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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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AAV mediated carboxyl terminus of Hsp70 interacting protein overexpression mitigates the cognitive and pathological phenotypes of APP/PS1 mice

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Neural Regeneration Research 2025年第1期20卷 253-264页

作者： Zhengwei Hu Jing Yang Shuo Zhang Mengjie Li Chunyan Zuo Chengyuan Mao Zhongxian Zhang Mibo Tang Changhe Shi Yuming Xu Department of Neurology The First Affiliated Hospital of Zhengzhou UniversityZhengzhou UniversityZhengzhouHenan ProvinceChina Academy of Medical Sciences of Zhengzhou University ZhengzhouHenan ProvinceChina NHC key laboratory of Prevention and treatment of cerebrovascular diseases The First Affiliated Hospital of Zhengzhou UniversityZhengzhou UniversityZhengzhouHenan ProvinceChina henan key laboratory of cerebrovascular diseases The First Affiliated Hospital of Zhengzhou UniversityZhengzhou UniversityZhengzhouHenan ProvinceChina Institute of Neuroscience Zhengzhou UniversityZhengzhouHenan ProvinceChina Sino-British Research Centre for Molecular Oncology National Centre for International Research in Cell and Gene TherapySchool of Basic Medical SciencesAcademy of Medical SciencesZhengzhou UniversityZhengzhouHenan ProvinceChina Department of Gerontology The First Affiliated Hospital of Zhengzhou UniversityZhengzhou UniversityZhengzhouHenan ProvinceChina

The E3 ubiquitin ligase,carboxyl terminus of heat shock protein 70(Hsp70)interacting protein(CHIP),also functions as a co-chaperone and plays a crucial role in the protein quality control *** this study,we aimed to investigate the neuroprotective effect of overexpressed CHIP on Alzheimer’s *** used an adeno-associated virus vector that can cross the blood-brain barrier to mediate CHIP overexpression in APP/PS1 mouse *** overexpression significantly ameliorated the performance of APP/PS1 mice in the Morris water maze and nest building tests,reduced amyloid-βplaques,and decreased the expression of both amyloid-βand phosphorylated *** also alleviated the concentration of microglia and astrocytes around *** APP/PS1 mice of a younger age,CHIP overexpression promoted an increase in ADAM10 expression and inhibitedβ-site APP cleaving enzyme 1,insulin degrading enzyme,and neprilysin *** of HSP70 and HSP40,which have functional relevance to CHIP,were also *** nuclei transcriptome sequencing in the hippocampus of CHIP overexpressed mice showed that the lysosomal pathway and oligodendrocyte-related biological processes were up-regulated,which may also reflect a potential mechanism for the neuroprotective effect of *** research shows that CHIP effectively reduces the behavior and pathological manifestations of APP/PS1 ***,overexpression of CHIP could be a beneficial approach for the treatment of Alzheimer’s disease.

关键词： adeno-associated virus Alzheimer’s disease APP/PS1 mice carboxyl terminus of Hsp70 interacting protein gene therapy

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Tumor necrosis factor-stimulated gene-6 ameliorates early brain injury after subarachnoid hemorrhage by suppressing NLRC4 inflammasome-mediated astrocyte pyroptosis

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Neural Regeneration Research 2024年第5期19卷 1064-1071页

作者： Mingxiang Ding Lei Jin Boyang Wei Wenping Cheng Wenchao Liu Xifeng Li Chuanzhi Duan Neurosurgery Center Department of Cerebrovascular SurgeryThe National Key Clinical SpecialtyThe Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular DiseaseGuangdong Provincial Key Laboratory on Brain Function Repair and RegenerationThe Neurosurgery Institute of Guangdong ProvinceZhujiang HospitalSouthern Medical UniversityGuangzhouGuangdong ProvinceChina Department of cerebrovascular Intervention Zhongshan City People’s HospitalZhongshanGuangdong ProvinceChina

Subarachnoid hemorrhage is associated with high morbidity and mortality and lacks effective *** is a crucial mechanism underlying early brain injury after subarachnoid *** studies have confirmed that tumor necrosis factor-stimulated gene-6(TSG-6)can exert a neuroprotective effect by suppressing oxidative stress and ***,no study to date has explored whether TSG-6 can alleviate pyroptosis in early brain injury after subarachnoid *** this study,a C57BL/6J mouse model of subarachnoid hemorrhage was established using the endovascular perforation *** results indicated that TSG-6 expression was predominantly detected in astrocytes,along with NLRC4 and gasdermin-D(GSDMD).The expression of NLRC4,GSDMD and its N-terminal domain(GSDMD-N),and cleaved caspase-1 was significantly enhanced after subarachnoid hemorrhage and accompanied by brain edema and neurological *** explore how TSG-6 affects pyroptosis during early brain injury after subarachnoid hemorrhage,recombinant human TSG-6 or a siRNA targeting TSG-6 was injected into the cerebral *** TSG-6 administration downregulated the expression of NLRC4 and pyroptosis-associated proteins and alleviated brain edema and neurological ***,TSG-6 knockdown further increased the expression of NLRC4,which was accompanied by more severe astrocyte *** summary,our study revealed that TSG-6 provides neuroprotection against early brain injury after subarachnoid hemorrhage by suppressing NLRC4 inflammasome activation-induced astrocyte pyroptosis.

关键词： astrocyte early brain injury inflammasome NLRC4 pyroptosis subarachnoid hemorrhage tumor necrosis factor-stimulated gene-6(TSG-6)

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Ethanol extract of Cyathulae Radix inhibits osteoclast differentiation and bone loss

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Chinese Journal of Natural Medicines 2024年第3期22卷 212-223页

作者： SHI Liying REN Liuyi LI Jinping LIU Xin LU Jingjing JIA Lujuan XIE Baoping TANG Siyuan LIU Wei ZHANG Jie Department of Pharmachemistry Xiangya School of Pharmaceutical SciencesCentral South UniversityChangsha 410013China Hunan key laboratory of Diagnostic and Therapeutic Drug Research for Chronic diseases Central South UniversityChangsha 410013China key laboratory of Prevention and Treatment of Cardiovascular and cerebrovascular diseases Ministry of EducationGannan Medical UniversityGanzhou 341000China Xiangya Nursing School Central South UniversityChangsha 410013China The Third Xiangya Hospital Central South UniversityChangsha 410013China

Cyathulae Radix,a traditional Chinese medicine and a common vegetable,boasts a history spanning *** enhances bone density,boosts metabolism,and effectively alleviates osteoporosis-induced *** its historical use,the molecular mechanisms behind Cyathulae Radix’s impact on osteoporosis remain *** this study,we investigated the effects and mechanisms of Cyathulae Radix ethanol extract(CEE)in inhibiting osteoporosis and ***-week-old female mice underwent ovariectomy and were treated with CEE for eight ***-computed tomography(micro-CT)assessed histomorphometric parameters,bone tissue staining observed distal femur histomorphology,and three-point bending tests evaluated tibia mechanical ***-linked immunosorbent assay(ELISA)measured serum estradiol(E2),receptor activator for nuclear factor B ligand(RANKL),and osteoprotegerin(OPG)***-related markers were analyzed via Western blotting(WB)and quantitative real-time polymerase chain reaction(qRT-PCR).Additionally,CEE effects on RANKL-induced osteoclast formation and bone resorption were investigated in vitro using tartrate-resistant acid phosphatase(TRAP)staining,qRT-PCR,and WB *** with the ovariectomy(OVX)group,CEE treatment enhanced trabecular bone density,maximal load-bearing capacity,and various histomorphometric *** E2 and OPG levels significantly increased,while Receptor activator of nuclear factor-κB(RANK)decreased in the CEE *** downregulated matrix metallopeptidase 9(MMP-9),Cathepsin K(CTSK),and TRAP gene and protein *** bone marrow macrophages(BMMs),CEE reduced mature osteoclasts,bone resorption pit areas,and MMP-9,CTSK,and TRAP expression during osteoclast *** with DMSO treatment,CEE markedly inhibited RANK,TNF receptor associated factor 6(TRAF6),Proto-oncogene c-Fos(c-Fos),Nuclear factor of activated T-cells cytoplasmic 1(NFATc1)expressions,and Extracellular regula

关键词： Osteoporosis Osteoclast BMMs Cyathulae Radix RANKL ER/RANK/NFATc1 signaling pathway

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Blood pressure targets in patients with chronic kidney disease:Comments and controversies

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Chinese Medical Journal 2024年第3期137卷 270-272页

作者： Ying Zheng Guangyan Cai Xiangmei Chen Department of Nephrology First Medical Center of Chinese PLA General HospitalNational Key Laboratory of Kidney DiseasesNational Clinical Research Center for Kidney DiseasesBeijing Key Laboratory of Kidney Disease ResearchBeijing 100853China

According to the Global Burden of Disease Study 2017,there are 132 million patients with chronic kidney disease(CKD)in China,^([1])and the prevalence of hypertension in Chinese patients with CKD(67.3%)is significantly higher than that in the general population(23.2%).^([2,3])CKD is both a cause and a consequence of hypertension,and these two conditions form a vicious cycle that leads to the high prevalence rate of hypertension in patients with *** hypertension accelerates the deterioration of renal function,which significantly increases the risk of developing end-stage renal disease(ESRD),as well as cardiovascular and cerebrovascular diseases,leading to poor patient outcomes.

关键词： patients Blood hypertension

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ASF1A-dependent P300-mediated histone H3 lysine 18 lactylation promotes atherosclerosis by regulating EndMT

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Acta Pharmaceutica Sinica B 2024年第7期14卷 3027-3048页

作者： Mengdie Dong Yunjia Zhang Minghong Chen Yongkang Tan Jiao Min Xian He Fuhao Liu Jiaming Gu Hong Jiang Longbin Zheng Jiajing Chen Quanwen Yin Xuesong Li Xiang Chen Yongfeng Shao Yong Ji Hongshan Chen Department of Cardiovascular Surgery the First Affiliated Hospital of Nanjing Medical Universityand Key Laboratory of Cardiovascular and Cerebrovascular MedicineSchool of PharmacyNational Vaccine Innovation PlatformNanjing Medical UniversityNanjing 211166China key laboratory of Cardiovascular and cerebrovascular Medicine School of PharmacyNanjing Medical UniversityNanjing 211166China Department of Clinical Medicine Nanjing Medical University TIANYUAN Honors SchoolNanjing Medical UniversityNanjing 211166China Department of Anesthesiology Sir Run Run HospitalNanjing Medical UniversityNanjing 211166China Department of Cardiovascular Surgery the First Affiliated Hospital of Nanjing Medical UniversityNanjing 211166China key laboratory of Cardiovascular and cerebrovascular Medicine Key Laboratory of Targeted Intervention of Cardiovascular DiseaseCollaborative Innovation Center for Cardiovascular Disease Translational MedicineState Key Laboratory of Reproductive MedicineSchool of Pharmacythe Affiliated Suzhou Hospital of Nanjing Medical UniversityGusu SchoolNanjing Medical UniversityNanjing 211166China National key laboratory of Frigid Zone Cardiovascular diseases(NKLFZCD) Department of Pharmacology(State-Province Key Laboratories of Biomedicine-Pharmaceutics of China)College of PharmacyKey Laboratory of Cardiovascular Medicine Research and Key Laboratory of Myocardial IschemiaChinese Ministry of EducationNHC Key Laboratory of Cell Transplantationthe Central Laboratory of the First Affiliated HospitalHarbin Medical UniversityHarbin 150081China key laboratory of Targeted Intervention of Cardiovascular Disease Collaborative Innovation Center for Cardiovascular Disease Translational MedicineNanjing Medical UniversityNanjing 211166China Department of Cardiology Huai’an First People’s Hospital Affiliated with Nanjing Medical UniversityHuai’an 223399China

Endothelial-to-mesenchymal transition(EndMT)is a key driver of *** glycolysis is increased in the endothelium of atheroprone areas,accompanied by elevated lactate *** lactylation,mediated by lactate,can regulate gene expression and participate in disease ***,whether histone lactylation is involved in atherosclerosis remains ***,we report that lipid peroxidation could lead to EndMT-induced atherosclerosis by increasing lactatedependent histone H3 lysine 18 lactylation(H3K18la)in vitro and in vivo,as well as in atherosclerotic patients’***,the histone chaperone ASF1A was first identified as a cofactor of P300,which precisely regulated the enrichment of H3K18la at the promoter of SNAI1,thereby activating SNAI1 transcription and promoting *** found that deletion of ASF1A inhibited EndMT and improved endothelial *** analysis based on Apoe^(KO)Asf1a^(ECKO) mice in the atherosclerosis model confirmed the involvement of H3K18la in atherosclerosis and found that endotheliumspecific ASF1A deficiency inhibited EndMT and alleviated atherosclerosis *** of glycolysis by pharmacologic inhibition and advanced PROTAC attenuated H3K18la,SNAI1 transcription,and EndMT-induced *** study illustrates precise crosstalk between metabolism and epigenetics via H3K18la by the P300/ASF1A molecular complex during EndMT-induced atherogenesis,which provides emerging therapies for atherosclerosis.

关键词： Histone lactylation Atherosclerosis Endothelial-tomesenchymal transition ASF1A SNAI1 Endothelial dysfunction Lactate Epigenetic

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Transient induction of actin cytoskeletal remodeling associated with dedifferentiation,proliferation,and redifferentiation stimulates cardiac regeneration

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Acta Pharmaceutica Sinica B 2024年第6期14卷 2537-2553页

作者： Wenbin Fu Qiao Liao Yu Shi Wujian Liu Hongmei Ren Chunmei Xu Chunyu Zeng Department of Cardiology Daping Hospitalthe Third Military Medical University(Army Medical University)Chongqing 400042China key laboratory of Geriatric Cardiovascular and cerebrovascular Disease Research Ministry of Education of ChinaChongqing 400042China Chongqing key laboratory for Hypertension Research Chongqing Cardiovascular Clinical Research CenterChongqing Institute of CardiologyChongqing 400042China State key laboratory of Trauma Burns and Combined InjuryDaping Hospitalthe Third Military Medical UniversityChongqing 400042China Cardiovascular Research Center Chongqing CollegeUniversity of Chinese Academy of SciencesChongqing 400042China State key laboratory of Trauma and Chemical Poisoning Chongqing 400042China

The formation of new and functional cardiomyocytes requires a 3-step process:dedifferentiation,proliferation,and redifferentiation,but the critical genes required for efficient dedifferentiation,proliferation,and redifferentiation remain *** our study,a circular trajectory using single-nucleus RNA sequencing of the pericentriolar material 1 positive(PCM1^(+))cardiomyocyte nuclei from hearts 1 and 3 days after surgery-induced myocardial infarction(MI)on postnatal Day 1 was reconstructed and demonstrated that actin remodeling contributed to the dedifferentiation,proliferation,and redifferentiation of cardiomyocytes after *** identified four top actin-remodeling regulators,namely Tmsb4x,Tmsb10,Dmd,and Ctnna3,which we collectively referred to as *** expressed changes of 2D2P,using a polycistronic non-integrating lentivirus driven by Tnnt2(cardiac-specific troponin T)promoters(Tnnt2-2D2P-NIL),efficiently induced transiently proliferative activation and actin remodeling in postnatal Day 7 cardiomyocytes and adult ***,the intramyocardial delivery of Tnnt2-2D2P-NIL resulted in a sustained improvement in cardiac function without ventricular dilatation,thickened septum,or fatal arrhythmia for at least 4 *** conclusion,this study highlights the importance of actin remodeling in cardiac regeneration and provides a foundation for new gene-cocktail-therapy approaches to improve cardiac repair and treat heart failure using a novel transient and cardiomyocyte-specific viral construct.

关键词： Single cell analysis Actin remodeling Tmsb4x Tmsb10 Dmd Ctnna3 Myocardial infarction Cardiomyocytes proliferation Cardiac regeneration Genetic therapy

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The burgeoning importance of PIWI-interacting RNAs in cancer progression

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Science China(Life Sciences) 2024年第4期67卷 653-662页

作者： Xinpei Deng Tianle Liao Jindong Xie Da Kang Yiwei He Yuying Sun Zhangling Wang Yongluo Jiang Xuan Miao Yixuan Yan Hailin Tang Lewei Zhu Yutian Zou Peng Liu State key laboratory of Oncology in South China Guangdong Provincial Clinical Research Center for CancerSun Yat-sen University Cancer CenterGuangzhou 510060China School of Medicine Sun Yat-sen UniversityShenzhen 518107China key laboratory of Cardiovascular and cerebrovascular Medicine Nanjing Medical UniversityNanjing 211166China Guanghua School of Stomatology Sun Yat-sen UniversityGuangzhou 510062China The First People’s Hospital of Foshan Foshan 528000China

PIWI-interacting RNAs(pi RNAs)are a class of small noncoding RNA molecules that specifically bind to piwi protein family members to exert regulatory functions in germ *** studies have found that pi RNAs,as tissue-specific molecules,both play oncogenic and tumor suppressive roles in cancer progression,including cancer cell proliferation,metastasis,chemoresistance and ***,the atypical manifestation of pi RNAs and PIWI proteins in various malignancies presents a promising strategy for the identification of novel biomarkers and therapeutic targets in the diagnosis and management of ***,the precise functions of pi RNAs in cancer progression and their underlying mechanisms have yet to be fully *** review aims to examine current research on the biogenesis and functions of pi RNA and its burgeoning importance in cancer progression,thereby offering novel perspectives on the potential utilization of pi RNAs and piwi proteins in the management and treatment of advanced cancer.

关键词： PIWI-interacting RNAs/piRNAs cancer progression metastasis chemoresistance stemness

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Reveal the pharmacodynamic substances and mechanism of an edible medicinal plant Rhodiola crenulate in DSS-induced colitis through plasma pharmacochemistry and metabolomics

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Food Science and Human Wellness 2024年第4期13卷 2116-2131页

作者： Yu Peng Xiaoao Xiao Tingting Ji Xinyuan Wang Yixuan Xu Jianbo Xiao Hui Cao Zhiyong Chen Huifan Liu Yuanqing Gao Hongxun Tao key laboratory of Cardiovascular and cerebrovascular Medicine School of PharmacyNanjing Medical UniversityNanjing 211166China School of Food and Biological Engineering Jiangsu UniversityZhenjiang 212013China Department of Analytical Chemistry and Food Science Faculty of ScienceUniversity of VigoVigo 36310Spain CISPAC Fontan BuildingCity of CultureSantiago de Compostela 15707Spain Shaanxi Academy of Traditional Chinese Medicine Xi'an 710003China Guangdong key laboratory of Science and Technology of Lingnan Specialty Food Zhongkai University of Agriculture and EngineeringGuangzhou 510550China State key laboratory of Southwestern Chinese Medicine Resources Chengdu 610075China

Rhodiola crenulate is the edible medicinal herbal medicine widely used for altitude sickness in ***,our previous work has found that *** extract(RCE)could significantly improve the pathology associated with dextran sulfate sodium-induced ***,the current research aims to reveal the pharmacodynamic material basis of RCE,as well as its mechanism against *** chemical characterization of RCE was performed by UHPLC-HR-MS,through which a total of 88 constituents were ***,our results also found 29 constituents absorbed into blood and 8 metabolized absorbable *** decreased flavonoids prototype and the elevated sulfated products of phenols were observed under pathophysiological conditions of *** metabolomics study revealed that colitis caused the alternation of fatty acid metabolism,steroid hormone biosynthesis and bile acid ***,RCE could prevent colitis by improving fatty acid metabolism and secondary bile acid metabolism.

关键词： Rhodiola crenulate Colitis Chemical characterization Plasma pharmacochemistry Metabolomics

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Peroxisome proliferator-activated receptor gamma coactivator-1(PGC-1)family in physiological and pathophysiological process and diseases

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Signal Transduction and Targeted Therapy 2024年第4期9卷 1249-1292页

作者： Lu Qian Yanli Zhu Chao Deng Zhenxing Liang Junmin Chen Ying Chen Xue Wang Yanqing Liu Ye Tian Yang Yang Xi'an key laboratory of Cardiovascular and cerebrovascular diseases Xi'an No.3 HospitalThe Affiliated Hospital of Northwest UniversityNorthwest UniversityXi'an 710021China Xi'an key laboratory of Innovative Drug Research for Heart Failure Faculty of Life Sciences and MedicineNorthwest University229 Taibai North RoadXi'an 710069China Department of Cardiovascular Surgery The First Affiliated Hospital of Xi'an Jiaotong University277 Yanta West RoadXi'an 710061China Department of Cardiothoracic Surgery The First Affiliated Hospital of Zhengzhou University1 Jianshe EastZhengzhou 450052China Department of Hematology The First Affiliated Hospital of Xi'an JiaotongUniversity277 Yanta West RoadXi'an 710061China

Peroxisome proliferator-activated receptor gamma coactivator-1(PGC-1)family(PGC-1s),consisting of three members encompassing PGC-1a,PGC-1β,and PGC-1-related coactivator(PRC),was discovered more than a quarter-century ***-1s are essential coordinators of many vital cellular events,including mitochondrial functions,oxidative stress,endoplasmic reticulum homeostasis,and *** evidence has shown that PGC-1s are implicated in many diseases,such as cancers,cardiac diseases and cardiovascular diseases,neurological disorders,kidney diseases,motor system diseases,and metabolic *** the upstream modulators and co-activated partners of PGC-1s and identifying critical biological events modulated by downstream effectors of PGC-1s contribute to the presentation of the elaborate network of ***,discussing the correlation between PGC-1s and diseases as well as summarizing the therapy targeting PGC-1s helps make individualized and precise intervention *** this review,we summarize basic knowledge regarding the PGC-1s family as well as the molecular regulatory network,discuss the physio-pathological roles of PGc-1s in human diseases,review the application of PGC-1s,including the diagnostic and prognostic value of PGC-1s and several therapies in pre-clinical studies,and suggest several directions for future *** review presents the immense potential of targeting PGC-1s in the treatment of diseases and hopefully facilitates the promotion of PGC-1s as new therapeutic targets.

关键词： diseases life precise

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