Small molecule inhibitors have dominated the pharmaceutical landscape for a long time as the primary therapeutic paradigm targeting pathogenic proteins.However,their efficacy heavily relies on the amino acid compositi...Small molecule inhibitors have dominated the pharmaceutical landscape for a long time as the primary therapeutic paradigm targeting pathogenic proteins.However,their efficacy heavily relies on the amino acid composition and spatial constitution of proteins,rendering them susceptible to drug resistance and failing to target undruggable proteins.In recent years,the advent of targeted protein degradation(TPD)technology has captured substantial attention from both industry and academia.Employing an event-driven mode,TPD offers a novel approach to eliminate pathogenic proteins by promoting their degrada-tion,thus circumventing the limitations associated with traditional small molecule inhibitors.Hydropho-bic tag tethering degrader(HyTTD)technology represents one such TPD approach that is currently in the burgeoning stage.HyTTDs employ endogenous protein degradation systems to induce the degrada-tion of target proteins through the proteasome pathway,which displays significant potential for medical value.In this review,we provide a comprehensive overview of the development history and the reported mechanism of action of HyTTDs.Additionally,we delve into the physiological roles,structure-activity re-lationships,and medical implications of HyTTDs targeting various disease-associated proteins.Moreover,we propose insights into the challenges that necessitate resolution for the successful development of HyTTDs,with the ultimate goal of initiating a new age of clinical treatment leveraging the immense po-tential of HyTTDs.展开更多
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...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.展开更多
PrPSc,a misfolded,aggregation-prone isoform of the cellular prion protein(PrPC),is the infectious prion agent responsible for fatal neurodegenerative diseases of humans and other mammals.PrPSccan adopt different patho...PrPSc,a misfolded,aggregation-prone isoform of the cellular prion protein(PrPC),is the infectious prion agent responsible for fatal neurodegenerative diseases of humans and other mammals.PrPSccan adopt different pathogenic conformations(prion strains),which can be resistant to potential drugs,or acquire drug resistance,posing challenges for the development of effective therapies.Since PrPCis the obligate precursor of any prion strain and serves as the mediator of prion neurotoxicity,it represents an attractive therapeutic target fo r prion diseases.In this minireview,we briefly outline the approaches to target PrPCand discuss our recent identification of Zn(Ⅱ)-Bn PyP,a PrPC-targeting porphyrin with an unprecedented bimodal mechanism of action.We argue that in-depth understanding of the molecular mechanism by which Zn(Ⅱ)-Bn PyP targets PrPCmay lead toward the development of a new class of dual mechanism anti-prion compounds.展开更多
Hexokinase 2(HK2)is the rate-limiting enzyme in the first step of glycolysis,catalyzing glucose to glucose-6-phosphate,and overexpressed in most cancer cells.HK2 also binds to voltage-dependent anion channel(VDAC)to s...Hexokinase 2(HK2)is the rate-limiting enzyme in the first step of glycolysis,catalyzing glucose to glucose-6-phosphate,and overexpressed in most cancer cells.HK2 also binds to voltage-dependent anion channel(VDAC)to stabilize the mitochondrial outer membrane,which inhibits cancer cell apoptosis.Therefore,HK2 has become a potential target for cancer treatment.Proteolysis targeting chimeras(PROTACs)are hetero-bifunctional molecules that recruit an E3 ubiquitin ligase to a given substrate protein resulting in its targeted degradation.Many potent and specific PROTACs targeting dissimilar targets have been developed.In this study,an HK2 PROTAC,4H-5P-M,was developed and induced the degradation of HK2 relying on the ubiquitin-proteasome system.It was found that 4H-5P-M as an effective HK2 degrader induced HK2 degradation in a dose-and time-dependent manner and suppressed the growth of SW480 cells.4H-5P-M selectively induced HK2 degradation at a lower concentration than other hexokinase isozymes.Moreover,it could suppress glycolysis and accelerate the apoptosis of cancer cells.Therefore,it provided a new insight into the development of anti-tumor drugs.展开更多
The proton beam energy determines the range of particles and thus where the dose is deposited. According to the depth of tumors, an energy degrader is needed to modulate the proton beam energy in proton therapy facili...The proton beam energy determines the range of particles and thus where the dose is deposited. According to the depth of tumors, an energy degrader is needed to modulate the proton beam energy in proton therapy facilities based on cyclotrons, because the energy of beam extracted from the cyclotron is fixed. The energy loss was simulated for the graphite degrader used in the beamline at the superconducting cyclotron of 200 MeV in Hefei(SC200). After adjusting the mean excitation energy of the graphite used in the degrader to 76 eV, we observed an accurate match between the simulations and measurements.We also simulated the energy spread of the degraded beam and the transmission of the degrader using theoretical formulae. The results agree well with the Monte Carlo simulation.展开更多
Triple-negative breast cancer(TNBC)is a nasty disease with extremely high malignancy and poor prognosis.Annexin A3(ANXA3)is a potential prognosis biomarker,displaying an excellent correlation of ANXA3 overexpression w...Triple-negative breast cancer(TNBC)is a nasty disease with extremely high malignancy and poor prognosis.Annexin A3(ANXA3)is a potential prognosis biomarker,displaying an excellent correlation of ANXA3 overexpression with patients'poor prognosis.Silencing the expression of ANXA3effectively inhibits the proliferation and metastasis of TNBC,suggesting that ANXA3 can be a promising therapeutic target to treat TNBC.Herein,we report a first-in-class ANXA3-targeted small molecule(R)-SL18,which demonstrated excellent anti-proliferative and anti-invasive activities to TNBC cells.(R)-SL18 directly bound to ANXA3 and increased its ubiquitination,thereby inducing ANXA3 degradation with moderate family selectivity.Importantly,(R)-SL18 showed a safe and effective therapeutic potency in a high ANXA3-expressing TNBC patient-derived xenograft model.Furthermore,(R)-SL18 could reduce theβ-catenin level,and accordingly inhibit the Wnt/β-catenin signaling pathway in TNBC cells.Collectively,our data suggested that targeting degradation of ANXA3 by(R)-SL18 possesses the potential to treat TNBC.展开更多
The cell cycle is a complex process that involves DNA replication,protein expression,and cell division.Dysregulation of the cell cycle is associated with various diseases.Cyclin-dependent kinases(CDKs)and their corres...The cell cycle is a complex process that involves DNA replication,protein expression,and cell division.Dysregulation of the cell cycle is associated with various diseases.Cyclin-dependent kinases(CDKs)and their corresponding cyclins are major proteins that regulate the cell cycle.In contrast to inhibition,a new approach called proteolysis-targeting chimeras(PROTACs)and molecular glues can eliminate both enzymatic and scaffold functions of CDKs and cyclins,achieving targeted degradation.The field of PROTACs and molecular glues has developed rapidly in recent years.In this article,we aim to summarize the latest developments of CDKs and cyclin protein degraders.The selectivity,application,validation and the current state of each CDK degrader will be overviewed.Additionally,possible methods are discussed for the development of degraders for CDK members that still lack them.Overall,this article provides a comprehensive summary of the latest advancements in CDK and cyclin protein degraders,which will be helpful for researchers working on this topic.展开更多
溴结构域蛋白4(bromodomain-containing protein 4,BRD4)是溴结构域和超末端结构域家族中最重要的蛋白,其过度表达与多种肿瘤的发生发展密切相关,成为肿瘤治疗的新靶点。BRD4的抑制策略主要包括BRD4抑制剂和BRD4降解剂,其单独用药或与...溴结构域蛋白4(bromodomain-containing protein 4,BRD4)是溴结构域和超末端结构域家族中最重要的蛋白,其过度表达与多种肿瘤的发生发展密切相关,成为肿瘤治疗的新靶点。BRD4的抑制策略主要包括BRD4抑制剂和BRD4降解剂,其单独用药或与化学治疗、光热治疗、免疫治疗等治疗手段联合使用均显示出良好的抗肿瘤效果,为肿瘤治疗开辟了新的方向。本文介绍了BRD4的结构及其在肿瘤发生发展中的作用,综述了BRD4的抑制策略、在肿瘤联合治疗中应用以及耐药性的研究进展,为以BRD4为靶点的肿瘤治疗提供理论参考。展开更多
In this paper, we synthesized a series of proteolysis targeting chimeras（PROTACs） using VHL E3 ligase ligands for BRD4 protein degradation. One of the most promising compound 19g exhibited robust potency of BRD4 inh...In this paper, we synthesized a series of proteolysis targeting chimeras（PROTACs） using VHL E3 ligase ligands for BRD4 protein degradation. One of the most promising compound 19g exhibited robust potency of BRD4 inhibition with IC50 value of （18.6±1.3） nmol/L, respectively. Furthermore, compound 19g potently inhibited cell proliferation in BRIM-sensitive cell lines RS4;11 with IC50 value of （34.2±4.3） nmol/L and capable of inducing de- gradation of BRD4 protein at 0.4-0.6 μmol/L in the RS4;11 leukemia cells. These data show that compound 19g is a highly potent and efficacious BRIM degrader.展开更多
Proteolysis targeting chimeras（PROTACs） are bispecific molecules containing a target protein binder and a ubiquitin ligase binder connected by a linker. Recently, some heterobifunctional small molecule bromodomain-c...Proteolysis targeting chimeras（PROTACs） are bispecific molecules containing a target protein binder and a ubiquitin ligase binder connected by a linker. Recently, some heterobifunctional small molecule bromodomain-containing protein 4（BRD4） degraders based on the concept of PROTACs were designed to induce the degradation of BRD4 protein. Herein, we synthesized a new class of PROTAC BRD4 degraders. One of the most promising compound 22f exhibited robust potency of BRD4 inhibition with IC50 value of （9.4±0.6） nmol/L. Furthermore, com- pound 22f potently inhibited cell proliferation in BRD4-sensitive cell lines RS4;11 with IC50 value of （27.6±1.6） nmol/L and capable of inducing degradation of BRD4 protein at 0.5-1.0 μmol/L in the RS4;11 cells. These data establish that compound 22f is a potent and efficacious BRD4 degrader.展开更多
The significant advantage of proton therapy over other particle-based techniques is in the unique physical characteristics of the Bragg peak.It can achieve a highly conformal dose distribution and maximize the probabi...The significant advantage of proton therapy over other particle-based techniques is in the unique physical characteristics of the Bragg peak.It can achieve a highly conformal dose distribution and maximize the probability of tumor control by varying the irradiation energy.Most proton facilities use cyclotrons for fixed energy beam extraction and are equipped with degrader and collimator systems for energy modulation and emittance suppression.However,interactions between charged particles and degrader materials inevitably cause beam loss and divergence and deteriorate beam performance,which present great challenges for downstream transport and clinical treatment.In this work,we investigate a method of energy reduction by combining boron carbide and graphite in a degrader to obtain greater beam transmission at lower energy.The results demonstrate that the beam size and emittance at the exit of the combined degrader diverge less than those of multi-wedge one in the energy range of 70-160 MeV.Correspondingly,the transmission efficiency after the first dipole also shows improvements of 36.26%at 70 MeV and 70.55%at 110 MeV.As a component with a high activity level,the degrader causes additional ambient radiation during operation.Residual induced radiation even remains several hours after system shutdown.Analysis of material activation and induced radiation based on 1 h irradiation with a 400 nA beam current shows that the combined degrader has a definite advantage in shielding despite producing more secondary particles.Both radioactivity and average ambient dose equivalent are reduced by 50%compared with the multiwedge degrader at the important cooling time of 1 h.After 12 h and 24 h of cooling,the radiation levels of degraders decrease slightly due to the presence of long half-life residual nuclides.The average dose generated from the multi-wedge degrader is still 1.25 times higher than that of the combined one.展开更多
基金supported by grants from the National Natural Science Foundation of China(Nos.82103978,81874286)the Natural Science Foundation of Jiangsu Province(No.BK20210423)“Double-First-Class”University Project(Nos.CPU 2018PZQ02,CPU 2018GY07).
文摘Small molecule inhibitors have dominated the pharmaceutical landscape for a long time as the primary therapeutic paradigm targeting pathogenic proteins.However,their efficacy heavily relies on the amino acid composition and spatial constitution of proteins,rendering them susceptible to drug resistance and failing to target undruggable proteins.In recent years,the advent of targeted protein degradation(TPD)technology has captured substantial attention from both industry and academia.Employing an event-driven mode,TPD offers a novel approach to eliminate pathogenic proteins by promoting their degrada-tion,thus circumventing the limitations associated with traditional small molecule inhibitors.Hydropho-bic tag tethering degrader(HyTTD)technology represents one such TPD approach that is currently in the burgeoning stage.HyTTDs employ endogenous protein degradation systems to induce the degrada-tion of target proteins through the proteasome pathway,which displays significant potential for medical value.In this review,we provide a comprehensive overview of the development history and the reported mechanism of action of HyTTDs.Additionally,we delve into the physiological roles,structure-activity re-lationships,and medical implications of HyTTDs targeting various disease-associated proteins.Moreover,we propose insights into the challenges that necessitate resolution for the successful development of HyTTDs,with the ultimate goal of initiating a new age of clinical treatment leveraging the immense po-tential of HyTTDs.
基金supported by the National Natural Science Foundation of China(Nos.82173668,82260676)Jiangxi Provincial Natural Science Foundation(20232BAB216131,China)+2 种基金the Scientific and Technological Key Projects of Guangdong Province(Nos.2021B1111110003,2019B020202002,China)the Science and Technology Projects of Ganzhou(202101094462,China)the Start-Up Foundation of Gannan Medical University(No.QD202144-2067,China).
文摘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.
基金supported by Telethon Italy award GGP15225(to RC and GM)Italian Ministry of Health award RF-2016-02362950(to RC and CZ)+1 种基金the CJD Foundation USA(to RC)the Associazione Italiana Encefalopatie da Prioni(AIEnP)(to RC).
文摘PrPSc,a misfolded,aggregation-prone isoform of the cellular prion protein(PrPC),is the infectious prion agent responsible for fatal neurodegenerative diseases of humans and other mammals.PrPSccan adopt different pathogenic conformations(prion strains),which can be resistant to potential drugs,or acquire drug resistance,posing challenges for the development of effective therapies.Since PrPCis the obligate precursor of any prion strain and serves as the mediator of prion neurotoxicity,it represents an attractive therapeutic target fo r prion diseases.In this minireview,we briefly outline the approaches to target PrPCand discuss our recent identification of Zn(Ⅱ)-Bn PyP,a PrPC-targeting porphyrin with an unprecedented bimodal mechanism of action.We argue that in-depth understanding of the molecular mechanism by which Zn(Ⅱ)-Bn PyP targets PrPCmay lead toward the development of a new class of dual mechanism anti-prion compounds.
基金Chunhui Program-Cooperative Research Project of the Ministry of EducationLiaoning Province Natural Science Foundation (No.2022-MS-241)+3 种基金Shenyang Young and Middle-aged Innovative Talents Support Program (No.RC210446)for financial supportsthe support from National-Local Joint Engineering Research Center for Molecular Biotechnology of Fujian&Taiwan TCMFujian Key Laboratory of Chinese Materia MedicaFujian University Key Laboratory for Research and Development of TCM Resources,at Fujian University of Traditional Chinese Medicine
文摘Hexokinase 2(HK2)is the rate-limiting enzyme in the first step of glycolysis,catalyzing glucose to glucose-6-phosphate,and overexpressed in most cancer cells.HK2 also binds to voltage-dependent anion channel(VDAC)to stabilize the mitochondrial outer membrane,which inhibits cancer cell apoptosis.Therefore,HK2 has become a potential target for cancer treatment.Proteolysis targeting chimeras(PROTACs)are hetero-bifunctional molecules that recruit an E3 ubiquitin ligase to a given substrate protein resulting in its targeted degradation.Many potent and specific PROTACs targeting dissimilar targets have been developed.In this study,an HK2 PROTAC,4H-5P-M,was developed and induced the degradation of HK2 relying on the ubiquitin-proteasome system.It was found that 4H-5P-M as an effective HK2 degrader induced HK2 degradation in a dose-and time-dependent manner and suppressed the growth of SW480 cells.4H-5P-M selectively induced HK2 degradation at a lower concentration than other hexokinase isozymes.Moreover,it could suppress glycolysis and accelerate the apoptosis of cancer cells.Therefore,it provided a new insight into the development of anti-tumor drugs.
基金supported in part by the National Natural Science Foundation of China(No.51525703)
文摘The proton beam energy determines the range of particles and thus where the dose is deposited. According to the depth of tumors, an energy degrader is needed to modulate the proton beam energy in proton therapy facilities based on cyclotrons, because the energy of beam extracted from the cyclotron is fixed. The energy loss was simulated for the graphite degrader used in the beamline at the superconducting cyclotron of 200 MeV in Hefei(SC200). After adjusting the mean excitation energy of the graphite used in the degrader to 76 eV, we observed an accurate match between the simulations and measurements.We also simulated the energy spread of the degraded beam and the transmission of the degrader using theoretical formulae. The results agree well with the Monte Carlo simulation.
基金supported by the National Natural Science Foundation of China(Nos.82073688,82103971 and 81930075)Shanghai Science and Technology Development Fund from Central Leading Local Government(No.YDZX20223100001004,China)+1 种基金Science and Technology Commission of Shanghai Municipality(No.21S11907300,China)Program of Shanghai Academic/Technology Research Leader(No.20XD1400700,China)。
文摘Triple-negative breast cancer(TNBC)is a nasty disease with extremely high malignancy and poor prognosis.Annexin A3(ANXA3)is a potential prognosis biomarker,displaying an excellent correlation of ANXA3 overexpression with patients'poor prognosis.Silencing the expression of ANXA3effectively inhibits the proliferation and metastasis of TNBC,suggesting that ANXA3 can be a promising therapeutic target to treat TNBC.Herein,we report a first-in-class ANXA3-targeted small molecule(R)-SL18,which demonstrated excellent anti-proliferative and anti-invasive activities to TNBC cells.(R)-SL18 directly bound to ANXA3 and increased its ubiquitination,thereby inducing ANXA3 degradation with moderate family selectivity.Importantly,(R)-SL18 showed a safe and effective therapeutic potency in a high ANXA3-expressing TNBC patient-derived xenograft model.Furthermore,(R)-SL18 could reduce theβ-catenin level,and accordingly inhibit the Wnt/β-catenin signaling pathway in TNBC cells.Collectively,our data suggested that targeting degradation of ANXA3 by(R)-SL18 possesses the potential to treat TNBC.
基金supported by National Key R&D Program of China (Nos.2021YFA1302100,2020YFE0202200,and 2021YFA1300200)National Natural Science Foundation of China (No.82125034)+1 种基金Fellowship of China Postdoctoral Science Foundation (No.2021M701953)the Foundation of Shuimu Tsinghua Scholar Program (No.2021SM110).
文摘The cell cycle is a complex process that involves DNA replication,protein expression,and cell division.Dysregulation of the cell cycle is associated with various diseases.Cyclin-dependent kinases(CDKs)and their corresponding cyclins are major proteins that regulate the cell cycle.In contrast to inhibition,a new approach called proteolysis-targeting chimeras(PROTACs)and molecular glues can eliminate both enzymatic and scaffold functions of CDKs and cyclins,achieving targeted degradation.The field of PROTACs and molecular glues has developed rapidly in recent years.In this article,we aim to summarize the latest developments of CDKs and cyclin protein degraders.The selectivity,application,validation and the current state of each CDK degrader will be overviewed.Additionally,possible methods are discussed for the development of degraders for CDK members that still lack them.Overall,this article provides a comprehensive summary of the latest advancements in CDK and cyclin protein degraders,which will be helpful for researchers working on this topic.
文摘溴结构域蛋白4(bromodomain-containing protein 4,BRD4)是溴结构域和超末端结构域家族中最重要的蛋白,其过度表达与多种肿瘤的发生发展密切相关,成为肿瘤治疗的新靶点。BRD4的抑制策略主要包括BRD4抑制剂和BRD4降解剂,其单独用药或与化学治疗、光热治疗、免疫治疗等治疗手段联合使用均显示出良好的抗肿瘤效果,为肿瘤治疗开辟了新的方向。本文介绍了BRD4的结构及其在肿瘤发生发展中的作用,综述了BRD4的抑制策略、在肿瘤联合治疗中应用以及耐药性的研究进展,为以BRD4为靶点的肿瘤治疗提供理论参考。
文摘In this paper, we synthesized a series of proteolysis targeting chimeras（PROTACs） using VHL E3 ligase ligands for BRD4 protein degradation. One of the most promising compound 19g exhibited robust potency of BRD4 inhibition with IC50 value of （18.6±1.3） nmol/L, respectively. Furthermore, compound 19g potently inhibited cell proliferation in BRIM-sensitive cell lines RS4;11 with IC50 value of （34.2±4.3） nmol/L and capable of inducing de- gradation of BRD4 protein at 0.4-0.6 μmol/L in the RS4;11 leukemia cells. These data show that compound 19g is a highly potent and efficacious BRIM degrader.
文摘Proteolysis targeting chimeras（PROTACs） are bispecific molecules containing a target protein binder and a ubiquitin ligase binder connected by a linker. Recently, some heterobifunctional small molecule bromodomain-containing protein 4（BRD4） degraders based on the concept of PROTACs were designed to induce the degradation of BRD4 protein. Herein, we synthesized a new class of PROTAC BRD4 degraders. One of the most promising compound 22f exhibited robust potency of BRD4 inhibition with IC50 value of （9.4±0.6） nmol/L. Furthermore, com- pound 22f potently inhibited cell proliferation in BRD4-sensitive cell lines RS4;11 with IC50 value of （27.6±1.6） nmol/L and capable of inducing degradation of BRD4 protein at 0.5-1.0 μmol/L in the RS4;11 cells. These data establish that compound 22f is a potent and efficacious BRD4 degrader.
基金supported in part by the National Natural Science Foundation of China (No. 52077211)
文摘The significant advantage of proton therapy over other particle-based techniques is in the unique physical characteristics of the Bragg peak.It can achieve a highly conformal dose distribution and maximize the probability of tumor control by varying the irradiation energy.Most proton facilities use cyclotrons for fixed energy beam extraction and are equipped with degrader and collimator systems for energy modulation and emittance suppression.However,interactions between charged particles and degrader materials inevitably cause beam loss and divergence and deteriorate beam performance,which present great challenges for downstream transport and clinical treatment.In this work,we investigate a method of energy reduction by combining boron carbide and graphite in a degrader to obtain greater beam transmission at lower energy.The results demonstrate that the beam size and emittance at the exit of the combined degrader diverge less than those of multi-wedge one in the energy range of 70-160 MeV.Correspondingly,the transmission efficiency after the first dipole also shows improvements of 36.26%at 70 MeV and 70.55%at 110 MeV.As a component with a high activity level,the degrader causes additional ambient radiation during operation.Residual induced radiation even remains several hours after system shutdown.Analysis of material activation and induced radiation based on 1 h irradiation with a 400 nA beam current shows that the combined degrader has a definite advantage in shielding despite producing more secondary particles.Both radioactivity and average ambient dose equivalent are reduced by 50%compared with the multiwedge degrader at the important cooling time of 1 h.After 12 h and 24 h of cooling,the radiation levels of degraders decrease slightly due to the presence of long half-life residual nuclides.The average dose generated from the multi-wedge degrader is still 1.25 times higher than that of the combined one.
