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01-12-2020 | Lymphoma | Research

DT2216—a Bcl-xL-specific degrader is highly active against Bcl-xL-dependent T cell lymphomas

Authors: Yonghan He, Raphael Koch, Vivekananda Budamagunta, Peiyi Zhang, Xuan Zhang, Sajid Khan, Dinesh Thummuri, Yuma T. Ortiz, Xin Zhang, Dongwen Lv, Janet S. Wiegand, Wen Li, Adam C. Palmer, Guangrong Zheng, David M. Weinstock, Daohong Zhou

Published in: Journal of Hematology & Oncology | Issue 1/2020

Abstract

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.

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Title: DT2216—a Bcl-xL-specific degrader is highly active against Bcl-xL-dependent T cell lymphomas
Authors: Yonghan He
Raphael Koch
Vivekananda Budamagunta
Peiyi Zhang
Xuan Zhang
Sajid Khan
Dinesh Thummuri
Yuma T. Ortiz
Xin Zhang
Dongwen Lv
Janet S. Wiegand
Wen Li
Adam C. Palmer
Guangrong Zheng
David M. Weinstock
Daohong Zhou
Publication date: 01-12-2020
Publisher: BioMed Central
Keyword: Lymphoma
Published in: Journal of Hematology & Oncology / Issue 1/2020
Electronic ISSN: 1756-8722
DOI: https://doi.org/10.1186/s13045-020-00928-9

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Abstract

Background

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