Studies in the past few years have provided compelling evidence for the critical role of aberrant Signal Transducer and Activator of Transcription 3 （STAT3） in malignant transformation and tumorigenesis. Thus, it is...Studies in the past few years have provided compelling evidence for the critical role of aberrant Signal Transducer and Activator of Transcription 3 （STAT3） in malignant transformation and tumorigenesis. Thus, it is now generally accepted that STAT3 is one of the critical players in human cancer formation and represents a valid target for novel anticancer drug design. This review focuses on aberrant STAT3 and its role in promoting tumor cell survival and sup- porting the malignant phenotype. A brief evaluation of the current strategies targeting STAT3 for the development of novel anticancer agents against human tumors harboring constitutively active STAT3 will also be presented.展开更多
Autophagy,defined as a scavenging process of protein aggregates and damaged organelles mediated by lysosomes,plays a significant role in the quality control of macromolecules and organelles.Since protein kinases are i...Autophagy,defined as a scavenging process of protein aggregates and damaged organelles mediated by lysosomes,plays a significant role in the quality control of macromolecules and organelles.Since protein kinases are integral to the autophagy process,it is critically important to understand the role of kinases in autophagic regulation.At present,intervention of autophagic processes by small-molecule modulators targeting specific kinases has becoming a reasonable and prevalent strategy for treating several varieties of human disease,especially cancer.In this review,we describe the role of some autophagy-related kinase targets and kinase-mediated phosphorylation mechanisms in autophagy regulation.We also summarize the small-molecule kinase inhibitors/activators of these targets,highlighting the opportunities of these new therapeutic agents.展开更多
Ovarian cancer is the leading cause of death in women with gynecological cancer. Most patients are diagnosed at an advanced stage and have a poor prognosis.Currently, surgical tumor debulking, followed by platinum- an...Ovarian cancer is the leading cause of death in women with gynecological cancer. Most patients are diagnosed at an advanced stage and have a poor prognosis.Currently, surgical tumor debulking, followed by platinum- and taxane-based chemotherapy is the standard treatment for advanced ovarian cancer. However, these patients are at great risk of recurrence and emerging drug resistance. Therefore, novel treatment strategies are required to improve outcomes for women with advanced ovarian cancer. A variety of molecular targeted agents, the majority of which are monoclonal antibodies and small-molecule protein-kinase inhibitors, have been explored in the management of ovarian cancer. The targets of these agents include angiogenesis, the human epidermal growth factor receptor family, ubiquitinproteasome pathway, epigenetic modulators, poly(ADPribose) polymerase (PARP), and mammalian target of rapamycin (mTOR) signaling pathway, which are aberrant in tumor tissue. The antiangiogenic agent, bevacizumab, has been reported as the most effective targeted agent and should be included in the standard chemotherapeutic regimen for advanced ovarian cancer. PARP inhibitors, which are mainly used in breast and ovarian cancer susceptibility gene-mutated patients, and mTOR inhibitors are also attractive treatment strategies, either alone or combination with chemotherapy, for ovarian cancer. Understanding the tumor molecular biology and identification of predictive biomarkers are essential steps for selection of the best treatment strategies. This article reviews the molecular mechanisms of the most promising targeted agents that are under early phase clinical evaluation for ovarian cancer.展开更多
Parkinson’s disease(PD),known as one of the most universal neurodegenerative diseases,is a serious threat to the health of the elderly.The current treatment has been demonstrated to relieve symptoms,and the discovery...Parkinson’s disease(PD),known as one of the most universal neurodegenerative diseases,is a serious threat to the health of the elderly.The current treatment has been demonstrated to relieve symptoms,and the discovery of new small-molecule compounds has been regarded as a promising strategy.Of note,the homeostasis of the autolysosome pathway(ALP)is closely associated with PD,and impaired autophagy may cause the death of neurons and thereby accelerating the progress of PD.Thus,pharmacological targeting autophagy with small-molecule compounds has been drawn a rising attention so far.In this review,we focus on summarizing several autophagy-associated targets,such as AMPK,m TORC1,ULK1,IMPase,LRRK2,beclin-1,TFEB,GCase,ERRα,C-Abelson,and as well as their relevant small-molecule compounds in PD models,which will shed light on a clue on exploiting more potential targeted small-molecule drugs tracking PD treatment in the near future.展开更多
With the development of modern industry,global warming is becoming a challenging issue due to the emissions of large quantities of greenhouse gases,mainly carbon dioxide(CO_(2)).The conversion of CO_(2)to useful compo...With the development of modern industry,global warming is becoming a challenging issue due to the emissions of large quantities of greenhouse gases,mainly carbon dioxide(CO_(2)).The conversion of CO_(2)to useful compounds is considered as an effective and economic way to solve such a climate problem.Metal-organic frameworks(MOFs)are an emerging class of porous crystalline materials that have shown great potential in the conversion of CO_(2).The advantages of MOFs in CO 2 conversion lie in their high surface areas,adjustable pore size,and high porosity.More importantly,desirable functional sites can be easily designed and precisely installed to the pore wall of target MOFs by pre-assembly and/or post-synthetic modification(PSM)ways.This review summarizes the recent advances in constructing MOF catalysts for the application in CO_(2)conversion.We believe that the design and synthesis of MOF catalysts for CO_(2)conversion can be a promising way to solve the“greenhouse effect”.展开更多
A new acceptor-donor-acceptor(A-D-A) type small-molecule acceptor NCBDT-4 Cl using chlorinated end groups is reported.This new-designed molecule demonstrates wide and efficient absorption ability in the range of 600–...A new acceptor-donor-acceptor(A-D-A) type small-molecule acceptor NCBDT-4 Cl using chlorinated end groups is reported.This new-designed molecule demonstrates wide and efficient absorption ability in the range of 600–900 nm with a narrow optical bandgap of 1.40 eV. The device based on PBDB-T-SF:NCBDT-4 Cl shows a power conversion efficiency(PCE) of 13.1%without any post-treatment, which represents the best result for all as-cast organic solar cells(OSCs) to date. After device optimizations, the PCE was further enhanced to over 14% with a high short-circuit current density(Jsc) of 22.35 m A cm-2 and a fill-factor(FF) of 74.3%. The improved performance was attributed to the more efficient photo-electron conversion process in the optimal device. To our knowledge, this outstanding efficiency of 14.1% with an energy loss as low as 0.55 eV is among the best results for all single-junction OSCs.展开更多
Tropomyosin receptor kinase A,B and C(TRKA,TRKB and TRKC),which are well-known members of the cell surface receptor tyrosine kinase(RTK)family,are encoded by the neurotrophic receptor tyrosine kinase 1,2 and 3(NTRK1,N...Tropomyosin receptor kinase A,B and C(TRKA,TRKB and TRKC),which are well-known members of the cell surface receptor tyrosine kinase(RTK)family,are encoded by the neurotrophic receptor tyrosine kinase 1,2 and 3(NTRK1,NTRK2 and NTRK3)genes,respectively.TRKs can regulate cell proliferation,differentiation and even apoptosis through the RAS/MAPKs,PI3 K/AKT and PLCγtyrosine kinase fusions;Small-molecule inhibitor;NTRK fusion cancer pathways.Gene fusions involving NTRK act as oncogenic drivers of a broad diversity of adult and pediatric tumors,and TRKs have become promising antitumor targets.Therefore,achieving a comprehensive understanding of TRKs and relevant TRK inhibitors should be urgently pursued for the further development of novel TRK inhibitors for potential clinical applications.This review focuses on summarizing the biological functions of TRKs and NTRK fusion proteins,the development of small-molecule TRK inhibitors with different chemotypes and their activity and selectivity,and the potential therapeutic applications of these inhibitors for future cancer drug discovery efforts.展开更多
UNC-51-like kinase 1(ULK1),as a serine/threonine kinase,is an autophagic initiator in mammals and a homologous protein of autophagy related protein(Atg)1 in yeast and of UNC-51 in Caenorhabditis elegans.ULK1 is well-k...UNC-51-like kinase 1(ULK1),as a serine/threonine kinase,is an autophagic initiator in mammals and a homologous protein of autophagy related protein(Atg)1 in yeast and of UNC-51 in Caenorhabditis elegans.ULK1 is well-known for autophagy activation,which is evolutionarily conserved in protein transport and indispensable to maintain cell homeostasis.As the direct target of energy and nutrition-sensing kinase,ULK1 may contribute to the distribution and utilization of cellular resources in response to metabolism and is closely associated with multiple pathophysiological processes.Moreover,ULK1 has been widely reported to play a crucial role in human diseases,including cancer,neurodegenerative diseases,cardiovascular disease,and infections,and subsequently targeted small-molecule inhibitors or activators are also demonstrated.Interestingly,the non-autophagy function of ULK1 has been emerging,indicating that non-autophagy-relevant ULK1 signaling network is also linked with diseases under some specific contexts.Therefore,in this review,we summarized the structure and functions of ULK1 as an autophagic initiator,with a focus on some new approaches,and further elucidated the key roles of ULK1 in autophagy and non-autophagy.Additionally,we also discussed the relationships between ULK1 and human diseases,as well as illustrated a rapid progress for better understanding of the discovery of more candidate small-molecule drugs targeting ULK1,which will provide a clue on novel ULK1-targeted therapeutics in the future.展开更多
Recently,solution-processed organic solar cells combining small-molecule donor and nonfullerene acceptor have achieved breakthrough results with the certified efficiency over 15%.These impressive progresses are driven...Recently,solution-processed organic solar cells combining small-molecule donor and nonfullerene acceptor have achieved breakthrough results with the certified efficiency over 15%.These impressive progresses are driven by the concerted efforts of modifying the donor and acceptor materials and optimizing the morphology.Considering the defined chemical structures and easily tuned properties of small-molecule materials,it is of great necessity and importance to pay more attentions on the topic of all-small molecule organic solar cells.Here,we summarize the recent progress of all-small molecule organic solar cells from the prospect of materials'evolutions and expect to provide some hints for its future developments.The involved small-molecule donors including oligothiophene-,benzodithiophene-,naphthodithiophene-,and porphyrin-based materials are discussed to illustrate the relationship of chemical structures,properties,and device performance.Then,the small-molecule nonfullerene acceptors in all-small molecules organic solar cells are discussed to highlight their vital role.Finally,we will present the challenges and future of this research area.展开更多
Sirtuins(SIRTs) are nicotinamide adenine dinucleotide(NAD^+)-dependent protein deacetylases,which regulate important biological processes ranging from apoptosis,age-associated pathophysiologies,adipocyte and muscle di...Sirtuins(SIRTs) are nicotinamide adenine dinucleotide(NAD^+)-dependent protein deacetylases,which regulate important biological processes ranging from apoptosis,age-associated pathophysiologies,adipocyte and muscle differentiation,and energy expenditure to gluconeogenesis.Very recently,sirtuin 5(SIRT5) has received considerable attention due to that it was found to have weak deacetylase activity but strong desuccinylase,demalonylase and deglutarylase activities,and it was also found to be associated with several human diseases such as cancer,Alzheimer's disease,and Parkinson's disease.In this review,we for the first time summarized the structure characteristics,known peptide and small-molecule inhibitors of SIRT5,extracted some clues from current available information and introduced some feasible,practical in silico methods,which might be useful in further efforts to develop new SIRT5 inhibitors.展开更多
Developing high‐performance adhesive materials not only aims at industrial and social requirements but also bears the fundamental importance of understanding the chemical factors of biological adhesion to develop bio...Developing high‐performance adhesive materials not only aims at industrial and social requirements but also bears the fundamental importance of understanding the chemical factors of biological adhesion to develop biomimetic adhesive materials.Owing to the wide development of supramolecular chemistry,numerous supramolecular tools are exploited and proved to be reliable in the replacement of traditional covalent materials by reversible noncovalent or dynamic covalent materials.Taking advantage of these readyto‐use supramolecular toolboxes,supramolecular adhesive materials are rising and promising toward“smart”adhesives,that is,enabling responsiveness,reversibility,and recyclability.Compared with polymeric adhesive materials,low‐molecular‐weight adhesives feature chemically precise structure,easier engineering by molecular design,and hence higher reproducibility.However,it remains highly challenging to make high‐performance adhesive materials by low‐molecular‐weight feedstocks.This review will focus on the recent advancement in the construction of supramolecular adhesive materials by smallmolecule self‐assembly.The design guidelines and consideration on the molecular scale will be discussed and summarized on how to enhance the strength of adhesives.Meanwhile,owing to the dynamic nature of supramolecular self‐assembly,several“smart”functions of such materials will be presented,such as stimuli–responsiveness and adaptiveness.Finally,current challenges and future perspectives of this emerging field will be proposed.展开更多
CD36 is a highly glycosylated integral membrane protein that belongs to the scavenger receptor class B family and regulates the pathological progress of metabolic diseases.CD36 was recently found to be widely expresse...CD36 is a highly glycosylated integral membrane protein that belongs to the scavenger receptor class B family and regulates the pathological progress of metabolic diseases.CD36 was recently found to be widely expressed in various cell types in the nervous system,including endothelial cells,pericytes,astrocytes,and microglia.CD36 mediates a number of regulatory processes,such as endothelial dysfunction,oxidative stress,mitochondrial dysfunction,and inflammatory responses,which are involved in many central nervous system diseases,such as stroke,Alzheimer’s disease,Parkinson’s disease,and spinal cord injury.CD36 antagonists can suppress CD36 expression or prevent CD36 binding to its ligand,thereby achieving inhibition of CD36-mediated pathways or functions.Here,we reviewed the mechanisms of action of CD36 antagonists,such as Salvianolic acid B,tanshinone IIA,curcumin,sulfosuccinimidyl oleate,antioxidants,and small-molecule compounds.Moreover,we predicted the structures of binding sites between CD36 and antagonists.These sites can provide targets for more efficient and safer CD36 antagonists for the treatment of central nervous system diseases.展开更多
Small-molecule organic electrode materials(SMOEMs)have shown tremendous potential as cathodes or anodes for various rechargeable batteries including lithium and sodium batteries,due to their easy material availability...Small-molecule organic electrode materials(SMOEMs)have shown tremendous potential as cathodes or anodes for various rechargeable batteries including lithium and sodium batteries,due to their easy material availability,high structure designability,attractive theoretical capacity,and wide adaptability to counterions.However,they suffer from the severe dissolution problem and the subsequent shuttle effect in nonaqueous electrolytes,which cause the poor cycling stability and Coulombic efficiency.To satisfy the demands on the energy density and cycling stability simultaneously,the molecular structures of SMOEMs need to be rationally designed,and extrinsic approaches including electrode engineering and electrolyte optimizations can be further conducted.In this review,we summarize the fundamental knowledge about SMOEMs,including their working principles and applications,structure classifications,molecular structure design methods,and extrinsic optimization strategies.Moreover,we also provide some original insights aiming at guiding the research and development of SMOEMs in a more scientific and practical way.In brief,SMOEMs are facing huge opportunities and challenges as candidates to enable the next-generation of efficient,sustainable,and green rechargeable batteries.展开更多
The COVID-19 pandemic caused by the novel SARS-CoV-2 virus has caused havoc across the entire world.Even though several COVID-19 vaccines are currently in distribution worldwide,with others in the pipeline,treatment m...The COVID-19 pandemic caused by the novel SARS-CoV-2 virus has caused havoc across the entire world.Even though several COVID-19 vaccines are currently in distribution worldwide,with others in the pipeline,treatment modalities lag behind.Accordingly,researchers have been working hard to understand the nature of the virus,its mutant strains,and the pathogenesis of the disease in order to uncover possible drug targets and effective therapeutic agents.As the research continues,we now know the genome structure,epidemiological and clinical features,and pathogenic mechanism of SARS-CoV-2.Here,we summarized the potential therapeutic targets involved in the life cycle of the virus.On the basis of these targets,small-molecule prophylactic and therapeutic agents have been or are being developed for prevention and treatment of SARS-CoV-2 infection.展开更多
Aptamers are single-stranded DNA or RNA sequences that can specifically bind with the target protein or molecule via specific secondary structures.Compared to antibody-drug conjugates(ADC),aptamer-drug conjugate(ApDC)...Aptamers are single-stranded DNA or RNA sequences that can specifically bind with the target protein or molecule via specific secondary structures.Compared to antibody-drug conjugates(ADC),aptamer-drug conjugate(ApDC)is also an efficient,targeted drug for cancer therapy with a smaller size,higher chemical stability,lower immunogenicity,faster tissue penetration,and facile engineering.Despite all these advantages,several key factors have delayed the clinical translation of ApDC,such as in vivo off-target effects and potential safety issues.In this review,we highlight the most recent progress in the development of ApDC and discuss solutions to the problems noted above.展开更多
Cancer immunotherapy,exemplified by the remarkable clinical benefits of the immune checkpoint blockade and chimeric antigen receptor T-cell therapy,is revolutionizing cancer therapy.They induce long-term tumor regress...Cancer immunotherapy,exemplified by the remarkable clinical benefits of the immune checkpoint blockade and chimeric antigen receptor T-cell therapy,is revolutionizing cancer therapy.They induce long-term tumor regression and overall survival benefit in many types of cancer.With the advances in our knowledge about the tumor immune microenvironment,remarkable progress has been made in the development of small-molecule drugs for immunotherapy.Small molecules targeting PRR-associated pathways,immune checkpoints,oncogenic signaling,metabolic pathways,cytokine/chemokine signaling,and immune-related kinases have been extensively investigated.Monotherapy of smallmolecule immunotherapeutic drugs and their combinations with other antitumor modalities are under active clinical investigations to overcome immune tolerance and circumvent immune checkpoint inhibitor resistance.Here,we review the latest development of small-molecule agents for cancer immunotherapy by targeting defined pathways and highlighting their progress in recent clinical investigations.展开更多
Autophagy is a cellular process in which proteins and organelles are engulfed in autophagosomal vesicles and transported to the lysosome/vacuole for degradation.Protein–protein interactions(PPIs)play a crucial role a...Autophagy is a cellular process in which proteins and organelles are engulfed in autophagosomal vesicles and transported to the lysosome/vacuole for degradation.Protein–protein interactions(PPIs)play a crucial role at many stages of autophagy,which present formidable but attainable targets for autophagy regulation.Moreover,selective regulation of PPIs tends to have a lower risk in causing undesired off-target effects in the context of a complicated biological network.Thus,small-molecule regulators,including peptides and peptidomimetics,targeting the critical PPIs involved in autophagy provide a new opportunity for innovative drug discovery.This article provides general background knowledge of the critical PPIs involved in autophagy and reviews a range of successful attempts on discovering regulators targeting those PPIs.Successful strategies and existing limitations in this field are also discussed.展开更多
文摘Studies in the past few years have provided compelling evidence for the critical role of aberrant Signal Transducer and Activator of Transcription 3 （STAT3） in malignant transformation and tumorigenesis. Thus, it is now generally accepted that STAT3 is one of the critical players in human cancer formation and represents a valid target for novel anticancer drug design. This review focuses on aberrant STAT3 and its role in promoting tumor cell survival and sup- porting the malignant phenotype. A brief evaluation of the current strategies targeting STAT3 for the development of novel anticancer agents against human tumors harboring constitutively active STAT3 will also be presented.
基金supported by grants from National Key R&D Program of China(Grants 2017YFC0909301 and 2017YFC0909302)National Natural Science Foundation of China(Grants 81874290,81673290,81673455,81602953,and 81903502)the Opening Foundation of State Key Laboratory of Pharmaceutical Biotechnology,Nanjing University,China(Grant KF-GN-201904).
文摘Autophagy,defined as a scavenging process of protein aggregates and damaged organelles mediated by lysosomes,plays a significant role in the quality control of macromolecules and organelles.Since protein kinases are integral to the autophagy process,it is critically important to understand the role of kinases in autophagic regulation.At present,intervention of autophagic processes by small-molecule modulators targeting specific kinases has becoming a reasonable and prevalent strategy for treating several varieties of human disease,especially cancer.In this review,we describe the role of some autophagy-related kinase targets and kinase-mediated phosphorylation mechanisms in autophagy regulation.We also summarize the small-molecule kinase inhibitors/activators of these targets,highlighting the opportunities of these new therapeutic agents.
文摘Ovarian cancer is the leading cause of death in women with gynecological cancer. Most patients are diagnosed at an advanced stage and have a poor prognosis.Currently, surgical tumor debulking, followed by platinum- and taxane-based chemotherapy is the standard treatment for advanced ovarian cancer. However, these patients are at great risk of recurrence and emerging drug resistance. Therefore, novel treatment strategies are required to improve outcomes for women with advanced ovarian cancer. A variety of molecular targeted agents, the majority of which are monoclonal antibodies and small-molecule protein-kinase inhibitors, have been explored in the management of ovarian cancer. The targets of these agents include angiogenesis, the human epidermal growth factor receptor family, ubiquitinproteasome pathway, epigenetic modulators, poly(ADPribose) polymerase (PARP), and mammalian target of rapamycin (mTOR) signaling pathway, which are aberrant in tumor tissue. The antiangiogenic agent, bevacizumab, has been reported as the most effective targeted agent and should be included in the standard chemotherapeutic regimen for advanced ovarian cancer. PARP inhibitors, which are mainly used in breast and ovarian cancer susceptibility gene-mutated patients, and mTOR inhibitors are also attractive treatment strategies, either alone or combination with chemotherapy, for ovarian cancer. Understanding the tumor molecular biology and identification of predictive biomarkers are essential steps for selection of the best treatment strategies. This article reviews the molecular mechanisms of the most promising targeted agents that are under early phase clinical evaluation for ovarian cancer.
基金financially supported by National Science and Technology Major Project of the Ministry of Science and Technology of the People’s Republic of China(No.2018ZX09735005)National Natural Science Foundation of China(Grant Nos.81803755,81673455 and 81922064)+1 种基金Sichuan University Postdoctoral Research and Development Foundation(Grant No.2020SCU12062,China)Sichuan Science and Technology Program(Grant No.2019JDRC0091,China)。
文摘Parkinson’s disease(PD),known as one of the most universal neurodegenerative diseases,is a serious threat to the health of the elderly.The current treatment has been demonstrated to relieve symptoms,and the discovery of new small-molecule compounds has been regarded as a promising strategy.Of note,the homeostasis of the autolysosome pathway(ALP)is closely associated with PD,and impaired autophagy may cause the death of neurons and thereby accelerating the progress of PD.Thus,pharmacological targeting autophagy with small-molecule compounds has been drawn a rising attention so far.In this review,we focus on summarizing several autophagy-associated targets,such as AMPK,m TORC1,ULK1,IMPase,LRRK2,beclin-1,TFEB,GCase,ERRα,C-Abelson,and as well as their relevant small-molecule compounds in PD models,which will shed light on a clue on exploiting more potential targeted small-molecule drugs tracking PD treatment in the near future.
基金This work was supported by NSFC(21421001,21531005,91856124,and 21978138)the Program of Introducing Talents of Discipline to Universities(B18030),China.
文摘With the development of modern industry,global warming is becoming a challenging issue due to the emissions of large quantities of greenhouse gases,mainly carbon dioxide(CO_(2)).The conversion of CO_(2)to useful compounds is considered as an effective and economic way to solve such a climate problem.Metal-organic frameworks(MOFs)are an emerging class of porous crystalline materials that have shown great potential in the conversion of CO_(2).The advantages of MOFs in CO 2 conversion lie in their high surface areas,adjustable pore size,and high porosity.More importantly,desirable functional sites can be easily designed and precisely installed to the pore wall of target MOFs by pre-assembly and/or post-synthetic modification(PSM)ways.This review summarizes the recent advances in constructing MOF catalysts for the application in CO_(2)conversion.We believe that the design and synthesis of MOF catalysts for CO_(2)conversion can be a promising way to solve the“greenhouse effect”.
基金supported by the National Natural Science Foundation of China (91633301, 51773095)MoST of China (2014CB643502)+1 种基金Tianjin city (17JCJQJC44500, 17CZDJC31100)111 Project (B12015)
文摘A new acceptor-donor-acceptor(A-D-A) type small-molecule acceptor NCBDT-4 Cl using chlorinated end groups is reported.This new-designed molecule demonstrates wide and efficient absorption ability in the range of 600–900 nm with a narrow optical bandgap of 1.40 eV. The device based on PBDB-T-SF:NCBDT-4 Cl shows a power conversion efficiency(PCE) of 13.1%without any post-treatment, which represents the best result for all as-cast organic solar cells(OSCs) to date. After device optimizations, the PCE was further enhanced to over 14% with a high short-circuit current density(Jsc) of 22.35 m A cm-2 and a fill-factor(FF) of 74.3%. The improved performance was attributed to the more efficient photo-electron conversion process in the optimal device. To our knowledge, this outstanding efficiency of 14.1% with an energy loss as low as 0.55 eV is among the best results for all single-junction OSCs.
基金supported by grants from National Natural Science Foundation of China(Grants 81922064,81874290,81803755,and 91853109)Sichuan Science and Technology Program(Grants 2019YFSY0038 and 2019JDRC0091,China)
文摘Tropomyosin receptor kinase A,B and C(TRKA,TRKB and TRKC),which are well-known members of the cell surface receptor tyrosine kinase(RTK)family,are encoded by the neurotrophic receptor tyrosine kinase 1,2 and 3(NTRK1,NTRK2 and NTRK3)genes,respectively.TRKs can regulate cell proliferation,differentiation and even apoptosis through the RAS/MAPKs,PI3 K/AKT and PLCγtyrosine kinase fusions;Small-molecule inhibitor;NTRK fusion cancer pathways.Gene fusions involving NTRK act as oncogenic drivers of a broad diversity of adult and pediatric tumors,and TRKs have become promising antitumor targets.Therefore,achieving a comprehensive understanding of TRKs and relevant TRK inhibitors should be urgently pursued for the further development of novel TRK inhibitors for potential clinical applications.This review focuses on summarizing the biological functions of TRKs and NTRK fusion proteins,the development of small-molecule TRK inhibitors with different chemotypes and their activity and selectivity,and the potential therapeutic applications of these inhibitors for future cancer drug discovery efforts.
基金supported in part by National Natural Science Foundation of China (Grant Nos. 82172649 and 82173666)Shenzhen science and technology research and development funds (Grant No. JCYJ20210324094612035, China)the Key R&D Program of Sichuan Province (Grant No. 2021YFS0046, China)
文摘UNC-51-like kinase 1(ULK1),as a serine/threonine kinase,is an autophagic initiator in mammals and a homologous protein of autophagy related protein(Atg)1 in yeast and of UNC-51 in Caenorhabditis elegans.ULK1 is well-known for autophagy activation,which is evolutionarily conserved in protein transport and indispensable to maintain cell homeostasis.As the direct target of energy and nutrition-sensing kinase,ULK1 may contribute to the distribution and utilization of cellular resources in response to metabolism and is closely associated with multiple pathophysiological processes.Moreover,ULK1 has been widely reported to play a crucial role in human diseases,including cancer,neurodegenerative diseases,cardiovascular disease,and infections,and subsequently targeted small-molecule inhibitors or activators are also demonstrated.Interestingly,the non-autophagy function of ULK1 has been emerging,indicating that non-autophagy-relevant ULK1 signaling network is also linked with diseases under some specific contexts.Therefore,in this review,we summarized the structure and functions of ULK1 as an autophagic initiator,with a focus on some new approaches,and further elucidated the key roles of ULK1 in autophagy and non-autophagy.Additionally,we also discussed the relationships between ULK1 and human diseases,as well as illustrated a rapid progress for better understanding of the discovery of more candidate small-molecule drugs targeting ULK1,which will provide a clue on novel ULK1-targeted therapeutics in the future.
基金the financial support from the Office of Naval Research(N00014-17-1-2260 and N00014-20-1-2191).
文摘Recently,solution-processed organic solar cells combining small-molecule donor and nonfullerene acceptor have achieved breakthrough results with the certified efficiency over 15%.These impressive progresses are driven by the concerted efforts of modifying the donor and acceptor materials and optimizing the morphology.Considering the defined chemical structures and easily tuned properties of small-molecule materials,it is of great necessity and importance to pay more attentions on the topic of all-small molecule organic solar cells.Here,we summarize the recent progress of all-small molecule organic solar cells from the prospect of materials'evolutions and expect to provide some hints for its future developments.The involved small-molecule donors including oligothiophene-,benzodithiophene-,naphthodithiophene-,and porphyrin-based materials are discussed to illustrate the relationship of chemical structures,properties,and device performance.Then,the small-molecule nonfullerene acceptors in all-small molecules organic solar cells are discussed to highlight their vital role.Finally,we will present the challenges and future of this research area.
基金supported by the Chun hui of Ministry of Education Project(Z2015120)the National Natural Science Foundation of China(81502989)the China Postdoctoral Science Foundation Funded Project(2015M570789)
文摘Sirtuins(SIRTs) are nicotinamide adenine dinucleotide(NAD^+)-dependent protein deacetylases,which regulate important biological processes ranging from apoptosis,age-associated pathophysiologies,adipocyte and muscle differentiation,and energy expenditure to gluconeogenesis.Very recently,sirtuin 5(SIRT5) has received considerable attention due to that it was found to have weak deacetylase activity but strong desuccinylase,demalonylase and deglutarylase activities,and it was also found to be associated with several human diseases such as cancer,Alzheimer's disease,and Parkinson's disease.In this review,we for the first time summarized the structure characteristics,known peptide and small-molecule inhibitors of SIRT5,extracted some clues from current available information and introduced some feasible,practical in silico methods,which might be useful in further efforts to develop new SIRT5 inhibitors.
基金Shanghai Municipal Science and Technology Major Project,Grant/Award Number:2018SHZDZX03Programme of Introducing Talents of Discipline to Universities,Grant/Award Number:B16017+2 种基金Shanghai Science and Technology Committee,Grant/Award Number:17520750100National Natural Science Foundation of China,Grant/Award Numbers:21672060,21790361,21871084,22025503Program of Shanghai Academic/Technology Research Leader,Grant/Award Number:19XD1421100。
文摘Developing high‐performance adhesive materials not only aims at industrial and social requirements but also bears the fundamental importance of understanding the chemical factors of biological adhesion to develop biomimetic adhesive materials.Owing to the wide development of supramolecular chemistry,numerous supramolecular tools are exploited and proved to be reliable in the replacement of traditional covalent materials by reversible noncovalent or dynamic covalent materials.Taking advantage of these readyto‐use supramolecular toolboxes,supramolecular adhesive materials are rising and promising toward“smart”adhesives,that is,enabling responsiveness,reversibility,and recyclability.Compared with polymeric adhesive materials,low‐molecular‐weight adhesives feature chemically precise structure,easier engineering by molecular design,and hence higher reproducibility.However,it remains highly challenging to make high‐performance adhesive materials by low‐molecular‐weight feedstocks.This review will focus on the recent advancement in the construction of supramolecular adhesive materials by smallmolecule self‐assembly.The design guidelines and consideration on the molecular scale will be discussed and summarized on how to enhance the strength of adhesives.Meanwhile,owing to the dynamic nature of supramolecular self‐assembly,several“smart”functions of such materials will be presented,such as stimuli–responsiveness and adaptiveness.Finally,current challenges and future perspectives of this emerging field will be proposed.
基金supported by the National Major Project of Research and Development,No.2022YFA1105500(to SZ)the National Natural Science Foundation of China,No.81870975(to SZ)Innovation Program for Graduate Students in Jiangsu Province of China,No.KYCX223335(to MZ)。
文摘CD36 is a highly glycosylated integral membrane protein that belongs to the scavenger receptor class B family and regulates the pathological progress of metabolic diseases.CD36 was recently found to be widely expressed in various cell types in the nervous system,including endothelial cells,pericytes,astrocytes,and microglia.CD36 mediates a number of regulatory processes,such as endothelial dysfunction,oxidative stress,mitochondrial dysfunction,and inflammatory responses,which are involved in many central nervous system diseases,such as stroke,Alzheimer’s disease,Parkinson’s disease,and spinal cord injury.CD36 antagonists can suppress CD36 expression or prevent CD36 binding to its ligand,thereby achieving inhibition of CD36-mediated pathways or functions.Here,we reviewed the mechanisms of action of CD36 antagonists,such as Salvianolic acid B,tanshinone IIA,curcumin,sulfosuccinimidyl oleate,antioxidants,and small-molecule compounds.Moreover,we predicted the structures of binding sites between CD36 and antagonists.These sites can provide targets for more efficient and safer CD36 antagonists for the treatment of central nervous system diseases.
基金financially supported from the National Natural Science Foundation of China(21975189 and 22179102)the National Key Research and Development Program of China(2022YFB2402201)the Recruitment Program for Young Professionals。
文摘Small-molecule organic electrode materials(SMOEMs)have shown tremendous potential as cathodes or anodes for various rechargeable batteries including lithium and sodium batteries,due to their easy material availability,high structure designability,attractive theoretical capacity,and wide adaptability to counterions.However,they suffer from the severe dissolution problem and the subsequent shuttle effect in nonaqueous electrolytes,which cause the poor cycling stability and Coulombic efficiency.To satisfy the demands on the energy density and cycling stability simultaneously,the molecular structures of SMOEMs need to be rationally designed,and extrinsic approaches including electrode engineering and electrolyte optimizations can be further conducted.In this review,we summarize the fundamental knowledge about SMOEMs,including their working principles and applications,structure classifications,molecular structure design methods,and extrinsic optimization strategies.Moreover,we also provide some original insights aiming at guiding the research and development of SMOEMs in a more scientific and practical way.In brief,SMOEMs are facing huge opportunities and challenges as candidates to enable the next-generation of efficient,sustainable,and green rechargeable batteries.
基金This work was supported by grants from the National Natural Science Foundation of China(81974302 and 82041025)the Program for“333 Talents Project”of Hebei Province(A202002003,China)Science and Technology Project of Hebei Education Department(QN2021071,China).
文摘The COVID-19 pandemic caused by the novel SARS-CoV-2 virus has caused havoc across the entire world.Even though several COVID-19 vaccines are currently in distribution worldwide,with others in the pipeline,treatment modalities lag behind.Accordingly,researchers have been working hard to understand the nature of the virus,its mutant strains,and the pathogenesis of the disease in order to uncover possible drug targets and effective therapeutic agents.As the research continues,we now know the genome structure,epidemiological and clinical features,and pathogenic mechanism of SARS-CoV-2.Here,we summarized the potential therapeutic targets involved in the life cycle of the virus.On the basis of these targets,small-molecule prophylactic and therapeutic agents have been or are being developed for prevention and treatment of SARS-CoV-2 infection.
基金supported by the Zhejiang Provincial Natural Science Foundation of China(No.Y21C050001,China)Zhejiang Provincial Research Center for Diagnosis and Treatment of Major Diseases(No.JBZX-202003,China)+2 种基金the National Natural Science Foundation of China(Nos.22104132 and 22204144)the Zhejiang Province“Kunpeng”Program。
文摘Aptamers are single-stranded DNA or RNA sequences that can specifically bind with the target protein or molecule via specific secondary structures.Compared to antibody-drug conjugates(ADC),aptamer-drug conjugate(ApDC)is also an efficient,targeted drug for cancer therapy with a smaller size,higher chemical stability,lower immunogenicity,faster tissue penetration,and facile engineering.Despite all these advantages,several key factors have delayed the clinical translation of ApDC,such as in vivo off-target effects and potential safety issues.In this review,we highlight the most recent progress in the development of ApDC and discuss solutions to the problems noted above.
基金supported by the National Natural Science Foundation of China(Nos.U21A20421,82073882,82073317,81772540 and 82272996)the Key Project of Science Technology Program of Guangzhou(No.2023B03J0029,China)+1 种基金the National Key R&D Program of China(No.2022YFE0209700)the Science and Technology Program of Guangzhou(Nos.202201010819 and 202206010081,China)。
文摘Cancer immunotherapy,exemplified by the remarkable clinical benefits of the immune checkpoint blockade and chimeric antigen receptor T-cell therapy,is revolutionizing cancer therapy.They induce long-term tumor regression and overall survival benefit in many types of cancer.With the advances in our knowledge about the tumor immune microenvironment,remarkable progress has been made in the development of small-molecule drugs for immunotherapy.Small molecules targeting PRR-associated pathways,immune checkpoints,oncogenic signaling,metabolic pathways,cytokine/chemokine signaling,and immune-related kinases have been extensively investigated.Monotherapy of smallmolecule immunotherapeutic drugs and their combinations with other antitumor modalities are under active clinical investigations to overcome immune tolerance and circumvent immune checkpoint inhibitor resistance.Here,we review the latest development of small-molecule agents for cancer immunotherapy by targeting defined pathways and highlighting their progress in recent clinical investigations.
基金supports by the National Natural Science Foundation of China (Grant Nos.81725022,82173739,81430083,21661162003,21472227)the Ministry of Science and Technology of China (Grant No.2016YFA0502302)Science and Technology Commission of Shanghai Municipality (Grant No.20S11900500,China).
文摘Autophagy is a cellular process in which proteins and organelles are engulfed in autophagosomal vesicles and transported to the lysosome/vacuole for degradation.Protein–protein interactions(PPIs)play a crucial role at many stages of autophagy,which present formidable but attainable targets for autophagy regulation.Moreover,selective regulation of PPIs tends to have a lower risk in causing undesired off-target effects in the context of a complicated biological network.Thus,small-molecule regulators,including peptides and peptidomimetics,targeting the critical PPIs involved in autophagy provide a new opportunity for innovative drug discovery.This article provides general background knowledge of the critical PPIs involved in autophagy and reviews a range of successful attempts on discovering regulators targeting those PPIs.Successful strategies and existing limitations in this field are also discussed.
