用蛋白水解靶向嵌合体（Protac）探测I类组蛋白脱乙酰基酶（HDAC），以开发高效和选择性降解器
Probing class I histone deacetylases (HDAC) with proteolysis targeting chimera (PROTAC) for the development of highly potent and selective degraders
影响因子:4.70000
分区:医学2区 / 有机化学1区 生化与分子生物学2区
发表日期:2024 Dec
作者:
Hany S Ibrahim, Menglu Guo, Sebatian Hilscher, Frank Erdmann, Matthias Schmidt, Mike Schutkowski, Chunquan Sheng, Wolfgang Sippl
摘要
I类HDAC由于其在表观遗传修饰中的作用而被认为是有希望的癌症靶标。开发新的，有效和无毒的I类HDAC抑制剂的主要挑战是选择性和适当的药代动力学。 Protac技术（靶向嵌合体的蛋白水解）是一种用于生产活性物质的药物开发的新方法，可以降解感兴趣的蛋白质（POI）而不是抑制它。该技术将开放以高度安全余量生产有选择性和有效药物的时代。以前，我们报道了针对I类HDAC的不同抑制剂，该类别用氨基苯甲酰胺或羟氨酸组功能化。在当前的研究工作中，我们将根据先前报道的抑制剂来开发Protac技术来开发I类HDAC降解器。我们合成了两种基于氨基苯胺的Protac和基于羟氨酸的Protac，并在体外对I类HDAC进行了测试。为了确保它们的降解，所有这些都以HDAC2为代表性的例子进行了筛选。在各种HDAC亚型下，以不同浓度评估了最佳候选者。这导致了Protac（32a）（HI31.1），该Protac以8.9 nm的DC50降解HDAC8，并且针对其他同工酶具有适当的选择性。此外，Protac 32a能够使用DC50 = 14.3 nm降解HDAC6。对白血病细胞的凋亡研究（MV-4-11）表现出超过50％的细胞凋亡。 Protac 32a（HI31.1）在正常细胞系和适当的化学稳定性方面显示出良好的安全余量。
Abstract
Class I HDACs are considered promising targets for cancer due to their role in epigenetic modifications. The main challenges in developing a new, potent and non-toxic class I HDAC inhibitor are selectivity and appropriate pharmacokinetics. The PROTAC technique (Proteolysis Targeting Chimera) is a new method in drug development for the production of active substances that can degrade a protein of interest (POI) instead of inhibiting it. This technique will open the era to produce selective and potent drugs with a high margin of safety. Previously, we reported different inhibitors targeting class I HDACs functionalized with aminobenzamide or hydroxamate groups. In the current research work, we will employ PROTAC technique to develop class I HDAC degraders based on our previously reported inhibitors. We synthesized two series of aminobenzamide-based PROTACs and hydroxamate-based PROTACs and tested them in vitro against class I HDACs. To ensure their degradation, all of them were screened against HDAC2 as representative example of class I. The best candidates were evaluated at different concentrations at various HDAC subtypes. This resulted in the PROTAC (32a) (HI31.1) that degrades HDAC8 with a DC50 of 8.9 nM with a proper margin of selectivity against other isozymes. Moreover, PROTAC 32a is able to degrade HDAC6 with DC50 = 14.3 nM. Apoptotic study on leukemic cells (MV-4-11) displayed more than 50 % apoptosis took place at 100 nM. PROTAC 32a (HI31.1) showed a good margin of safety against normal cell line and proper chemical stability.