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Machine Learning Modeling of protein-intrinsic Features Predicts Tractability of targeted protein degradation

Genomics, Proteomics & Bioinformatics 2022年第5期20卷 882-898页

作者： Wubing Zhang Shourya S.Roy Burman Jiaye Chen Katherine A.Donovan Yang Cao Chelsea Shu Boning Zhang Zexian Zeng Shengqing Gu Yi Zhang Dian Li Eric S.Fischer Collin Tokheim X.Shirley Liu Department of Data Science Dana-Farber Cancer InstituteBostonMA 02215USA Department of Biostatistics Harvard T.H.Chan School of Public HealthBostonMA 02115USA Department of Cancer Biology Dana-Farber Cancer InstituteBostonMA 02215USA Department of Biological Chemistry and Molecular Pharmacology Harvard Medical SchoolBostonMA 02115USA Department of Biomedical Informatics Harvard Medical SchoolBostonMA 02115USA Center of Growth Metabolismand AgingKey Laboratory of Bio-resource and Eco-environmentMinistry of EducationCollege of Life SciencesSichuan UniversityChengdu 610064China Research Scholar Initiative Graduate School of Arts and SciencesHarvard UniversityCambridgeMA 02138USA

targeted protein degradation(TPD)has rapidly emerged as a therapeutic modality to eliminate previously undruggable proteins by repurposing the cell’s endogenous protein degradation ***,the susceptibility of proteins for targeting by TPD approaches,termed“degradability”,is largely ***,we developed a machine learning model,model-free analysis of protein degradability(MAPD),to predict degradability from features intrinsic to protein *** shows accurate performance in predicting kinases that are degradable by TPD compounds[with an area under the precision–recall curve(AUPRC)of 0.759 and an area under the receiver operating characteristic curve(AUROC)of 0.775]and is likely generalizable to independent non-kinase *** found five features with statistical significance to achieve optimal prediction,with ubiquitination potential being the most *** structural modeling,we found that E2-accessible ubiquitination sites,but not lysine residues in general,are particularly associated with kinase ***,we extended MAPD predictions to the entire proteome to find964 disease-causing proteins(including proteins encoded by 278 cancer genes)that may be tractable to TPD drug development.

关键词： targeted protein degradation Degradability protein-intrinsic feature Ubiquitination Machine learning

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Expanding the horizons of targeted protein degradation:A non-small molecule perspective

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Acta Pharmaceutica Sinica B 2024年第6期14卷 2402-2427页

作者： Xiaowei Huang Fengbo Wu Jing Ye Lian Wang Xiaoyun Wang Xiang Li Gu He Department of Pharmacy and Department of Dermatology&Venerology West China HospitalSichuan UniversityChengdu 610041China Department of Urology West China HospitalSichuan UniversityChengdu 610041China Laboratory of Dermatology Clinical Institute of Inflammation and ImmunologyFrontiers Science Center for Disease-Related Molecular Network and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu 610041China

targeted protein degradation(TPD)represented by proteolysis targeting chimeras(PROTACs)marks a significant stride in drug discovery.A plethora of innovative technologies inspired by PROTAC have not only revolutionized the landscape of TPD but have the potential to unlock functionalities beyond ***-small-molecule-based approaches play an irreplaceable role in this field.A wide variety of agents spanning a broad chemical spectrum,including peptides,nucleic acids,antibodies,and even vaccines,which not only prove instrumental in overcoming the constraints of conventional small molecule entities but also provided rapidly renewing *** we summarize the burgeoning non-small molecule technological platforms inspired by PROTACs,including three major trajectories,to provide insights for the design strategies based on novel paradigms.

关键词： targeted protein degradation Proteolysis targeting chimera Endocytosis Autophagy Proximity-inducing modality Post-translational modification

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E3 Ligases and COVID-19:Insights into Viral Control andTherapeutic Potential

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BIOCELL 2025年第1期49卷 127-147页

作者： Mukul Mishra Deeba Khan Sehbanul Islam Department of Cancer Biology Abramson Family Cancer Research InstitutePerelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPA 19104USA Department of Pathology Jawaharlal Nehru Medical CollegeAligarh Muslim UniversityAligarh202002Uttar PradeshIndia

The COVID-19 pandemic,caused by the newly emerged coronavirus SARS-CoV-2,has resulted in unprecedented global health challenges,including millions of infections and *** the direct effects of the virus are critical,the interplay between SARS-CoV-2 and cellular host factors significantly impacts the replication cycle of the virus and the clinical severity of *** review provides a comprehensive analysis of hostpathogen interactions,focusing on the functional roles and regulatory mechanisms of SARS-CoV-2 viral *** systematically review the literature to detail how SARS-CoV-2 engages with host cellular machinery,with a specific emphasis on their modulation by E3 ubiquitin *** dissecting these intricate interactions and the impact of E3 ligases on SARS-CoV-2 infection,we aimto uncover novel therapeutic opportunities and strategies to effectively combat COVID-19.

关键词： SARS-CoV-2 COVID-19 viral proteins host-pathogen interaction E3 ubiquitin ligases ubiquitination targeted protein degradation

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Molecular glue triggers degradation of PHGDH by enhancing the interaction between DDB1 and PHGDH

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Acta Pharmaceutica Sinica B 2024年第9期14卷 4001-4013页

作者： Ziqi Huang Kun Zhang Yurui Jiang Mengmeng Wang Mei Li Yuda Guo Ruolin Gao Ning Li Chenyang Wang Jia Chen Jiefu Wang Ning Liu Xiang Liu Shuangwei Liu Mingming Wei Cheng Yang Guang Yang The State Key Laboratory of Medicinal Chemical Biology College of Life SciencesCollege of PharmacyNankai UniversityTianjin 300071China Tianjin Medical University Cancer Institute and Hospital National Clinical Research Center for CancerTianjin’s Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjin 300060China

Cancer stem cells(CSCs)play a pivotal role in tumor initiation,proliferation,metastasis,drug resistance,and ***,targeting CSCs has emerged as a promising avenue for cancer ***,3-phosphoglycerate dehydrogenase(PHGDH)has been identified as being intricately associated with the regulation of numerous cancer stem ***,reports detailing the functional regulators of PHGDH that can mitigate the stemness across cancer types are *** this study,the novel“molecular glue”LXH-3-71 was identified,and it robustly induced degradation of PHGDH,thereby modulating the stemness of colorectal cancer cells(CRCs)both in vitro and in ***,LXH-3-71 was observed to form a dynamic chimera,between PHGDH and the DDB1-CRL E3 *** insights not only elucidate the anti-CSCs mechanism of the lead compound but also suggest that degradation of PHGDH may be a more viable therapeutic strategy than the development of PHGDH ***,compound LXH-3-71 was leveraged as a novel ligand for the DDB1-CRL E3 ligase,facilitating the development of new PROTAC molecules targeting EGFR and CDK4 degradation.

关键词： Molecular glue targeted protein degradation PHGDH Cancer stem cells PROTACs

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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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Current strategies for improving limitations of proteolysis targeting chimeras

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Chinese Chemical Letters 2023年第6期34卷 144-156页

作者： Chunlan Pu Shirui Wang Lei Liu Zhonghui Feng Hongjia Zhang Qianyuan Gong Yueshan Sun Yuanbiao Guo Rui Li Medical Research Center The Third People’s Hospital of ChengduThe Affiliated Hospital of Southwest Jiaotong UniversityThe Second Chengdu Hospital Affiliated to Chongqing Medical UniversityChengdu 610031China State Key Laboratory of Biotherapy Collaborative Innovation Center of Biotherapy and Cancer CenterWest China Hospital of Sichuan UniversityChengdu 610041China

Proteolysis targeting chimeras(PROTACs)are bifunctional degrader molecules via hijacking the ubiquitinproteasome system(UPS)to specifically eliminate targeted *** have gained momentum as a new modality of attractive technologies in the drug discovery landscape,since it allows to degrade disease-related proteins *** some PROTACs drugs reached the clinical research,they are still facing some bottlenecks and challenges that should not be neglected,such as poor oral bioavailability and potential toxic side *** overcome these limitations,herein,we provide an overview of recent strategies for improving the durability of PROTACs by enhancing cell permeability and reducing toxic side ***,the impact of these strategies on improving oral bioavailability as well as their advantages and drawbacks will also be *** review will give a useful reference toolbox for PROTACs design and further promote its clinical application.

关键词： PROTACs targeted protein degradation Oral bioavailability Cell permeability Tumor targeting

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Artificial Nucleic Acid Tractor-Directed Simultaneous Depletion of Oncogenic Membrane proteins Without Hijacking Proteolysis-Specific Actuator

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CCS Chemistry 2024年第2期6卷 439-449页

作者： Zhen Zou Songlan Pan Qian Xue Ting Chen Ziyun Huang Bei Qing Pengfei Liu Conghui Zhao Yunlin Sun Erhu Xiong Ronghua Yang Key Laboratory of Chemical Biology and Traditional Chinese Medicine Research Ministry of EducationCollege of Chemistry and Chemical EngineeringHunan Normal UniversityChangsha 410081 School of Chemistry and Chemical Engineering Hunan Provincial Key Laboratory of CytochemistryChangsha University of Science and TechnologyChangsha 410114 The Second Xiangya Hospital Central South UniversityChangsha 410011

targeted protein degradation(TPD)is an emerging tool for degrading proteins of interest,which affords an attractive modality for cancer ***,the present TPD technologies must engage a proteolysis-specific actuator to initiate degradation of targeted proteins in the proteasome or ***,we report an artificial tractor that can induce endocytosis-mediated protein depletion without hijacking a proteolysis-specific *** this design,bispecific aptamer chimeras(BSACs)are established,which can bridge human epidermal growth factor receptor 2(ErbB-2),an important biomarker in a common important biomarker in cancer,with membrane proteins of *** advantage of the property of aptamer-induced endocytosis and digestion of ErbB-2,another membrane protein is translocated into the lysosome in a hitchhike-like manner,resulting in lysosomal proteolysis along with *** strategy frees the TPD from the fundamental limitation of proteolysis-specific actuator and allows simultaneous regulation of the quantity and function of two oncogenic receptors in a cell-type-specific manner,expanding the application scope of TPD-based therapeutics.

关键词： targeted protein degradation aptamer epidermal growth factor receptor 2 lysosome membrane proteins cancer therapy

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靶向难成药蛋白——蛋白质降解剂的力量

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Science Bulletin 2024年第11期69卷 1776-1797页

作者：张超刘永波李广晨杨周立韩驰孙秀云盛春泉丁克饶燏 State Key Laboratory of Molecular Oncology MOE Key Laboratory of Protein SciencesMOE Key Laboratory of Bioorganic Phosphorus Chemistry&Chemical BiologySchool of Pharmaceutical SciencesTsinghua UniversityBeijing 100084China Changping Laboratory Beijing 102206China School of Pharmacy Second Military Medical UniversityShanghai 200433China State Key Laboratory of Chemical Biology Shanghai Institute of Organic ChemistryChinese Academy of SciencesShanghai 200032China

Undruggable targets typically refer to a class of therapeutic targets that are difficult to target through conventional methods or have not yet been targeted,but are of great clinical *** to statistics,over 80%of disease-related pathogenic proteins cannot be targeted by current conventional treatment *** recent years,with the advancement of basic research and new technologies,the development of various new technologies and mechanisms has brought new perspectives to overcome challenging drug *** them,targeted protein degradation technology is a breakthrough drug development strategy for challenging drug *** technology can specifically identify target proteins and directly degrade pathogenic target proteins by utilizing the inherent protein degradation pathways within *** new form of drug development includes various types such as proteolysis targeting chimera(PROTAC),molecular glue,lysosome-targeting Chimaera(LYTAC),autophagosometethering compound(ATTEC),autophagy-targeting chimera(AUTAC),autophagy-targeting chimera(AUTOTAC),degrader-antibody conjugate(DAC).This article systematically summarizes the application of targeted protein degradation technology in the development of degraders for challenging drug ***,the article looks forward to the future development direction and application prospects of targeted protein degradation technology.

关键词： Undruggables targeted protein degradation PROTAC Molecule glue DAC LYTAC

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