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XNA enzymes by evolution and design XNA酶的进化和设计
Pub Date : 2021-01-01 DOI: 10.1016/j.crchbi.2021.100012
Turnee N. Malik , John C. Chaput

The last decade has witnessed tremendous growth in the field of synthetic genetics, an area of synthetic biology that applies concepts that are commonly associated with the field of genetics, such as heredity and evolution, to artificial genetic polymers with novel backbone structures (XNAs). In addition to the emergence of biologically stable affinity reagents (aptamers), progress in this area has led to the discovery of XNA enzymes (XNAzymes) that are capable of mediating transphosphorylation chemistry with multiple turnover activity. This review explores the evolution and rational design of XNAzymes as well as their potential as reagents in biomedical applications.

合成遗传学是合成生物学的一个领域,它将遗传和进化等通常与遗传学领域相关的概念应用于具有新型主链结构(XNAs)的人工遗传聚合物。除了生物稳定的亲和试剂(适体)的出现外,这一领域的进展还导致了XNA酶(XNAzymes)的发现,这些酶能够介导具有多次转换活性的转磷酸化化学。本文综述了XNAzymes的演变、合理设计及其作为生物医学试剂的潜力。
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引用次数: 8
Removal of ammonia and nitrates from contaminated water by using solid waste bio-adsorbents 利用固体废物生物吸附剂去除污水中的氨和硝酸盐
Pub Date : 2021-01-01 DOI: 10.1016/j.crchbi.2021.100005
S. Dey, N. Haripavan, S.R. Basha, G.V. Babu

The presence of pollutants in aqueous solution mainly from hazardous heavy metals and metalloids is creating an environmental and social problem. The ammonia and nitrates are one of the major groundwater contaminants present in the rural areas. A nitrate was regulated in drinking water quality mainly due to excess amounts can cause methemoglobinemia disease. Ammonia in both gaseous and liquid form can be irritating to the eyes, respiratory tract failure and skin due to its alkaline nature. The biological effects of ammonia and nitrates in humans after acute exposures are dose-related depend on their concentration; the amount is taken by the body and duration of exposure. Biosorption is a physiochemical process that occurs naturally in certain biomass which allows it to passively concentrate and bind contaminants onto its cellular structure. It is metabolically passive process not require energy and amount of contaminants in sorbent can remove is dependent on kinetic equilibrium and composition of the sorbents at cellular surface. Every biosorbent had different physical, chemical and biological properties for heavy metals removal by biosorption from the water. The oxygen functional groups are very important characteristics of biosorbents because they measured the surface properties and hence their quality as biosorbents. The analysis of isotherm data by fitting them to different models is important to find a sustainable model that can be used. From the biosorption isotherms describe how the sorbate molecules are distributed between the liquid phase and solid phase when the system reaches equilibrium. The process can be made economical by regenerating and reusing of biosorbent after removing the metals. Various bioreactors can be used in biosorption for the removal of metal ions from large volume of water.

水溶液中主要来自有害重金属和类金属的污染物的存在正在造成环境和社会问题。氨和硝酸盐是农村地区主要的地下水污染物之一。一种硝酸盐在饮用水质量中受到调节,主要是因为过量会导致高铁血红蛋白血症。由于氨的碱性,气态和液态的氨都会刺激眼睛,导致呼吸道衰竭和皮肤。急性暴露后人体内氨和硝酸盐的生物学效应与浓度有关;人体吸收的量和暴露的时间。生物吸附是在某些生物质中自然发生的一种物理化学过程,使其能够被动地将污染物浓缩并结合到其细胞结构上。它是一种代谢被动过程,不需要能量,吸收剂中污染物的去除量取决于细胞表面吸附剂的动力学平衡和组成。每种生物吸附剂对水中重金属的生物吸附都具有不同的物理、化学和生物性能。氧官能团是生物吸附剂非常重要的特征,因为它们测量了生物吸附剂的表面性质,从而决定了它们作为生物吸附剂的质量。通过将等温线数据拟合到不同的模型中进行分析,对于找到可使用的可持续模型非常重要。从生物吸附等温线描述了当系统达到平衡时山梨酸分子在液相和固相之间的分布情况。通过去除金属后对生物吸附剂进行再生和再利用,使该工艺具有经济效益。各种生物反应器可用于生物吸附,以去除大量水中的金属离子。
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引用次数: 21
Translating PROTAC chemical series optimization into functional outcomes underlying BRD7 and BRD9 protein degradation 将PROTAC化学系列优化转化为BRD7和BRD9蛋白质降解的功能结果
Pub Date : 2021-01-01 DOI: 10.1016/j.crchbi.2021.100009
Kristin M. Riching , James D. Vasta , Scott J. Hughes , Vittoria Zoppi , Chiara Maniaci , Andrea Testa , Marjeta Urh , Alessio Ciulli , Danette L. Daniels

Proteolysis targeting chimeras (PROTACs) are complex molecules to design and optimize as degraders, primarily because the linker that bridges the two binding ligands is a highly variable element of design, yet critical for simultaneous engagement of target and E3 ligase into a ternary complex, target ubiquitination and ultimately degradation. These chemical and mechanistic complexities mean that the PROTAC design process can be a daunting endeavour, and it remains unpredictable how to best optimize them into high-quality degraders. To understand how medicinal chemistry decisions could translate into functional outcomes, here we present a retrospective and holistic mechanistic study of a two-part sequential medicinal chemistry program, termed Series 1 and 2, which previously led to the discovery of VZ185, a potent VHL-based dual BRD7 and BRD9 degrader. Analysis of the initial Series 1 compounds across three different cell lines containing endogenously tagged CRISPR HiBiT BRD7 or BRD9 revealed only partial degradation of BRD9, and no degradation of BRD7. Analysis of Series 2 PROTACs, which was designed based on the degradation outcomes of Series 1 and in the absence of ternary complex structural information, showed the emergence of three lead compounds improved in BRD9 degradation and with additional specificity for BRD7. Biochemical analysis to interrogate ternary complex affinity and cooperativity demonstrated how subtle chemistry alterations impacted these parameters both positively and negatively, though on average, achieving only minor improvements in Series 2. In contrast, the greatest change between Series 1 and 2 was an improvement in cellular permeability, with the three lead degradation compounds showing high permeability. Lastly, cellular ubiquitination studies were performed and demonstrated the most potent degrader, VZ185, was the most robust for ubiquitination despite neither being the most permeable nor the best at forming ternary complex within the entire set. VZ185 and similarly active compounds were found to be efficacious degraders across all cell lines tested. Our mechanistic characterization provides insights that, while our structurally unguided medicinal chemistry campaign improved most notably cell permeability, increased degradation outcomes also required retaining productive ternary complex formation and target ubiquitination.

蛋白水解靶向嵌合体(PROTACs)是一种复杂的降解分子,需要设计和优化,主要是因为连接两个结合配体的连接体是一个高度可变的设计元素,但对于目标和E3连接酶同时结合成三元复合物、目标泛素化和最终降解至关重要。这些化学和机械的复杂性意味着PROTAC的设计过程可能是一项艰巨的任务,而且如何将它们优化成高质量的降解剂仍然是不可预测的。为了了解药物化学决策如何转化为功能结果,我们在这里对一个由两部分组成的顺序药物化学计划进行了回顾性和整体的机制研究,称为系列1和系列2,该计划先前导致了VZ185的发现,VZ185是一种有效的基于vhl的BRD7和BRD9双降解剂。对含有内源性标记的CRISPR HiBiT BRD7或BRD9的三种不同细胞系的初始系列1化合物的分析显示,BRD9仅部分降解,BRD7没有降解。在没有三元复合物结构信息的情况下,基于系列1的降解结果设计的系列2 PROTACs的分析显示,出现了三个先导化合物,改善了BRD9的降解,并对BRD7具有额外的特异性。对三元复合物亲和性和协同性的生化分析表明,细微的化学变化如何对这些参数产生积极和消极的影响,尽管平均而言,在系列2中只实现了微小的改进。相比之下,系列1和系列2的最大变化是细胞渗透性的改善,其中三种铅降解化合物表现出较高的渗透性。最后,进行了细胞泛素化研究,并证明了最有效的降解剂VZ185在泛素化方面是最强大的,尽管在整个集合中,它既不是最具渗透性的,也不是形成三元络合物的最好的。VZ185和类似的活性化合物被发现在所有测试的细胞系中都是有效的降解剂。我们的机制表征提供了见解,虽然我们的结构无指导的药物化学活动改善了最显著的细胞通透性,但增加的降解结果也需要保留生产性三元复合物的形成和靶泛素化。
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引用次数: 9
Metalloenzyme mechanisms correlated to their turnover number and metal lability 金属酶机制与其周转率和金属稳定性有关
Pub Date : 2021-01-01 DOI: 10.1016/j.crchbi.2021.100004
Caio B. Castro, Millena P. Ferreira, Caterina G.C. Marques Netto

Metalloenzymes are involved in several different reactions and the metal can display distinct roles, such as redox chemistry or substrate activation. The activation mechanism is mainly described to occur by bond polarization upon coordination to the metal center. However, the disregard of the outer sphere mechanism can have a profound impact on the mechanism proposition of reactions. In the outer sphere coordination, the metal acts as an electrostatic activator in its hydrated form. Since hydration is crucial in this mechanism, metal lability is related to the proposition of an enzyme mechanism. In this review, we will evidence the impact of metal lability in the design of metalloenzyme mechanisms from EC 1–6, correlating some of the enzymes to their biomimetic compounds.

金属酶参与多种不同的反应,金属可以表现出不同的作用,如氧化还原化学或底物活化。活化机理主要描述为与金属中心配位后的键极化。然而,对外球机制的忽视会对反应的机理命题产生深远的影响。在外球面配位中,金属以水合形式充当静电活化剂。由于水合作用在这一机制中起着至关重要的作用,金属的稳定性与酶机制的提出有关。在这篇综述中,我们将从EC 1-6中证明金属不稳定性对金属酶机制设计的影响,并将一些酶与其仿生化合物联系起来。
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引用次数: 6
Untangling the bioactive properties of therapeutic deep eutectic solvents based on natural terpenes 基于天然萜烯的治疗性深共晶溶剂的生物活性特性
Pub Date : 2021-01-01 DOI: 10.1016/j.crchbi.2021.100003
Eduardo Silva , Filipe Oliveira , Joana M. Silva , Rui L. Reis , Ana Rita C. Duarte

Treatment of microbial-related infections remains a clinical challenge that has been slowly aggravating over recent years, due to the dissemination of resistance against currently applied treatment protocols. In this current scenario, the design of novel treatment approaches is of great importance, being a prominent focus of the scientific community. In recent years deep eutectic systems (DES) have gained the attention of the scientific community due to their remarkable physicochemical and biological properties, versatility, and compliance with the green chemistry metrics. In this work, DES containing a monoterpenoid (thymol (THY) and menthol (ME)) in combination with ibuprofen (IBU) were formulated and characterized via thermal analyses and NMR spectroscopy. The biological activity of the most promising formulations was then explored, with focus on its antimicrobial and anticancer activity. Both ME and THY-based formulations presented relevant antibacterial activity against the panel of microorganisms tested. Among the THY-based formulation tested, THY:IBU 3:1 M ratio, showed the highest antibacterial activity, affecting all tested microorganisms, while ME:IBU 3:1 M ratio was only effective against Gram-positive bacteria and Candida albicans. Furthermore, both ME and THY-based formulations revealed cytotoxic effect towards the cancer cell model used (HT29), where ME:IBU 3:1 stood out as the most selective towards cancer cells without compromising normal cells viability. Overall, the results obtained highlight the potential use of terpene-based THEDES formulations that, due to their enhanced thermal properties, may represent a versatile alternative in several biomedical applications where an effective antimicrobial or anticancer therapeutic action remains a challenge.

微生物相关感染的治疗仍然是一项临床挑战,近年来,由于对目前应用的治疗方案的耐药性的传播,这一挑战一直在缓慢恶化。在目前的情况下,设计新的治疗方法是非常重要的,是科学界的一个突出焦点。近年来,深共晶体系(DES)因其卓越的物理化学和生物特性、通用性和符合绿色化学指标而受到科学界的关注。本文制备了含有单萜类化合物(百里酚(THY)和薄荷醇(ME))和布洛芬(IBU)的DES,并通过热分析和核磁共振光谱对其进行了表征。然后探讨了最有希望的配方的生物活性,重点是其抗菌和抗癌活性。基于ME和thys的配方对测试的微生物组均具有相关的抗菌活性。其中THY:IBU 3:1 M的抑菌活性最高,对所有被试微生物均有效,而ME:IBU 3:1 M的比例仅对革兰氏阳性菌和白色念珠菌有效。此外,基于ME和thy的配方都显示出对所使用的癌细胞模型(HT29)的细胞毒性作用,其中ME:IBU 3:1在不影响正常细胞活力的情况下对癌细胞最有选择性。总的来说,获得的结果突出了萜烯基THEDES配方的潜在用途,由于其增强的热性能,可能代表了几种生物医学应用的多功能替代方案,其中有效的抗菌或抗癌治疗作用仍然是一个挑战。
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引用次数: 14
Benefits and pitfalls: Epigenetic modulators in prostate cancer intervention 益处和缺陷:前列腺癌干预中的表观遗传调节剂
Pub Date : 2021-01-01 DOI: 10.1016/j.crchbi.2021.100006
Neha Upadhyay , Kalpana Tilekar , Jessica D. Hess , Vadim S. Pokrovsky , Renato J. Aguilera , Ramaa C S

Prostate cancer is a common malignancy in men worldwide. In the initial treatment, ADT has been used as the cornerstone, but unfortunately, mainstream patients transition to the refractory state of prostate cancer, i.e., CRPC. Thus, newer therapeutics are required for the treatment of patients un or less responsive to ADT. Epigenetic aberrations, namely, DNA methylation and histone modifications are the ultimate chauffeurs of prostate cancer with an emerging role to erase the roadmaps to this disease. However, more robust clinical evidence would be indispensable to put forward reliable therapeutics with the scope to effectively combat this disease. In this review, we have described the present status of epigenetic biomarkers and their clinical impacts on prostate cancer. We have also comprehensively deliberated the role of different epigenetic master regulators involved in the management of disease, appropriate treatment landscape, and the recent preclinical and ongoing clinical evaluations in prostate adenocarcinoma.

前列腺癌是世界范围内男性常见的恶性肿瘤。在最初的治疗中,ADT一直被用作基石,但不幸的是,主流患者过渡到前列腺癌的难治性状态,即CRPC。因此,需要更新的治疗方法来治疗对ADT无反应或反应较差的患者。表观遗传畸变,即DNA甲基化和组蛋白修饰是前列腺癌的终极司机,在消除这种疾病的路线图中发挥着新的作用。然而,更有力的临床证据将是不可或缺的,以提出可靠的治疗范围,有效地对抗这种疾病。在这篇综述中,我们描述了表观遗传生物标志物的现状及其在前列腺癌中的临床影响。我们还全面讨论了不同的表观遗传主调控因子在前列腺癌疾病管理、适当的治疗方案以及最近的临床前和正在进行的临床评估中的作用。
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引用次数: 3
Microwave-assisted extraction and matrix solid-phase dispersion as green analytical chemistry sample preparation techniques for the valorisation of mango processing waste 微波辅助萃取和基质固相分散作为绿色分析化学样品制备技术用于芒果加工废料的鉴定
Pub Date : 2021-01-01 DOI: 10.1016/j.crchbi.2021.100007
Mateus L. Segatto , Karine Zanotti , Vânia G. Zuin

Food supply chain waste is consisted not only by the visible part generated in commercial and consumer steps, but also by the residues generated during harvesting and processing of food-related plants. A great part of these materials is unavoidable, meaning that they cannot be prevented trough waste reduction policies currently being pushed to achieve better food distribution and end hunger across the globe. Valorising this waste stream may help increasing stability in the food sector, having not only a financial gain, but also an environmental and social positive impact. Mango Processing Waste (MPW) is one of the examples of how such residues are poorly explored, as its large volumes contain several valuable substances, such as bioactive compounds, that can be used in the food industry as ingredients and as nutraceuticals, pesticides in agriculture, biocides and other uses. The flavonol hyperoside and the xanthone mangiferin are the main secondary metabolites found in MPW, being reported to have biological activities that range from antioxidant to pesticidal and pharmacological potential uses. In a broader context considering the use of MPW in a biorefinery and circular economy concepts, sustainable processes are required to meet future sustainability parameters. Therefore, Microwave-Assisted Extraction (MAE) and Matrix Solid-Phase Dispersion (MPSD), two sample preparation techniques, were discussed and studied as proposed green and sustainable methodologies for the extraction of mangiferin and hyperoside from MPW. Doehlert and Box-Behnken experimental designs were used to help assessing the influences of the variables of each technique, allowing to employ a Response Surface Methodology (RSM) to visualize the best conditions and calculate optimum parameters. Fast extraction was achieved using MAE, which obtained maximum response of 261.39 mg kg−1 of mangiferin and 244.44 mg kg−1 of hyperoside. Higher yields were obtained using MSPD methodology, with an extraction yield of 352.90 mg kg−1 and 398.52 mg kg−1 of mangiferin and hyperoside, respectively. The conditions that allowed maximum simultaneous extraction concentrations were calculated using the desirability function. MAE and MSPD methodologies were compared, with an overall conclusion that both were adequate for the determination of the two analytes and can be further studied to be used in higher scales.

食品供应链废弃物不仅包括商业和消费环节产生的可见部分,还包括与食品有关的植物在收获和加工过程中产生的残留物。这些材料中的很大一部分是不可避免的,这意味着它们无法通过目前正在推动的减少废物政策来防止,以实现更好的粮食分配和消除全球饥饿。对这种废物流进行估价可能有助于提高粮食部门的稳定性,这不仅会带来经济收益,还会对环境和社会产生积极影响。芒果加工废弃物(MPW)是此类残留物未得到充分开发的例子之一,因为其大量含有几种有价值的物质,如生物活性化合物,可用于食品工业作为成分和营养药品,农业农药,杀菌剂和其他用途。黄酮醇金丝桃苷和山酮芒果苷是MPW中发现的主要次生代谢物,据报道具有从抗氧化到杀虫和药理潜在用途的生物活性。在更广泛的背景下,考虑到在生物炼制和循环经济概念中使用MPW,需要可持续的过程来满足未来的可持续性参数。因此,对微波辅助萃取(MAE)和基质固相分散(MPSD)两种样品制备技术进行了探讨和研究,提出了一种绿色、可持续的方法来提取芒果苷和金丝桃苷。采用Doehlert和Box-Behnken实验设计来帮助评估每种技术变量的影响,允许采用响应面法(RSM)可视化最佳条件并计算最佳参数。采用MAE快速提取,最大响应量分别为261.39 mg kg - 1和244.44 mg kg - 1。MSPD法提取率较高,芒果苷和金丝桃苷的提取率分别为352.90 mg kg - 1和398.52 mg kg - 1。使用期望函数计算允许最大同时提取浓度的条件。对MAE和MSPD方法进行了比较,总的结论是两者都足以用于两种分析物的测定,并且可以进一步研究以用于更高的规模。
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引用次数: 5
Development of an AchillesTAG degradation system and its application to control CAR-T activity AchillesTAG降解系统的研制及其在控制CAR-T活性中的应用
Pub Date : 2021-01-01 DOI: 10.1016/j.crchbi.2021.100010
Gesine K. Veits , Christina S. Henderson , Abigail Vogelaar , Scott J. Eron , Linda Lee , Ashley Hart , Richard W. Deibler , Joelle Baddour , W. Austin Elam , Roman V. Agafonov , Jessica Freda , Prasoon Chaturvedi , Brendon Ladd , Mark W. Carlson , Harit U. Vora , Thomas G. Scott , Trang Tieu , Arushi Jain , Chi-Li Chen , Emily S. Kibbler , Rhamy Zeid

In addition to the therapeutic applicability of targeted protein degradation (TPD), the modality also harbors unique properties that enable the development of innovative chemical biology tools to interrogate complex biology. TPD offers an all-chemical strategy capable of the potent, durable, selective, reversible, and time-resolved control of the levels of a given target protein in both in vitro and in vivo contexts. These properties are particularly well-suited for enabling the precise perturbation of a given gene to understand its biology, identify dependencies/vulnerabilities in disease contexts, and as a strategy to control gene therapies. To leverage these elegant properties, we developed the AchillesTag (aTAG) degradation system to serve as a tool in target identification and validation efforts. The aTAG degradation system provides a novel degradation tag based on the MTH1 protein paired with three fully validated bifunctional degraders with both in vitro and in vivo applicability. We catalog the development of the aTAG system from selection and validation of the novel MTH1 aTAG, alongside a comprehensive SAR campaign to identify high performing tool degraders. To demonstrate the utility of the aTAG system to dissect a complex biological system, we apply the technology to the control of Chimeric Antigen Receptor (CAR) activity. Using aTAG, we demonstrate the ability to potently and selectively control CAR protein levels, resulting in the exquisite rheostat control of CAR mediated T-cell activity. Furthermore, we showcase the in vivo application of the system via degradation of the aTAG-fused CAR protein in a human xenograft model. The aTAG degradation system provides a complete chemical biology tool to aid foundational target validation efforts that inspire drug discovery campaigns towards therapeutic applicability.

除了靶向蛋白降解(TPD)的治疗适用性外,该模式还具有独特的特性,可以开发创新的化学生物学工具来询问复杂的生物学。TPD提供了一种全化学策略,能够在体外和体内对给定目标蛋白的水平进行有效、持久、选择性、可逆和时间分辨的控制。这些特性特别适合于对给定基因进行精确扰动,以了解其生物学,识别疾病背景下的依赖性/脆弱性,并作为控制基因治疗的策略。为了利用这些优雅的特性,我们开发了AchillesTag (aTAG)降解系统,作为目标识别和验证工作的工具。aTAG降解系统提供了一种基于MTH1蛋白的新型降解标签,该标签与三种完全验证的双功能降解剂配对,具有体外和体内适用性。我们对aTAG系统的发展进行了分类,从新型MTH1 aTAG的选择和验证,到全面的SAR活动,以确定高性能的工具降解剂。为了证明aTAG系统在解剖复杂生物系统中的实用性,我们将该技术应用于嵌合抗原受体(CAR)活性的控制。使用aTAG,我们证明了有效和选择性控制CAR蛋白水平的能力,从而对CAR介导的t细胞活性进行了精细的变阻器控制。此外,我们通过在人类异种移植模型中降解atag融合的CAR蛋白,展示了该系统的体内应用。aTAG降解系统提供了一个完整的化学生物学工具,以帮助基础靶标验证工作,激发药物发现运动的治疗适用性。
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引用次数: 6
Synthesis and structure-activity relationships of targeted protein degraders for the understudied kinase NEK9 NEK9激酶靶向蛋白降解物的合成及构效关系研究
Pub Date : 2021-01-01 DOI: 10.1016/j.crchbi.2021.100008
SeongShick Ryu , Gillian E. Gadbois , Andrew J. Tao , Benjamin J. Fram , Jie Jiang , Bridget Boyle , Katherine A. Donovan , Noah M. Krupnick , Bethany C. Berry , Debabrata Bhunia , Injae Shin , Eric S. Fischer , Nathanael S. Gray , Taebo Sim , Fleur M. Ferguson

Nek9 is a member of the understudied Nek family of dark kinases. Aberrant activation of Nek9 kinase signaling has been linked to poor keratinocyte differentiation phenotypes, and is a key driver of nevus comedonicus, a rare, localized form of acne. Nek9 also has essential scaffolding roles; during mitosis the non-catalytic C-terminal domain of Nek9 binds to Nek6 and Nek7, releasing them from an auto-inhibitory conformation, and enabling proper mitotic progression. Finally, Nek9 expression has been linked to cancer proliferation. SiRNA mediated Nek9 knock-down in a panel of cancer cell lines induces G1 cell cycle arrest and inhibits proliferation when p53 is also inactivated; cell lines with functional p53 are unaffected. Presently, no selective small molecule Nek9 chemical probes are available, though a subset of promiscuous kinase inhibitors have Nek9 activity. Recently described targeted protein degradation approaches have shown that degrader molecules based on multi-targeted kinase inhibitors may effect selective kinase degradation, despite binding to many targets. In this study we report the identification and SAR of potent degraders of the NEK9 kinase that represent attractive leads for further development. Future work is needed to optimize the selectivity of the compounds.

Nek9是未被充分研究的Nek暗激酶家族的一员。Nek9激酶信号的异常激活与角质细胞分化不良表型有关,并且是粉刺痣(一种罕见的局部痤疮)的关键驱动因素。Nek9还具有基本的脚手架角色;在有丝分裂过程中,Nek9的非催化性c端结构域与Nek6和Nek7结合,将它们从自抑制构象中释放出来,并使有丝分裂正常进行。最后,Nek9的表达与癌症增殖有关。在一组癌细胞系中,SiRNA介导的Nek9敲低诱导G1细胞周期阻滞并抑制p53失活时的增殖;具有功能性p53的细胞系不受影响。目前,没有选择性的小分子Nek9化学探针可用,尽管混杂激酶抑制剂的一个子集具有Nek9活性。最近描述的靶向蛋白降解方法表明,基于多靶向激酶抑制剂的降解分子可能影响选择性激酶降解,尽管与许多靶标结合。在这项研究中,我们报告了NEK9激酶的有效降解物的鉴定和合成孔径(SAR),这些降解物代表了进一步开发的有吸引力的线索。需要进一步优化化合物的选择性。
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引用次数: 3
Enabling cancer target validation with genetically encoded systems for ligand-induced protein degradation 利用基因编码系统对配体诱导的蛋白质降解进行癌症靶标验证
Pub Date : 2021-01-01 DOI: 10.1016/j.crchbi.2021.100011
Yuxiang Zhang, Michael A. Erb

Recent technological advances have improved the ability of functional genetic approaches to discover new targets for anti-cancer therapeutics. At the same time, advances in discovery chemistry promise to deliver on an ever-larger fraction of these new targets. However, the fundamental difference in the kinetics of genetic and chemical perturbations can make it difficult to judge the performance of new chemical tools when only genetic information is available. Here, we review a series of genetically encoded, ligand-inducible protein degradation systems that can bridge the gap between genetics and pharmacology. These approaches rely on tagging a protein of interest with a small-molecule-responsive degron that enables conditional protein degradation. Given their rapid effects, these systems can facilitate mechanistic interpretations that are not typically possible using traditional genetic approaches. Therefore, inducible degradation systems can be employed at the earliest stages of target validation to provide mechanistic insights that will better guide future drug discovery efforts.

最近的技术进步提高了功能遗传学方法发现抗癌治疗新靶点的能力。与此同时,化学发现方面的进步有望实现这些新目标中越来越大的一部分。然而,遗传和化学扰动动力学的根本差异使得仅在遗传信息可用时难以判断新化学工具的性能。在这里,我们回顾了一系列遗传编码,配体诱导的蛋白质降解系统,可以弥合遗传学和药理学之间的差距。这些方法依赖于用小分子反应性降解标记感兴趣的蛋白质,从而实现有条件的蛋白质降解。考虑到它们的快速作用,这些系统可以促进使用传统遗传方法通常不可能实现的机械解释。因此,诱导降解系统可以在靶标验证的早期阶段使用,以提供机制见解,从而更好地指导未来的药物发现工作。
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引用次数: 5
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Current research in chemical biology
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