1, Raphael Koch2, Vivekananda Budamagunta1
1Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, USA.
Background:
Patients with advanced T cell lymphomas (TCLs) have limited therapeutic options and poor outcomes in part because their TCLs evade apoptosis through upregulation of anti-apoptotic Bcl-2 proteins. Subsets of TCL cell lines, patient-derived xenografts (PDXs), and primary patient samples depend on Bcl-xL for survival. However, small molecule Bcl-xL inhibitors such as ABT263 have failed during clinical development due to on-target and dose-limiting thrombocytopenia.
Methods:
We have developed DT2216, a proteolysis targeting chimera (PROTAC) targeting Bcl-xL for degradation via Von Hippel-Lindau (VHL) E3 ligase, and shown that it has better anti-tumor activity but is less toxic to platelets compared to ABT263. Here, we examined the therapeutic potential of DT2216 for TCLs via testing its anti-TCL activity in vitro using MTS assay, immunoblotting, and flow cytometry and anti-TCL activity in vivo using TCL cell xenograft and PDX model in mice.
Results:
The results showed that DT2216 selectively killed various Bcl-xL-dependent TCL cells including MyLa cells in vitro. In vivo, DT2216 alone was highly effective against MyLa TCL xenografts in mice without causing significant thrombocytopenia or other toxicity. Furthermore, DT2216 combined with ABT199 (a selective Bcl-2 inhibitor) synergistically reduced disease burden and improved survival in a TCL PDX mouse model dependent on both Bcl-2 and Bcl-xL.
Conclusions:
These findings support the clinical testing of DT2216 in patients with Bcl-xL-dependent TCLs, both as a single agent and in rational combinations.
Insights
A new drug, DT2216, effectively targets Bcl-xL in T cell lymphomas (TCLs) and shows promise for treating these cancers with reduced platelet toxicity compared to older drugs.
Area of Science:
- Oncology
- Molecular Biology
- Drug Development
Background:
- Advanced T cell lymphomas (TCLs) have poor prognoses due to resistance to apoptosis, often mediated by anti-apoptotic Bcl-2 proteins.
- Bcl-xL is crucial for the survival of subsets of TCLs, but its inhibition by small molecules like ABT263 is limited by dose-dependent thrombocytopenia.
- Limited therapeutic options exist for patients with advanced TCLs, highlighting the need for novel treatment strategies.
Purpose of the Study:
- To evaluate the therapeutic potential of DT2216, a novel proteolysis targeting chimera (PROTAC) that degrades Bcl-xL, in T cell lymphomas (TCLs).
- To assess the in vitro and in vivo anti-tumor activity and toxicity profile of DT2216 in TCL models.
- To investigate the efficacy of DT2216 in combination with a Bcl-2 inhibitor in TCL models.
Main Methods:
- DT2216, a Bcl-xL-targeting PROTAC, was developed using the Von Hippel-Lindau (VHL) E3 ligase.
- In vitro studies utilized MTS assays, immunoblotting, and flow cytometry to assess anti-TCL activity.
- In vivo efficacy was evaluated in mouse models, including TCL cell xenografts and patient-derived xenografts (PDXs), assessing anti-tumor activity and toxicity.
Main Results:
- DT2216 demonstrated selective killing of Bcl-xL-dependent TCL cells in vitro, including MyLa cells.
- In vivo, DT2216 monotherapy effectively reduced MyLa TCL xenografts without significant thrombocytopenia or toxicity.
- Combination therapy with DT2216 and ABT199 (a Bcl-2 inhibitor) synergistically decreased disease burden and improved survival in a TCL PDX model dependent on both Bcl-2 and Bcl-xL.
Conclusions:
- DT2216 exhibits potent anti-TCL activity and a favorable toxicity profile, particularly regarding platelet function.
- The findings support the clinical investigation of DT2216 as a single agent for Bcl-xL-dependent TCLs.
- Rational combinations of DT2216 with other agents, such as Bcl-2 inhibitors, may offer enhanced therapeutic benefits for TCL patients.
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