Global PROTAC Toolbox for Degrading BCR-ABL Overcomes Drug-Resistant Mutants and Adverse Effects.,Journal of Medicinal Chemistry

当前位置： X-MOL 学术 › J. Med. Chem. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Global PROTAC Toolbox for Degrading BCR-ABL Overcomes Drug-Resistant Mutants and Adverse Effects.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-07-13 , DOI: 10.1021/acs.jmedchem.0c00967
Yiqing Yang _{1,

2} , Hongying Gao _{1,

2} , Xiuyun Sun _{1,

2} , Yonghui Sun _{1,

2} , Yueping Qiu ₃ , Qinjie Weng _{3,

4} , Yu Rao ₁

Affiliation

The BCR–ABL fusion oncoprotein causes chronic myeloid leukemia or acute lymphoblastic leukemia in Ph⁺ patients because the ABL kinase is constitutively activated. However, current clinical treatment with ABL inhibitors is seriously limited by drug resistance and adverse effects. Although the emerging proteolysis-targeting chimeras (PROTACs) have been introduced to degrade BCR–ABL, most of them showed limited activity and could not overcome the common drug-resistant mutants, especially for T315I mutant. Herein, we systematically designed a set of unique PROTACs by globally targeting all the three binding sites of BCR–ABL, including dasatinib-, ponatinib-, and asciminib-based PROTACs. Our ponatinib-based PROTACs showed practical activity as dasatinib-based PROTACs, while no reported ponatinib-based PROTACs could degrade BCR–ABL before. As a proof of concept, some additional dasatinib-based PROTACs were then designed to degrade T315I mutant too. We provided a global PROTAC toolbox for degrading both wild-type and T315I-mutated BCR–ABL from each binding site. More importantly, these PROTACs showed better selectivity and less adverse effects than the inhibitors, indicating that PROTACs had great potential for overcoming clinical drug resistance and safety issues.

中文翻译：

用于降解BCR-ABL的全球PROTAC工具箱克服了抗药性突变和不良影响。

的BCR-ABL融合癌蛋白引起慢性髓细胞性白血病或pH急性淋巴细胞白血病⁺患者是因为ABL激酶被组成性激活。但是，目前的ABL抑制剂临床治疗受到耐药性和不良反应的严重限制。尽管已经引入了新兴的靶向蛋白水解的嵌合体（PROTAC）来降解BCR-ABL，但大多数都显示出有限的活性，不能克服常见的耐药突变体，特别是对于T315I突变体。在这里，我们通过全局靶向BCR-ABL的所有三个结合位点，包括基于dasatinib，ponatinib和asciminib的PROTAC，系统地设计了一套独特的PROTAC。我们的基于ponatinib的PROTAC与基于dasatinib的PROTAC相比显示出实际的活性，而以前没有报道的基于ponatinib的PROTAC可以降解BCR-ABL。作为概念验证，然后还设计了一些其他基于达萨替尼的PROTAC，以降解T315I突变体。我们提供了一个全球PROTAC工具箱，用于从每个结合位点降解野生型和T315I突变的BCR-ABL。更重要的是，与抑制剂相比，这些PROTAC具有更好的选择性和更少的不良反应，表明PROTAC具有克服临床耐药性和安全性问题的巨大潜力。

更新日期：2020-08-14

点击分享查看原文

点击收藏

阅读更多本刊新发论文本刊介绍/投稿指南