中国快递行业绿色低碳发展政策特征与评价——基于政策建模一致性(PMC)指数模型的量化分析

为丰富国内促进快递业绿色低碳发展政策体系的系统性研究,为进一步优化相关政策设计﹑加快实现“双碳”目标提供参考,以快递业国家级绿色低碳发展政策文件为研究样本,综合运用文本属性﹑内容分析和政策一致性(PMC)指数模型等方法,总结国内快递行业绿色低碳发展历程,归纳现行政策特征并开展政策支持评价。结果表明:国内快递业绿色低碳发展政策支持经历了探索期﹑起步期和战略体系形成期3个阶段,现有政策体系整体性﹑科学性较强,但存在政策工具分布不均衡﹑政策约束性与强制性不够﹑缺乏强有力的协调机制,以及未形成明确的邮政业碳排放测算﹑报告和核查机制等问题,并据此提出建立强有力的沟通协调机制﹑提升强制性政策比重﹑加大需求端政策工具供给等建议。

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.

Developing potent PROTACs tools for selective degradation of HDAC6 protein

Dear Editor, Histone deacetylases (HDACs) are a family of enzymes that remove acetyl groups on histone and non-histone proteins, thereby playing a vital role in the modulation of gene expression and protein activity. Eighteen HDACs have been identified in human and subdivided into four classes including I, II (Ila, lib), III and IV (Seto et al., 2014). Among them, HDAC6 is a unique lib HD AC with dominant cytoplasmic localization and two functional catalytic domains. Besides the functions for deacetylation of histone, and modulation of a-tubulin, HSP90 and cortactin, HDAC6 also participates in protein trafficking and degradation, cell shape and migration (Valenzuela-Fernandez et al., 2008). The deregulation of HDAC6 is related to various diseases, such as neurodegenerative diseases, cancer and pathological autoimmune response (Batchu et al., 2016). Hence, it is especially important for directly controlling cellular HDAC6 protein levels to achieve therapeutic purposes. The traditional approaches of red u ci ng cellular protein levels mainly rely on genetic modifications, such as RNA interference, transcription activator-like effector nucleases, recombination-based gene knockout and clustered regularly interspaced short palindromic repeats (CRISPR-Cas9)(Boettcher et al., 2015). However, these approaches have failed to a certain degree to achieve acute and reversible changes of gene function. Furthermore, the complications of potential genetic compensation and/or spontaneous mutations arising in geneknockout models may lead to misinterpretations (Davisson etal., 2012;El-Brolosy etal., 2017). Therefore, it is urgent for developing a rapid, robust, and reversible approach to directly modulate HDAC6 protein levels.

PROTACs: great opportunities for academia and industry

Although many kinds of therapies are applied in the clinic,drug-resistance is a major and unavoidable problem.Another disturbing statistic is the limited number of drug targets,which are presently only 20–25%of all protein targets that are currently being studied.Moreover,the focus of current explorations of targets are their enzymatic functions,which ignores the functions from their scaffold moiety.As a promising and appealing technology,PROteolysis TArgeting Chimeras(PROTACs)have attracted great attention both from academia and industry for finding available approaches to solve the above problems.PROTACs regulate protein function by degrading target proteins instead of inhibiting them,providing more sensitivity to drug-resistant targets and a greater chance to affect the nonenzymatic functions.PROTACs have been proven to show better selectivity compared to classic inhibitors.PROTACs can be described as a chemical knockdown approach with rapidity and reversibility,which presents new and different biology compared to other gene editing tools by avoiding misinterpretations that arise from potential genetic compensation and/or spontaneous mutations.PRTOACs have been widely explored throughout the world and have outperformed not only in cancer diseases,but also in immune disorders,viral infections and neurodegenerative diseases.Although PROTACs present a very promising and powerful approach for crossing the hurdles of present drug discovery and tool development in biology,more efforts are needed to gain to get deeper insight into the efficacy and safety of PROTACs in the clinic.More target binders and more E3 ligases applicable for developing PROTACs are waiting for exploration.

A review of recent studies on rotating internal cooling for gas turbine blades

Gas turbines have been used extensively for aircraft and marine propulsions as well as land-based power generation because of their high thermal efficiency and large power to weight ratios.To further increase the thermal efficiency,numerous prior researches on gas turbine blade internal cooling have been intensively carried out,majorly under stationary conditions.However,the stationary studies neglect the effects of Coriolis and buoyancy forces,which should change the velocity,turbulence and temperature distribution under rotating conditions.To elucidate the rotational effects on gas turbine internal cooling,the extensive results collected from recent investigations are discussed,which include the rotation and buoyancy effects on the rib turbulated cooling,pin fin cooling,jet impingement cooling,dimple/protrusion cooling,latticework cooling as well as swirl cooling.The rotational effects on the friction factors and the most employed experimental and numerical methods are also presented.Moreover,recommendations for future research are outlined.Therefore,this review article provides extensive literature information for the design of the next-generation high-efficiency internal cooling for rotating turbine blades.

FAK-targeting PROTAC as a chemical tool for the investigation of non-enzymatic FAK function in mice

Dear Editor,Animal models,most commonly mice,that lack a protein of interest play an important role in phenotypic and functional studies of a target gene,allowing researchers to answer various biological questions(Chaible et al,2010).At pre-sent,a variety of tools act at the DNA or RNA level to enable researchers to model gene function(and thus protein)deficiency,including nucleic acid based RNA interference(EI-bashir et al.,2001),antisense oligonucleotides(Schoch and Miller,2017),and genome editing-based CRISPR-Cas9(Doudna and Charpentier,2014)strategies.However,challenges remain.

Synthesis of selective PAK4 inhibitors for lung metastasis of lung cancer and melanoma cells

The p21 activated kinase 4(PAK4) is serine/threonine protein kinase that is critical for cancer progression.Guided by X-ray crystallography and structure-based optimization,we report a novel subseries of C-3-substituted 6-ethynyl-1 H-indole derivatives that display high potential and specificity towards group Ⅱ PAKs.Among these inhibitors,compound 55 exhibited excellent inhibitory activity and kinase selectivity,displayed superior anti-migratory and anti-invasive properties against the lung cancer cell line A549 and the melanoma cell line B16.Compound 55 exhibited potent in vivo antitumor metastatic efficacy,with over 80% and 90% inhibition of lung metastasis in A549 or B16-BL6 lung metastasis models,respectively.Further mechanistic studies demonstrated that compound 55 mitigated TGF-β1-induced epithelial-mesenchymal transition(EMT).

用于精准蛋白降解和癌症治疗的刺激响应型PROTAC进展

刺激响应型蛋白质降解靶向嵌合体(PROTAC)前药可在特定刺激条件下激活PROTAC分子,实现特定区域和细胞的靶蛋白降解,从而克服不可控蛋白降解导致的毒副作用,是改善PROTAC疗效和成药性的有效策略.本文系统总结了目前用于特异性降解病灶组织目标蛋白从而精准治疗肿瘤的各种刺激响应型PROTAC前药策略.首先,本文介绍了PROTAC的发展历程和作用原理,以及目前进入临床试验阶段的PROTAC分子;然后,介绍了细胞内原位生成PROTAC的前药策略,以及各种刺激手段激活的PROTAC前药,包括外源性的光、X-射线以及内源性的肿瘤微环境的乏氧、活性氧和酶等;接着,概括了配体修饰型的主动靶向PROTAC前药,包括抗体、叶酸、适配体等修饰策略.本文重点强调了基于纳米递药系统的PROTAC前药策略,其可实现特异性肿瘤组织药物递送和精准蛋白降解.最后,本文对PROTAC的未来发展进行了探讨和展望.

PROTACs:great opportunities for academia and industry (an update from 2020 to 2021)

PROteolysis TArgeting Chimeras(PROTACs)technology is a new protein-degradation strategy that has emerged in recent years.It uses bifunctional small molecules to induce the ubiquitination and degradation of target proteins through the ubiquitin–proteasome system.PROTACs can not only be used as potential clinical treatments for diseases such as cancer,immune disorders,viral infections,and neurodegenerative diseases,but also provide unique chemical knockdown tools for biological research in a catalytic,reversible,and rapid manner.In 2019,our group published a review article“PROTACs:great opportunities for academia and industry”in the journal,summarizing the representative compounds of PROTACs reported before the end of 2019.In the past 2 years,the entire field of protein degradation has experienced rapid development,including not only a large increase in the number of research papers on protein-degradation technology but also a rapid increase in the number of small-molecule degraders that have entered the clinical and will enter the clinical stage.In addition to PROTAC and molecular glue technology,other new degradation technologies are also developing rapidly.In this article,we mainly summarize and review the representative PROTACs of related targets published in 2020–2021 to present to researchers the exciting developments in the field of protein degradation.The problems that need to be solved in this field will also be briefly introduced.

Correction to: Developing potent PROTACs tools for selective degradation of HDAC6 protein

In the original publication the title of X axis in Fig.1G is in correctly published as"Compound(pmol/L)".The correct title of X axis in Fig.1G should be read as"Compound(nmol/L)M.Figure 1.Development of selective HDAC6-degrading PROTACs.(A)The principle of PROTAC.(B)The structure of PROTAC,as shown in the upper portion.A binding mode of PROTAC(ball stick),HDAC6(PDB 5G0J,purple)and CRL4-CRBN(PDB 2HYE and 4CI3,colored cyan and gray)was simulated by Pymol.

Design,synthesis,and biological evaluation of multiple targeting antimalarials

Malaria still threatens global health seriously today.While the current discoveries of antimalarials are almost totally focused on single mode-of-action inhibitors,multi-targeting inhibitors are highly desired to overcome the increasingly serious drug resistance.Here,we performed a structure-based drug design on mitochondrial respiratory chain of Plasmodium falciparum and identified an extremely potent molecule,RYL-581,which binds to multiple protein binding sites of P.falciparum simultaneously(allosteric site of type Ⅱ NADH dehydrogenase,Q_(o) and Q_(i) sites of cytochrome bc_(1)).Antimalarials with such multiple targeting mechanism of action have never been reported before.RYL-581 kills various drug-resistant strains in vitro and shows good solubility as well as in vivo activity.This structurebased strategy for designing RYL-581 from starting compound may be helpful for other medicinal chemistry projects in the future,especially for drug discovery on membrane-associated targets.

Are BCL6 and EZH2 novel therapeutic targets for systemic lupus erythematosus?

As a chronic systemic autoimmune disease,systemic lupus erythematosus(SLE)can influence multiple organs and systems.Although the pathological basis and risk factors for SLE have been extensively investigated,the exact pathogenesis of SLE remains to be explored.However,there is increasing evidence that T-cell−Bcell interactions promote the development of SLE,resulting in the generation of high-affinity antibodies[1].Tfh cells,a subgroup of T cells,can promote the formation of germinal centers,the maturation of B cells,and the differentiation of plasma cells[2].It has been found that multiple transcription factors(TFs)can regulate the generation of Tfh cells.For instance,B-cell lymphoma-6(BCL-6),an evolutionarily conserved zinc-finger protein,is an important positive transcription factor responsible for the differentiation and maturation of Tfh cells.In addition to maintaining the phenotype and GC response of Tfh cells,BCL-6 can also regulate the dynamics of T-cell−B-cell interactions and improve the efficiency of delivering help to B cells[3].

A gram-scale synthesis of multi-substituted arenes via palladium catalyzed C–H halogenation

（6-Amino-2-chloro-3-fluorophenyl）methanol is prepared through both traditional methods and palladium catalyzed iterative C–H halogenation reactions.In comparison to traditional approach,the C–H functionalization strategy demonstrated a few advantages including milder reaction conditions higher yields,better selectivity and practicality,and high chemical diversity.

Palladium-catalyzed ortho-selective C–H bond chlorination of aromatic ketones

A palladium-catalyzed ortho-selective C–H bond chlorination reaction for the preparation of 2-chloro aromatic ketones was described. Both electron-withdrawing and electron-donating groups on the aromatic rings are well tolerated under the optimized conditions. The 2-chloro aromatic ketones obtained by our method could be applied to synthesize the derivatives of 1H-indazole or benzo[d]isoxazole.

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.

Developing potent BTK^(C481S)PROTACs for ibrutinib-resistant malignant lymphoma

Ibrutinib is a first-line treatment drug for B-cell malignancies.However,resistance to ibrutinib has been reported due to BTKC481Smutation.Although PROTAC strategy is expected to overcome this clinical resistance,it has limitations such as large molecular weight and moderate bioactivity,which restrict its potential clinical application.Herein,we report a new type of potent BTKC481S-targeting PROTAC degrader.Through design,computer-assisted optimization and SAR studies,we have developed a representative BTKC481Sdegrader L6 with a much smaller molecular weight and improved solubility.Notably,L6 demonstrates better BTK degrading activity and lower IC50value in ibrutinib-resistant cell line than the first-generation BTK degrader P13I.Optimization strategy of L6 provides a general approach in the development of PROTACs targeting BTK and other proteins for future study.

PROTAC mediated FKBP12 degradation enhances Hepcidin expression via BMP signaling without immunosuppression activity

Dear Editor,Hepcidin is a 25-amino acid peptide acting as a pivotal negative regulator in iron homeostasis,which can bind to an iron exporter,ferroportin 1,and induce its internalization and degradation.1 Hepcidin is produced in hepatocytes mainly under the control of BMP signaling.BMP2/6,secreted by liver endothelial cells in response to iron level,binds to BMP type I and type II receptors and triggers the phosphorylation of Smad1/5/8 which directly promotes hepcidin expression.1 The immunophilin family protein FKBP12 is associated with BMP type I receptors to prevent uncontrolled receptor activation.

Synthesis of Quaternary Carbon-Centered Benzoindolizidinones via Novel Photoredox-Catalyzed Alkene Aminoarylation: Facile Access to Tylophorine and Analogues

Photoredox-catalyzed aminoarylation and thioami-nation of unactivated alkenes have been developed,providing novel synthetic routes to access synthe-tically challenging quaternary carbon-centered benzoindolizidinones and trifluoromethylthiolated piperidines using readily available starting materials.Notably,these transformations were enabled by merging amidyl radical generation from N-alkyl benzamides with oxidant incorporation.Density functional theory calculations were performed to understand the reaction mechanism and to rationa-lize the regioselectivities.Moreover,the newly deve-loped catalytic aminoarylation provided a convenient synthetic route for natural product tylophorine and its gem-dimethyl analogues with greatly improved drug-like properties such as enhanced solubility and stability.