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Drug discovery of sclerostin inhibitors

Acta Pharmaceutica Sinica B 2022年第5期12卷 2150-2170页

作者： Sifan Yu Dijie Li Ning Zhang Shuaijian Ni Meiheng Sun Luyao Wang Huan Xiao Dingdong Liu Jin Liu Yuanyuan Yu Zongkang Zhang Samuel Tin Yui Yeung Shu Zhang Aiping Lu Zhenlin Zhang Baoting Zhang Ge Zhang Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases School of Chinese MedicineHong Kong Baptist UniversityKowloon TsaiHong Kong 999077China Institute of Integrated Bioinfomedicine and Translational Science School of Chinese MedicineHong Kong Baptist UniversityKowloon TsaiHong Kong 999077China Institute of Precision Medicine and Innovative Drug Discovery HKBU Institute for Research and Continuing EducationShenzhen 518000China School of Chinese Medicine Faculty of Medicinethe Chinese University of Hong KongHong Kong 999077China The Key Laboratory of Aerospace Medicine Ministry of EducationAir Force Medical UniversityXi’an 710000China Shanghai Clinical Research Center of Bone Disease Department of Osteoporosis and Bone DiseasesShanghai Jiao Tong University Afﬁliated Sixth People’s HospitalShanghai 200000China

Sclerostin, a protein secreted from osteocytes, negatively regulates the WNT signaling pathway by binding to the LRP5/6 co-receptors and further inhibits bone formation and promotes bone resorption. Sclerostin contributes to musculoskeletal system-related diseases, making it a promising therapeutic target for the treatment of WNT-related bone diseases. Additionally, emerging evidence indicates that sclerostin contributes to the development of cancers, obesity, and diabetes, suggesting that it may be a promising therapeutic target for these diseases. Notably, cardiovascular diseases are related to the protective role of sclerostin. In this review, we summarize three distinct types of inhibitors targeting sclerostin, monoclonal antibodies, aptamers, and small-molecule inhibitors, from which monoclonal antibodies have been developed. As the first-in-class sclerostin inhibitor approved by the U.S. FDA,the monoclonal antibody romosozumab has demonstrated excellent effectiveness in the treatment of postmenopausal osteoporosis;however, it conferred high cardiovascular risk in clinical trials. Furthermore,romosozumab could only be administered by injection, which may cause compliance issues for patients who prefer oral therapy. Considering these above safety and compliance concerns, we therefore present relevant discussion and offer perspectives on the development of next-generation sclerostin inhibitors by following several ways, such as concomitant medication, artificial intelligence-based strategy, druggable modification, and bispecific inhibitors strategy.

关键词： Sclerostin WNT signalling pathway Sclerostin inhibitors Antibody Bone diseases Aptamer small molecule inhibitors Artificial intelligence

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Therapeutic strategies of glioblastoma (GBM):The current advances in the molecular targets and bioactive small molecule compounds

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Acta Pharmaceutica Sinica B 2022年第4期12卷 1781-1804页

作者： Hui Liu Weimin Qiu Tianyu Sun Lei Wang Chenxi Du Yanyu Hu Wenyuan Liu Feng Feng Yao Chen Haopeng Sun School of Pharmacy China Pharmaceutical UniversityNanjing 211198China School of Pharmacy Nanjing University of Chinese MedicineNanjing 210023China Jiangsu Drug Development Engineering Research Center for Central Degenerative Disease Jiangsu Food and Pharmaceuticals Science CollegeHuaian 223005China Department of Natural Medicinal Chemistry China Pharmaceutical UniversityNanjing 211198China Department of Pharmaceutical Analysis Key Laboratory of Drug Quality Control and PharmacovigilanceChina Pharmaceutical UniversityNanjing 211198China

Glioblastoma(GBM)is the most common aggressive malignant tumor in brain neuroepithelial tumors and remains incurable.A variety of treatment options are currently being explored to improve patient survival,including small molecule inhibitors,viral therapies,cancer vaccines,and monoclonal antibodies.Among them,the unique advantages of small molecule inhibitors have made them a focus of attention in the drug discovery of glioblastoma.Currently,the most used chemotherapeutic agents are small molecule inhibitors that target key dysregulated signaling pathways in glioblastoma,including receptor tyrosine kinase,PI3K/AKT/mTOR pathway,DNA damage response,TP53 and cell cycle inhibitors.This review analyzes the therapeutic benefit and clinical development of novel small molecule inhibitors discovered as promising anti-glioblastoma agents by the related targets of these major pathways.Meanwhile,the recent advances in temozolomide resistance and drug combination are also reviewed.In the last part,due to the constant clinical failure of targeted therapies,this paper reviewed the research progress of other therapeutic methods for glioblastoma,to provide patients and readers with a more comprehensive understanding of the treatment landscape of glioblastoma.

关键词： Glioblastoma small molecule inhibitors Targeted therapy Clinical trials Temozolomide Combination therapy

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Modulation of protein fate decision by small molecules:targeting molecular chaperone machinery

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Acta Pharmaceutica Sinica B 2020年第10期10卷 1904-1925页

作者： Lei Wang Xiaoli Xu Zhengyu Jiang Qidong You State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization China Pharmaceutical UniversityNanjing 210009China Department of Medicinal Chemistry School of PharmacyChina Pharmaceutical UniversityNanjing 210009China

Modulation of protein fate decision and protein homeostasis plays a significant role in altering the protein level,which acts as an orientation to develop drugs with new mechanisms.The molecular chaperones exert significant biological functions on modulation of protein fate decision and protein homeostasis under constantly changing environmental conditions through extensive protein-protein interactions(PPIs)with their client proteins.With the help of molecular chaperone machinery the processes of protein folding,trafficking,quality control and degradation of client proteins could be arranged properly.The core members of molecular chaperones,including heat shock proteins(HSPs)family and their co-chaperones,are emerging as potential drug targets since they are involved in numerous disease conditions.Development of small molecule modulators targeting not only chaperones themselves but also the PPIs among chaperones,co-chaperones and clients is attracting more and more attention.These modulators are widely used as chemical tools to study chaperone networks as well as potential drug candidates for a broader set of diseases.Here,we reviewed the key checkpoints of molecular chaperone machinery HSPs as well as their co-chaperones to discuss the small molecules targeting on them for modulation of protein fate decision.

关键词： Molecular chaperone Heat shock protein family small molecule inhibitors Protein fate Protein-protein interaction

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Anticancer drug discovery by targeting cullin neddylation

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Acta Pharmaceutica Sinica B 2020年第5期10卷 746-765页

作者： Qing Yu Yihan Jiang Yi Sun Cancer Institute of the 2nd Affiliated Hospital Institute of Translational MedicineZhejiang University School of MedicineHangzhou 310029China Division of Radiation and Cancer Biology Department of Radiation OncologyUniversity of MichiganAnn ArborMI 48109.USA

Protein neddylation is a post-translational modification which transfers the ubiquitin-like protein NEDD8 to a lysine residue of the target substrate through a three-step enzymatic cascade.The bestknown substrates of neddylation are cullin family proteins,which are the core component of Cullin-RING E3 ubiquitin ligases(CRLs).Given that cullin neddylation is required for CRL activity,and CRLs control the turn-over of a variety of key signal proteins and are often abnormally activated in cancers,targeting neddylation becomes a promising approach for discovery of novel anti-cancer therapeutics.In the past decade,we have witnessed significant progress in the field of protein neddylation from preclinical target validation,to drug screening,then to the clinical trials of neddylation inhibitors.In this review,we first briefly introduced the nature of protein neddylation and the regulation of neddylation cascade,followed by a summary of all reported chemical inhibitors of neddylation enzymes.We then discussed the structure-based targeting of protein-protein interaction in neddylation cascade,and finally the available approaches for the discovery of new neddylation inhibitors.This review will provide a focused,up-to-date and yet comprehensive overview on the discovery effort of neddylation inhibitors.

关键词： Neddylation Anticancer Drug discovery Ubiquitin-proteasome system small molecule inhibitors Virtual screen High-throughput screening

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Therapeutic potential of TNFa inhibitors in chronic inflammatory disorders:Past and future

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Genes & Diseases 2021年第1期8卷 38-47页

作者： future Hongtao Zhang Nelson Shi Zhuo Diao Youhai Chen Yejia Zhang Department of Pathology and Laboratory Medicine Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPAUSA Department of Orthopaedic Surgery Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPAUSA Department of Physical Medicine&Rehabilitation Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPAUSA Translational Musculoskeletal Research Center(TMRC) Corporal Michael J.Crescenz Veterans Affairs Medical CenterPhiladelphiaPAUSA

In the past 20 years,patients with rheumatoid arthritis(RA),Crohn’s disease(CD),and other immune diseases have witnessed the impact of a great treatment advance with the availability of biological TNFa inhibitors.With 5 approved anti-TNFa biologics on the market and soon available biosimilars,patients have more treatment options and have benefited from understanding the biology of TNFa.Nevertheless,many unmet needs remain for people living with TNFa-related diseases,namely some side effects and tolerance of current anti-TNFa biologics and resistance to therapies.Furthermore,common diseases such as osteoarthritis and back/neck pain may respond to anti-TNFa therapies at early onset of symptoms.Development of new TNFa inhibitors focusing on TNFR1 specific inhibitors,preferably small molecules that can be delivered orally,is much needed.

关键词： Antibodies Receptors small molecule inhibitors TNFa TNFR1

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Kinases and glutathione transferases:selective and sensitive targeting

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Frontiers in Biology 2011年第2期6卷 156-169页

作者： Yasemin G.ISGOR Belgin S.ISGOR Chemistry Group Faculty of EngineeringAtilim UniversityAnkara 06836Turkey

Kinases,representing almost 500 proteins in the human genome,are responsible for catalyzing the phosphorylation reaction of amino acid residues at their targets.As the largest family of kinases,the protein tyrosine kinases(PTKs)have roles in controlling the essential cellular activities,and their deregulation is generally related to pathologic conditions.The recent efforts on identifying their signal transducer or mediator role in cellular signaling revealed the interaction of PTKs with numerous enzymes of different classes,such as Ser/Thr kinases(STKs),glutathione transferases(GSTs),and receptor tyrosine kinases(RTKs).In either regulation or enhancing the signaling,PTKs are determined in close interaction with these enzymes,under specific cellular conditions,such as oxidative stress and inflammation.In this concept,intensive research on thiol metabolizing enzymes recently showed their involvement in the physiologic functions in cellular signaling besides their well known traditional role in antioxidant defense.The shared signaling components between PTK and GST family enzymes will be discussed in depth in this research review to evaluate the results of recent studies important in drug targeting for therapeutic intervention,such as cell viability,migration,differentiation and proliferation.

关键词： glutathione transferase protein tyrosine kinase small molecule inhibitors c-Src signal transduction drug targeting

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Study on ribosome rescue pathway in Mycobacterium tuberculosis and development of new anti-tuberculosis drugs

Study on ribosome rescue pathway in Mycobacterium tuberculos...

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2017中国长三角遗传学大会

Bacteria require at least one pathway to rescue ribosomes stalled at the end of mRNAs.The primary pathway is trans-translation,which is conserved in >99%of sequenced bacterial genomes.Some species also have backup systems,such as ArfA or ArfB,which can rescue ribosomes in the absence of sufficient trans-translation activity.But whether there are backup systems in Mycobacterium tuberculosis have not been shown to date.Thus,we would like to detect the existence of these systems by knocking out smpB,a critical gene in regulating trans-translation.In addition,small molecule inhibitors of ribosome rescue such as KKL-10,which have broadspectrum antimicrobial activity against bacteria growth in liquid culture,were screened by high-throughput screen and secondary screening assays in Escherichia coli.To explore the trans-translation as a target for antibiotic development of Mycobacterium tuberculosis with these inhibitors,we would use these compounds to test against both attenuated and fully virulent strains of Mycobacterium Tuberculosis in vitro and during ex vivo infection.And we will perform a cytotoxicity assay using cultured cells such as HepG2 to examine the cytotoxicity of these inhibitors.These inhibitors are expected to develop into a new target drug for the treatment of tuberculosis.

关键词： Mycobacterium Tuberculosis trans-translation SmpB small molecule inhibitors

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