KU Leuven, Lab. Molecular & Cellular Signaling, Dep. Cellular & Molecular Medicine, Campus Gasthuisberg O/N-I bus 802, Herestraat 49, BE-3000 Leuven, Belgium.
KU Leuven, Molecular Design and Synthesis, Department of Chemistry, Celestijnenlaan 200F, B-3001 Leuven, Belgium.
Biochim Biophys Acta Mol Cell Res. 2021 Apr;1868(5):118983. doi: 10.1016/j.bbamcr.2021.118983. Epub 2021 Feb 5.
The Bcl-2-family proteins have long been known for their role as key regulators of apoptosis. Overexpression of various members of the family is associated with oncogenesis. Its founding member, anti-apoptotic Bcl-2 regulates cell death at different levels, whereby Bcl-2 emerged as a major drug target to eradicate cancers through cell death. This resulted in the development of venetoclax, a Bcl-2 antagonist that acts as a BH3 mimetic. Venetoclax already entered the clinic to treat relapse chronic lymphocytic leukemia patients. Here, we discuss the role of Bcl-2 as a decision-maker in cell death with focus on the recent advances in anti-cancer therapeutics that target the BH4 domain of Bcl-2, thereby interfering with non-canonical functions of Bcl-2 in Ca-signaling modulation. In particular, we critically discuss previously developed tools, including the peptide BIRD-2 (Bcl-2/IPR-disrupter-2) and the small molecule BDA-366. In addition, we present a preliminary analysis of two recently identified molecules that emerged from a molecular modeling approach to target Bcl-2's BH4 domain, which however failed to induce cell death in two Bcl-2-dependent diffuse large B-cell lymphoma cell models. Overall, antagonizing the non-canonical functions of Bcl-2 by interfering with its BH4-domain biology holds promise to elicit cell death in cancer, though improved tools and on-target antagonizing small molecules remain necessary and ought to be designed.
Bcl-2 家族蛋白长期以来一直因其作为细胞凋亡关键调节剂的作用而闻名。家族成员的过度表达与肿瘤发生有关。其创始成员抗凋亡 Bcl-2 在不同水平上调节细胞死亡，Bcl-2 作为一种主要的药物靶点，通过细胞死亡来消除癌症。这导致了 venetoclax 的开发，venetoclax 是一种 Bcl-2 拮抗剂，作为 BH3 模拟物发挥作用。venetoclax 已经进入临床，用于治疗复发性慢性淋巴细胞白血病患者。在这里，我们讨论了 Bcl-2 作为细胞死亡决策者的作用，重点介绍了针对 Bcl-2 的 BH4 结构域的抗癌治疗的最新进展，从而干扰了 Bcl-2 在 Ca 信号转导调节中的非典型功能。特别是，我们批判性地讨论了以前开发的工具，包括肽 BIRD-2（Bcl-2/IPR-disrupter-2）和小分子 BDA-366。此外，我们还对两种最近从分子建模方法中识别出的分子进行了初步分析，这些分子旨在靶向 Bcl-2 的 BH4 结构域，但在两种依赖 Bcl-2 的弥漫性大 B 细胞淋巴瘤细胞模型中未能诱导细胞死亡。总的来说，通过干扰其 BH4 结构域生物学来拮抗 Bcl-2 的非典型功能有望在癌症中引起细胞死亡，尽管需要改进的工具和针对靶点的拮抗小分子，并且应该设计它们。
