Discovery of novel 20S proteasome subunit β5 PROTAC degraders as potential therapeutics for pharyngeal carcinoma and Bortezomib-resistant multiple myeloma

IF 4.5 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Bioorganic Chemistry Pub Date : 2024-09-03 DOI:10.1016/j.bioorg.2024.107801

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Abstract

Resistance to proteasome inhibitors like Bortezomib is a major challenge in the treatment of multiple myeloma (MM). Proteolysis targeting chimeras (PROTACs), an emerging therapeutic approach that induces selective degradation of target proteins, offer a promising solution to overcome drug resistance. In this study, we designed and synthesized novel small-molecule PROTACs that induce 20S proteasome subunit β5 degradation as a strategy to overcome Bortezomib resistance. These 20S proteasome subunit β5 PROTACs demonstrated considerable binding affinity to 20S proteasome subunit β5 and cereblon (CRBN), effectively induced 20S proteasome subunit β5 degradation, and exhibited potent antiproliferative activity against a panel of cancer cell lines. Notably, PROTACs 12f and 14 displayed robust antitumor effects against both the pharyngeal carcinoma cell line FaDu and the Bortezomib-resistant MM cell line KM3/BTZ in vitro and in vivo with excellent safety profiles. Taken together, our findings highlight the potential of PROTACs 12f and 14 as novel 20S proteasome subunit β5-degrading agents for the treatment of pharyngeal carcinoma and overcoming Bortezomib resistance in MM.

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发现新型 20S 蛋白酶体亚基 β5 PROTAC 降解剂，作为治疗咽癌和硼替佐米耐药多发性骨髓瘤的潜在疗法

蛋白酶体抑制剂（如硼替佐米）的耐药性是治疗多发性骨髓瘤（MM）的一大挑战。蛋白水解靶向嵌合体（PROTACs）是一种新兴的治疗方法，可诱导靶蛋白选择性降解，为克服耐药性提供了一种前景广阔的解决方案。在这项研究中，我们设计并合成了新型小分子PROTACs，它们能诱导20S蛋白酶体亚基β5降解，作为克服硼替佐米耐药性的一种策略。这些20S蛋白酶体亚基β5 PROTACs与20S蛋白酶体亚基β5和cereblon（CRBN）具有相当高的结合亲和力，能有效诱导20S蛋白酶体亚基β5降解，并对一系列癌细胞株表现出强大的抗增殖活性。值得注意的是，PROTACs 12f 和 14 在体外和体内对咽癌细胞株 FaDu 和硼替佐米耐药 MM 细胞株 KM3/BTZ 均显示出强大的抗肿瘤作用，且安全性极佳。综上所述，我们的研究结果凸显了 PROTACs 12f 和 14 作为新型 20S 蛋白酶体亚基 β5 降解剂治疗咽癌和克服硼替佐米耐药 MM 的潜力。

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来源期刊

Bioorganic Chemistry 生物-生化与分子生物学

CiteScore

9.70

自引率

3.90%

发文量

679

审稿时长

31 days

期刊介绍： Bioorganic Chemistry publishes research that addresses biological questions at the molecular level, using organic chemistry and principles of physical organic chemistry. The scope of the journal covers a range of topics at the organic chemistry-biology interface, including: enzyme catalysis, biotransformation and enzyme inhibition; nucleic acids chemistry; medicinal chemistry; natural product chemistry, natural product synthesis and natural product biosynthesis; antimicrobial agents; lipid and peptide chemistry; biophysical chemistry; biological probes; bio-orthogonal chemistry and biomimetic chemistry. For manuscripts dealing with synthetic bioactive compounds, the Journal requires that the molecular target of the compounds described must be known, and must be demonstrated experimentally in the manuscript. For studies involving natural products, if the molecular target is unknown, some data beyond simple cell-based toxicity studies to provide insight into the mechanism of action is required. Studies supported by molecular docking are welcome, but must be supported by experimental data. The Journal does not consider manuscripts that are purely theoretical or computational in nature. The Journal publishes regular articles, short communications and reviews. Reviews are normally invited by Editors or Editorial Board members. Authors of unsolicited reviews should first contact an Editor or Editorial Board member to determine whether the proposed article is within the scope of the Journal.