DT2216-a 是一种针对 Bcl-xL 的降解剂，对依赖 Bcl-xL 的 T 细胞淋巴瘤具有高度活性。
DT2216-a Bcl-xL-specific degrader is highly active against Bcl-xL-dependent T cell lymphomas.
机构信息
Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, USA.
Department of Hematology and Medical Oncology, University Medical Center Göttingen, Göttingen, Germany.
出版信息
J Hematol Oncol. 2020 Jul 16;13(1):95. doi: 10.1186/s13045-020-00928-9.
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.
背景
晚期 T 细胞淋巴瘤（TCL）患者的治疗选择有限，预后较差，部分原因是其 TCL 通过上调抗凋亡 Bcl-2 蛋白来逃避凋亡。TCL 细胞系、患者来源异种移植物（PDX）和原发性患者样本的亚群依赖 Bcl-xL 存活。然而，由于靶标和剂量限制的血小板减少，小分子 Bcl-xL 抑制剂（如 ABT263）在临床开发中失败。
方法
我们开发了 DT2216，一种通过 Von Hippel-Lindau（VHL）E3 连接酶降解 Bcl-xL 的蛋白水解靶向嵌合体（PROTAC），并表明与 ABT263 相比，它具有更好的抗肿瘤活性，但对血小板的毒性较小。在这里，我们通过 MTS 测定、免疫印迹和流式细胞术在体外检测 DT2216 对 TCL 的治疗潜力，以及在小鼠 TCL 细胞异种移植和 PDX 模型中在体内检测 DT2216 的抗 TCL 活性。
结果
结果表明，DT2216 选择性地杀死了各种依赖 Bcl-xL 的 TCL 细胞，包括体外的 MyLa 细胞。在体内，单独使用 DT2216 对小鼠的 MyLa TCL 异种移植物非常有效，不会导致明显的血小板减少或其他毒性。此外，DT2216 与 ABT199（一种选择性 Bcl-2 抑制剂）联合使用可协同降低疾病负担并改善依赖 Bcl-2 和 Bcl-xL 的 TCL PDX 小鼠模型的存活率。
结论
这些发现支持 DT2216 在依赖 Bcl-xL 的 TCL 患者中的临床测试，无论是作为单一药物还是作为合理组合。
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