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Overview of epigenetic degraders based on PROTAC, molecular glue, and hydrophobic tagging technologies

Acta Pharmaceutica Sinica B 2024年第2期14卷 533-578页

作者： Xiaopeng Peng Zhihao Hu Limei Zeng Meizhu Zhang Congcong Xu Benyan Lu Chengpeng Tao Weiming Chen Wen Hou Kui Cheng Huichang Bi Wanyi Pan Jianjun Chen College of Pharmacy Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases of Ministry of EducationGannan Medical UniversityGanzhou 314000China College of Basic Medicine Gannan Medical UniversityGanzhou 314000China Guangdong Provincial Key Laboratory of New Drug Screening NMPA Key Laboratory for Research and Evaluation of Drug MetabolismSchool of Pharmaceutical SciencesSouthern Medical UniversityGuangzhou 510515China

Epigenetic pathways play a critical role in the initiation, progression, and metastasis of cancer. Over the past few decades, significant progress has been made in the development of targeted epigenetic modulators(e.g., inhibitors). However, epigenetic inhibitors have faced multiple challenges,including limited clinical efficacy, toxicities, lack of subtype selectivity, and drug resistance. As a result,the design of new epigenetic modulators(e.g., degraders) such as PROTACs, molecular glue, and hydrophobic tagging(Hy T) degraders has garnered significant attention from both academia and pharmaceutical industry, and numerous epigenetic degraders have been discovered in the past decade. In this review,we aim to provide an in-depth illustration of new degrading strategies(2017-2023) targeting epigenetic proteins for cancer therapy, focusing on the rational design, pharmacodynamics, pharmacokinetics, clinical status, and crystal structure information of these degraders. Importantly, we also provide deep insights into the potential challenges and corresponding remedies of this approach to drug design and development. Overall, we hope this review will offer a better mechanistic understanding and serve as a useful guide for the development of emerging epigenetic-targeting degraders.

关键词： Epigenetic Degrader PROTAC Molecularglue hydrophobic tagging

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Targeted Degradation of DNA/RNA Binding Proteins via Covalent hydrophobic tagging

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CCS Chemistry 2023年第10期5卷 2207-2214页

作者： Yan Wang Jingzi Zhang Jiafang Deng Chengzhi Wang Lei Fang Yan Zhang Jinbo Li State Key Laboratory of Analytical Chemistry for Life Sciences Jiangsu Key Laboratory of Advanced Organic MaterialsSchool of Chemistry and Chemical EngineeringChemistry and Biomedicine Innovation Center(ChemBIC)Nanjing UniversityNanjing 210023 Jiangsu Key Laboratory of Molecular Medicine Chemistry and Biomedicine Innovation Center(ChemBIC)Medical School of Nanjing UniversityNanjing 210093

Targeted protein degradation(TPD)holds great promise for biological inquiry and therapeutic ***,it still remains elusive to destruct DNA/RNA binding proteins(DBPs/RBPs)previously deemed ***,we report ligandassisted covalent hydrophobic tagging(LACHT)as a modular strategy for TPD of these difficult-totarget *** by a noncovalent protein ligand,LACHT leverages a reactive N-acyl-N-alkyl sulfonamide group to covalently label the protein target with a hydrophobic adamantane,which further engages the cellular quality control mechanism to induce proteolytic *** a smallmolecule ligand,we demonstrated that LACHT allowed TPD of a DBP,bromodomain-containing protein 4,in human leukemia cells with high *** studies revealed that LACHT-mediated TPD dependent on ligand-directed irreversible tagging and the covalently labeled proteins underwent polyubiquitination before removal through both the proteasome and the ***,when an RNA ligand was employed,we showed that LACHT also enabled TPD of an RBP,Lin28a,leading to upregulation of its downstream let-7 *** study thus provides a generalizable platform to expand the TPD toolbox for biomedical applications.

关键词： targeted protein degradation covalent labeling hydrophobic tagging DNA/RNA binding proteins miRNA

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N-Acetylenethio phthalimides: Sequential linkage for compositional click reaction

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Chinese Chemical Letters 2023年第2期34卷 183-187页

作者： Wen-Chao Gao Kai Feng Jun Tian Juan Zhang Hong-Hong Chang Xuefeng Jiang College of Biomedical Engineering Taiyuan University of TechnologyTaiyuan 030024China School of Chemistry and Molecular Engineering East China Normal UniversityShanghai 200062China

Click chemistry has become a useful tool for diverse molecular linkage and modification, and the development of new click strategy that enable reversibility and multifunctionality is of high demand for the multifunction and drug release. Herein, compositionally clicking combined regioselective iridium-catalyzed azide-alkynthio cycloaddition(Ir-AAC) and disulfuration has been developed for the sequential linkage from N-acetylenethio phthalimides, naturally occurring thiols and readily available azides. This method has been successfully applied to the construction of drug hybrids, peptide modification and glycosylation. Furthermore, by the design of diacetylenethio phthalimide as a platform molecule, trifunctional conjugants were sequentially linked through independent Ir-AAC, disulfuration and Cu-AAC reaction for hydrophobic tagging ternary PROTACs.

关键词： Diversity-oriented synthesis Compositional click Reversible linkage Iridium catalysis hydrophobic tagging

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