Energy loss of degrader in SC200 proton therapy facility

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.

Investigation of combined degrader for proton facility based on BDSIM/FLUKA Monte Carlo methods

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.

Relative Abundance and the Relationships between Aniline,Phenol and Catechol Degraders in Fresh Water

Relative abundance and relationships between aniline, phenol and catechol degraders were investigated in unpolluted and polluted fresh waters in Osaka prefecture, Japan. Phenol and catechol degraders were found more frequently compared to aniline degraders. The results indicate that these degraders were more abundant in polluted waters than in unpolluted waters. Aniline degraders isolated from the Ina River water showed a higher capability of degrading catechol than phenol. Analysis on sequence homology among these three kinds of degraders indicated a possible relationship between aniline degraders and certain strains of both catechol and phenol degraders.

Hydrophobic tag tethering degrader as a promising paradigm of protein degradation:Past,present and future perspectives

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.

Overview of epigenetic degraders based on PROTAC, molecular glue, and hydrophobic tagging technologies

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.

A selective HK2 degrader suppresses SW480 cancer cell growth by degrading HK2

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.

Design,synthesis and evaluation of the first DYRK1A degrader for promoting the proliferation of pancreaticβ-cells

Dual-specificity tyrosine-phosphorylation-regulated kinase 1A(DYRK1A)is the most promising target for diabetes treatment by promotingβ-cell proliferation.The desmethylbellidifolin(DMB)as a DYRK1A inhibitor could facilitateβ-cell proliferation in vivo and in vitro.However,DMB has the problem of weak binding affinity to DYRK1A,which means that continuous high concentration administration of DMB is effective for the diabetes.In order to solve this problem,we designed and synthesized a series of DMBbased proteolysis targeting chimeras(PROTACs)by taking advantage of the property of PROTAC that induce protein degradation in a cycle-catalytic manner.MDM2-based PROTAC X1-4P-MDM2 was identified as the most active PROTAC molecule.Mechanism research showed that X1-4P-MDM2 formed a ternary complex with DYRK1A and murine double minute 2(MDM2),and induced the degradation of DYRK1A through the ubiquitin-proteasome system pathway.At a dose much lower than that of DMB,X1-4PMDM2 still significantly enhancedβ-cell proliferation by inhibiting transforming growth factor beta(TGF-β)and promoting the mitogen-activated protein kinases/extracellular signal-regulated kinase(MAPK/ERK)signaling pathway,which may provide a new strategy for the application of DMB in diabetes.

Developing selective PI3K degraders to modulate both kinase and non-kinase functions

For the first time,proteolysis-targeting chimeras(PROTAC)technology was utilized to achieve the isoform-selective degradation of class I phosphoinositide 3-kinases(PI3Ks)in this study.Through screening and optimization,the PROTAC molecule ZM-PI05 was identified as a selective degrader of p110αin multiple breast cancer cells.More importantly,the degrader can down-regulate p85 regulatory subunit simultaneously,thereby inhibiting the non-enzymatic functions of PI3K that are independent on p110catalytic subunits.Therefore,compared with PI3K inhibitor copanlisib,ZM-PI05 displayed the stronger anti-proliferative activity on breast cancer cells.In brief,a selective and efficient PROTAC molecule was developed to induce the degradation of p110αand concurrent reduction of p85 proteins,providing a tool compound for the biological study of PI3K-αby blocking its enzymatic and non-enzymatic functions.

Therapeutic targeting of cellular prion protein: toward the development of dual mechanism anti-prion compounds

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.

Small-molecule MDM2/X inhibitors and PROTAC degraders for cancer therapy:advances and perspectives

Blocking the MDM2/X-P53 protein-protein interaction has been widely recognized as an attractive therapeutic strategy for the treatment of cancers.Numerous small-molecule MDM2 inhibitors have been reported since the release of the structure of the MDM2-P53 interaction in 1996,SAR405838,NVP-CGM097,MK-8242,RG7112,RG7388,DS-3032 b,and AMG232 currently undergo clinical evaluation for cancer therapy.This review is intended to provide a comprehensive and updated overview of MDM2 inhibitors and proteolysis targeting chimera(PROTAC)degraders with a particular focus on how these inhibitors or degraders are identified from starting points,strategies employed,structure-activity relationship(SAR)studies,binding modes or co-crystal structures,biochemical data,mechanistic studies,and preclinical/clinical studies.Moreover,we briefly discuss the challenges of designing MDM2/X inhibitors for cancer therapy such as dual MDM2/X inhibition,acquired resistance and toxicity of P53 activation as well as future directions.

Discovery of novel covalent selective estrogen receptor degraders against endocrine-resistant breast cancer

Endocrine-resistance remains a major challenge in estrogen receptorαpositive(ERα^(+))breast cancer(BC)treatment and constitutively active somatic mutations in ERαare a common mechanism.There is an urgent need to develop novel drugs with new mode of mechanism to fight endocrineresistance.Given aberrant ERαactivity,we herein report the identification of novel covalent selective estrogen receptor degraders(cSERDs)possessing the advantages of both covalent and degradation strategies.A highly potent cSERD 29c was identified with superior anti-proliferative activity than fulvestrant against a panel of ERa+breast cancer cell lines including mutant ERα.Crystal structure of ERα-29c complex alongside intact mass spectrometry revealed that 29c disrupted ERa protein homeostasis through covalent targeting C530 and strong hydrophobic interaction collied on H11,thus enforcing a unique antagonist conformation and driving the ERαdegradation.These significant effects of the cSERD on ERαhomeostasis,unlike typical ERαdegraders that occur directly via long side chains perturbing the morphology of H12,demonstrating a distinct mechanism of action(MoA).In vivo,29c showed potent antitumor activity in MCF-7 tumor xenograft models and low toxicity.This proof-of-principle study verifies that novel cSERDs offering new opportunities for the development of innovative therapies for endocrine-resistant BC.

Dynamic Regulation of Hydrogen Bonding Networks and Solvation Structures for Synergistic Solar‑Thermal Desalination of Seawater and Catalytic Degradation of Organic Pollutants

Although solar steam generation strategy is efficient in desalinating seawater,it is still challenging to achieve continuous solar-thermal desalination of seawater and catalytic degradation of organic pollutants.Herein,dynamic regulations of hydrogen bonding networks and solvation structures are realized by designing an asymmetric bilayer membrane consisting of a bacterial cellulose/carbon nanotube/Co_(2)(OH)_(2)CO_(3)nanorod top layer and a bacterial cellulose/Co_(2)(OH)_(2)CO_(3)nanorod(BCH)bottom layer.Crucially,the hydrogen bonding networks inside the membrane can be tuned by the rich surface–OH groups of the bacterial cellulose and Co_(2)(OH)_(2)CO_(3)as well as the ions and radicals in situ generated during the catalysis process.Moreover,both SO_(4)^(2−)and HSO_(5)−can regulate the solvation structure of Na^(+)and be adsorbed more preferentially on the evaporation surface than Cl^(−),thus hindering the de-solvation of the solvated Na^(+)and subsequent nucleation/growth of NaCl.Furthermore,the heat generated by the solar-thermal energy conversion can accelerate the reaction kinetics and enhance the catalytic degradation efficiency.This work provides a flow-bed water purification system with an asymmetric solar-thermal and catalytic membrane for synergistic solar thermal desalination of seawater/brine and catalytic degradation of organic pollutants.

Age-related driving mechanisms of retinal diseases and neuroprotection by transcription factor EB-targeted therapy

Retinal aging has been recognized as a significant risk factor for various retinal disorders,including diabetic retinopathy,age-related macular degeneration,and glaucoma,following a growing understanding of the molecular underpinnings of their development.This comprehensive review explores the mechanisms of retinal aging and investigates potential neuroprotective approaches,focusing on the activation of transcription factor EB.Recent meta-analyses have demonstrated promising outcomes of transcription factor EB-targeted strategies,such as exercise,calorie restriction,rapamycin,and metformin,in patients and animal models of these common retinal diseases.The review critically assesses the role of transcription factor EB in retinal biology during aging,its neuroprotective effects,and its therapeutic potential for retinal disorders.The impact of transcription factor EB on retinal aging is cell-specific,influencing metabolic reprogramming and energy homeostasis in retinal neurons through the regulation of mitochondrial quality control and nutrient-sensing pathways.In vascular endothelial cells,transcription factor EB controls important processes,including endothelial cell proliferation,endothelial tube formation,and nitric oxide levels,thereby influencing the inner blood-retinal barrier,angiogenesis,and retinal microvasculature.Additionally,transcription factor EB affects vascular smooth muscle cells,inhibiting vascular calcification and atherogenesis.In retinal pigment epithelial cells,transcription factor EB modulates functions such as autophagy,lysosomal dynamics,and clearance of the aging pigment lipofuscin,thereby promoting photoreceptor survival and regulating vascular endothelial growth factor A expression involved in neovascularization.These cell-specific functions of transcription factor EB significantly impact retinal aging mechanisms encompassing proteostasis,neuronal synapse plasticity,energy metabolism,microvasculature,and inflammation,ultimately offering protection against retinal aging and diseases.The review emphasizes transcription factor EB as a potential therapeutic target for retinal diseases.Therefore,it is imperative to obtain well-controlled direct experimental evidence to confirm the efficacy of transcription factor EB modulation in retinal diseases while minimizing its risk of adverse effects.

Coagulation indices and fibrinogen degradation products as predictive biomarkers for tumor-node-metastasis staging and metastasis in gastric cancer

BACKGROUND Gastric cancer(GC)is a prevalent malignancy with a substantial health burden and high mortality rate,despite advances in prevention,early detection,and treatment.Compared with the global average,Asia,notably China,reports disproportionately high GC incidences.The disease often progresses asymptoma-tically in the early stages,leading to delayed diagnosis and compromised out-comes.Thus,it is crucial to identify early diagnostic biomarkers and enhance treatment strategies to improve patient outcomes and reduce mortality.METHODS Retrospectively analyzed the clinical data of 148 patients with GC treated at the Civil Aviation Shanghai Hospital between December 2022 and December 2023.The associations of coagulation indices-partial thromboplastin time(APTT),prothrombin time(PT),thrombin time(TT),fibrinogen,fibrinogen degradation products(FDP),fasting blood glucose,and D-dimer(D-D)with TNM stage and distant metastasis were examined.RESULTS Prolongation of APTT,PT,and TT was significantly correlated with the GC TNM stage.Hence,abnormal coagulation system activation was closely related to disease progression.Elevated FDP and D-D were significantly associated with distant metastasis in GC(P<0.05),suggesting that increased fibrinolytic activity contributes to increased metastatic risk.CONCLUSION Our Results reveal coagulation indices,FDPs as GC biomarkers,reflecting abnormal coagulation/fibrinolysis,aiding disease progression,metastasis prediction,and helping clinicians assess thrombotic risk for early intervention and personalized treatment plans.

Regulation and function of endoplasmic reticulum autophagy in neurodegenerative diseases

The endoplasmic reticulum,a key cellular organelle,regulates a wide variety of cellular activities.Endoplasmic reticulum autophagy,one of the quality control systems of the endoplasmic reticulum,plays a pivotal role in maintaining endoplasmic reticulum homeostasis by controlling endoplasmic reticulum turnover,remodeling,and proteostasis.In this review,we briefly describe the endoplasmic reticulum quality control system,and subsequently focus on the role of endoplasmic reticulum autophagy,emphasizing the spatial and temporal mechanisms underlying the regulation of endoplasmic reticulum autophagy according to cellular requirements.We also summarize the evidence relating to how defective or abnormal endoplasmic reticulum autophagy contributes to the pathogenesis of neurodegenerative diseases.In summary,this review highlights the mechanisms associated with the regulation of endoplasmic reticulum autophagy and how they influence the pathophysiology of degenerative nerve disorders.This review would help researchers to understand the roles and regulatory mechanisms of endoplasmic reticulum-phagy in neurodegenerative disorders.

Discovery of small molecule degraders for modulating cell cycle

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.

Discovery of a first-in-class ANXA3 degrader for the treatment of triple-negative breast cancer

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.

Discovery of the first potent proteolysis targeting chimera(PROTAC) degrader of indoleamine 2,3-dioxygenase 1

Cancer immunotherapy is revolutionizing oncology and has emerged as a promising strategy for the treatment of multiple cancers.Indoleamine 2,3-dioxygenase 1(IDO1),an immune checkpoint,plays an important role in tumor immune escape through the regulation of multiple immune cells and has been regarded as an attractive target for cancer immunotherapy.Proteolysis Targeting Chimeras(PROTAC)technology has emerged as a new model for drug research and development for its advantageous mechanism.Herein,we reported the application of PROTAC technology in targeted degradation of IDO 1,leading to the discovery of the first IDO1 PROTAC degrader 2 c,which induced significant and persistent degradation of IDO1 with maximum degradation(Dmax)of 93%in HeLa cells.Western-blot based mechanistic studies indicated that IDO 1 was degraded by 2 c through the ubiquitin proteasome system(UPS).Label-free real-time cell analysis(RTCA)indicated that 2 c moderately improved tumorkilling activity of chimeric antigen receptor-modified T(CAR-T)cells.Collectively,these data provide a new insight for the application of PROTAC technology in tumor immune-related proteins and a promising tool to study the function of IDO1.

Inhibition of protein degradation increases the Bt protein concentration in Bt cotton

Bacillus thuringiensis(Bt)cotton production is challenged by two main problems,i.e.,the low concentration of Bt protein at the boll setting stage and the lowest insect resistance in bolls among all the cotton plant’s organs.Therefore,increasing the Bt protein concentration at the boll stage,especially in bolls,has become the main goal for increasing insect resistance in cotton.In this study,two protein degradation inhibitors(ethylene diamine tetra acetic acid(EDTA)and leupeptin)were sprayed on the bolls,subtending leaves,and whole cotton plants at the peak flowering stage of two Bt cultivars(medium maturation Sikang 1(SK1))and early maturation Zhongmian 425(ZM425)in 2019 and 2020.The Bt protein content and protein degradation metabolism were assessed.The results showed that the Bt protein concentrations were enhanced by 21.3 to 38.8%and 25.0 to 38.6%in the treated bolls of SK1 and ZM425 respectively,while they were decreased in the subtending leaves of these treated bolls.In the treated leaves,the Bt protein concentrations increased by 7.6 to 23.5%and 11.2 to 14.9%in SK1 and ZM425,respectively.The combined application of EDTA and leupeptin to the whole cotton plant increased the Bt protein concentrations in both bolls and subtending leaves.The Bt protein concentrations in bolls were higher,increasing by 22.5 to 31.0%and 19.6 to 32.5%for SK1 and ZM425,respectively.The organs treated with EDTA or/and leupeptin showed reduced free amino acid contents,protease and peptidase activities and significant enhancements in soluble protein contents.These results indicated that inhibiting protein degradation could improve the protein content,thus increasing the Bt protein concentrations in the bolls or/and leaves of cotton plants.Therefore,the increase in the Bt protein concentration without yield reduction suggested that these two protein degradation inhibitors may be applicable for improving insect resistance in cotton production.

Highly Efficient Aligned Ion‑Conducting Network and Interface Chemistries for Depolarized All‑Solid‑State Lithium Metal Batteries

Improving the long-term cycling stability and energy density of all-solid-state lithium(Li)-metal batteries(ASSLMBs)at room temperature is a severe challenge because of the notorious solid–solid interfacial contact loss and sluggish ion transport.Solid electrolytes are generally studied as two-dimensional(2D)structures with planar interfaces,showing limited interfacial contact and further resulting in unstable Li/electrolyte and cathode/electrolyte interfaces.Herein,three-dimensional(3D)architecturally designed composite solid electrolytes are developed with independently controlled structural factors using 3D printing processing and post-curing treatment.Multiple-type electrolyte films with vertical-aligned micro-pillar(p-3DSE)and spiral(s-3DSE)structures are rationally designed and developed,which can be employed for both Li metal anode and cathode in terms of accelerating the Li+transport within electrodes and reinforcing the interfacial adhesion.The printed p-3DSE delivers robust long-term cycle life of up to 2600 cycles and a high critical current density of 1.92 mA cm^(−2).The optimized electrolyte structure could lead to ASSLMBs with a superior full-cell areal capacity of 2.75 mAh cm^(−2)(LFP)and 3.92 mAh cm^(−2)(NCM811).This unique design provides enhancements for both anode and cathode electrodes,thereby alleviating interfacial degradation induced by dendrite growth and contact loss.The approach in this study opens a new design strategy for advanced composite solid polymer electrolytes in ASSLMBs operating under high rates/capacities and room temperature.