更新于：2024-11-01

PCNA

更新于：2024-11-01

基本信息

别名

Cyclin、PCNA、proliferating cell nuclear antigen

简介

Auxiliary protein of DNA polymerase delta and epsilon, is involved in the control of eukaryotic DNA replication by increasing the polymerase's processibility during elongation of the leading strand (PubMed:35585232). Induces a robust stimulatory effect on the 3'-5' exonuclease and 3'-phosphodiesterase, but not apurinic-apyrimidinic (AP) endonuclease, APEX2 activities. Has to be loaded onto DNA in order to be able to stimulate APEX2. Plays a key role in DNA damage response (DDR) by being conveniently positioned at the replication fork to coordinate DNA replication with DNA repair and DNA damage tolerance pathways (PubMed:24939902). Acts as a loading platform to recruit DDR proteins that allow completion of DNA replication after DNA damage and promote postreplication repair: Monoubiquitinated PCNA leads to recruitment of translesion (TLS) polymerases, while 'Lys-63'-linked polyubiquitination of PCNA is involved in error-free pathway and employs recombination mechanisms to synthesize across the lesion (PubMed:24695737).

关联

项与 PCNA 相关的药物

AOH-1996

靶点

PCNA

作用机制

PCNA inhibitors

在研机构

City of Hope National Medical Center

原研机构

City of Hope National Medical Center

在研适应症

平滑肌肉瘤 [+6]

非在研适应症-

最高研发阶段临床1期

首次获批国家/地区-

首次获批日期1800-01-20

ATX-101 (APIM Therapeutics)

靶点

PCNA

作用机制

PCNA调节剂

在研机构

Allay Therapeutics, Inc.初创企业

原研机构

Norwegian University of Science & Technology

在研适应症

术后疼痛

非在研适应症

膀胱癌 [+11]

最高研发阶段临床申请

首次获批国家/地区-

首次获批日期1800-01-20

PCNA-I1

靶点

PCNA

作用机制

PCNA inhibitors

在研机构

Beckman Research Institute of The City of Hope

原研机构

The University of Cincinnati College of Medicine

在研适应症

肿瘤

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

项与 PCNA 相关的临床试验

NCT05227326 / Recruiting临床1期IIT

First in Human Phase 1 Study of AOH1996 in Patients With Refractory Solid Tumors

This phase I trial studies the side effects and best dose of AOH1996 in treating patients with solid tumors that do not respond to treatment (refractory). AOH1996 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

开始日期2022-08-12

申办/合作机构

City of Hope National Medical Center

[+1]

NCT05116683 / Terminated临床2期IIT

A Phase II Study, With a Safety lead-in, to Evaluate ATX-101, a Peptide Drug Targeting PCNA, in Advanced Dedifferentiated Liposarcoma and Leiomyosarcoma

The purpose of this study is to evaluate the effectiveness of a new investigational drug, ATX-101, for the treatment of dedifferentiated liposarcoma (LPS) and leiomyosarcoma (LMS). ATX-101 is an intravenous (IV) drug which blocks the interaction of a protein called PCNA with a number of "stress response" proteins. These interactions are thought to be important for cancer cell survival and growth. ATX-101 may disrupt these interactions and therefore help treat the cancer. In this study, all patients will receive the same treatment. Most of the exams, tests, and procedures are part of the usual approach to medical care for this condition. However, some additional tests or procedures may be performed, and other tests may be performed more frequently than usual.

开始日期2022-01-11

申办/合作机构

Columbia University

NCT04814875 / Terminated临床1/2期

Phase 1b/2a Study Investigating ATX-101 in Combination With Platinum-based Chemotherapy in Platinum-sensitive, Recurrent Ovarian, Fallopian Tube and Primary Peritoneal Cancer

This is a Phase 1b/2a multicenter study, which consists of two parts:
Part 1: the Phase 1b part of the study will investigate the safety of the combination of ATX-101 with carboplatin/pegylated liposomal doxorubicin (ACD). ATX-101 will be administered intravenously in three escalation cohorts: 20, 30, and 45 mg/m² according to a 3+3 design. In the case where 20 mg/m² is not tolerated, the dose can be de-escalated to 15 mg/m².
Part 2: the Phase 2a part of the study will investigate the efficacy and safety of ACD.
ATX-101 will be administered at the dose defined in Part 1 of the study.
Treatment will continue up to six cycles or until disease progression or unacceptable toxicity, participant withdrawal of consent, non-compliance, lost to follow-up, or withdrawal at the Investigators discretion, whichever occurs first.

开始日期2021-09-01

申办/合作机构

Therapim Pty Ltd

[+1]

100 项与 PCNA 相关的临床结果

登录后查看更多信息

100 项与 PCNA 相关的转化医学

登录后查看更多信息

0 项与 PCNA 相关的专利（医药）

登录后查看更多信息

22,278

项与 PCNA 相关的文献（医药）

2025-01-01·Molecular medicine reports

Melittin promotes the proliferation of Schwann cells in hyperglycemic environment by up‑regulating the Crabp2/Wnt/β‑catenin signaling pathway.

Article

作者: Yang, Dawei ; Zhou, Jiaqian ; Chen, Yuxia ; Zhang, Qiuyi ; Huang, Wei

The present study aimed to explore the effect of melittin (MLT) on the growth of Schwann cells (SCs) in high glucose conditions and to understand the mechanisms involved. The goal was to provide a theoretical basis for using MLT in the treatment of diabetic peripheral neuropathy (DPN). The CCK‑8 assay was used to measure cell activity at different concentrations of glucose and MLT. Flow cytometry was employed to analyze the effect of MLT on cell cycle phases and apoptosis in SCs under high glucose conditions. To identify differentially expressed proteins, 4D label‑free quantitative proteomics with liquid chromatography‑mass spectrometry was used, followed by biological analysis to explore potential mechanisms. PCR, western blotting and immunofluorescence were conducted to confirm these mechanisms. Melittin (0.2 µg/ml) increased the proliferation of SCs in a high glucose environment. Flow cytometry showed that after MLT treatment, the proportion of cells in the G₂/M+S phase increased and the combined ratio of early and late apoptosis decreased under high glucose conditions. Proteomics identified 1,784 proteins with significant changes in expression; 725 were upregulated, and 1,059 were downregulated. Kyoto Encyclopedia of Genes and Genomes analysis indicated that the differentially expressed proteins were mainly involved in metabolic pathways and neurodegenerative disease pathways. PCR, western blotting and immunofluorescence confirmed the increase in Crabp2, Wnt3a, C‑Jun, CDK4, CyclinD1 and proliferating cell nuclear antigen. In high glucose conditions, MLT protects SCs from glucose toxicity by upregulating the Crabp2/Wnt/β‑catenin signaling pathway, potentially providing a new treatment for DPN.

2025-01-01·Journal of Inorganic Biochemistry

Bio-molecular Fe(III) and Zn(II) complexes stimulate the interplay between PI3K/AKT1/EGFR inhibition and induce autophagy and apoptosis in epidermal skin cell cancer

Article

作者: Alshehri, Khulud M ; Alhamdi, Heba W ; Elshaarawy, Reda F M ; Elbehairi, Serag Eldin I. ; Hafez, Hani S ; Alshehri, Khulud M. ; Elshaarawy, Reda F.M. ; Alhamdi, Heba W. ; Radwan, Nancy A.-F. ; Elbehairi, Serag Eldin I ; Shati, Ali A ; Hafez, Hani S. ; Welson, Mary ; Radwan, Nancy A-F ; Awaji, Aeshah A. ; Alfaifi, Mohammad Y ; Awaji, Aeshah A ; Alfaifi, Mohammad Y. ; Shati, Ali A.

This study investigated the effectiveness and safety of a hybrid thiosemicarbazone ligand (HL) and its metal complexes (Mn^II-L, Fe^III-L, Ni^II-HL, and Zn^II-HL) against epidermoid carcinoma (A-431). The results indicated that Fe^III-L is the most effective, with a high selectivity index of 8.01 and an IC₅₀ of 17.49 ± 2.12 μM for Fe^III-L. The study also revealed that the synthesized complexes effectively inhibited gene expression of the Phosphoinositide 3-kinases (PI3K), alpha serine/threonine-protein kinase (AKT1), epidermal growth factor receptor (EGFR2) axis mechanism (P < 0.0001). Additionally, these complexes trigger a chain of events that include the inhibition of proliferating cell nuclear antigen (PCNA), transforming growth factor β1 (TGF β1), and topoisomerase II, and leading to a decrease in epidermoid cell proliferation. Furthermore, the inhibitory activity also resulted in the upregulation of caspases 3 and 9, indicating the acceleration of apoptotic markers, and the down regulation of miRNA221, suggesting a decrease in epidermoid proliferation. Molecular modeling of Fe^III-L revealed that it had the best binding energy -8.02 kcal/mol and interacted with five hydrophobic π-interactions with Val270, Gln79, Leu210, and Trp80 against AKT1. Furthermore, the binding orientation of Fe^III-L with Topoisomerase II was found to be the most stable, with a binding energy -8.25 kcal/mol. This stability was attributed to the presence of five hydrophobic π-interactions with His759, Guanin13, Cytosin8, and Ala465, and numerous ionic interactions, which were more favorable than those of doxorubicin and etoposide for new regimens of chemotherapeutic activities against skin cancer.

2025-01-01·Brain Research

Quinic acid contributes to neurogenesis: Targeting Notch pathway a key player in hippocampus

Article

作者: Iftikhar, Kanwal ; Shahid, Maha ; Niaz, Maryam ; Faizi, Shaheen ; Usman Simjee, Shabana

Coordinated proliferation and differentiation of neural stem cells (NSCs) results in continuous neurogenesis. The present study provides novel insights into the Notch intracellular signaling in neuronal cell proliferation, maintenance, migration, and differentiation regulated by naturally based Quinic acid (QA) in primary hippocampal cell culture. Further, this study might help in the discovery and development of lead molecules that can overcome the challenges in the treatment of neurodegenerative diseases. The growth supporting effect of QA was studied using Alamar Blue assay. The migratory potential of QA was evaluated using scratch assay. The in vitro H₂O₂-induced oxidative stress model was used to upregulate neuronal survival after QA treatment. The RT-qPCR and immunocytochemical analysis were performed for selected markers of Notch signaling to determine the proliferation, differentiation, and maintenance of NSCs at gene and molecular levels. The Mash1 and Ngn2 are the upstream proneural genes of the Notch pathway which were included to evaluate the differentiation of NSCs into mature neurons after treatment with QA. Furthermore, regarding the role of QA in maintaining the pool of NPCs, we used Notch1 and Hes1 markers for proliferation analysis. Also, secondary neuronal markers i.e. Pax6, PCNA, and Mcm2 were included in this study and their gene expression analysis was analyzed following treatment with QA. Based on the study's results, we suggest that naturally based QA can promote the growth and differentiation of neonatal NSCs residing in hippocampal regions into neuronal lineage. Therefore, we propose that the neurogenic potential of QA can be employed to prevent and treat neurodegenerative diseases.

项与 PCNA 相关的新闻（医药）

2024-10-14

·精准药物

识别CyclinE-CDK2变构位点的新策略及小分子发现

在人类基因组中，有超过50%编码蛋白的基因具有同源亚型，这些亚型具有相似的序列和结构。同源亚型蛋白在细胞中产生重叠功能有助于细胞系统的稳健性。尤其在癌症等病理条件下，许多同源亚型蛋白对细胞的存活至关重要。近年来，发现许多仅在同源亚型蛋白中存在的半胱氨酸残基，通过与共价小分子探针的相互作用，能够帮助发现潜在的配体结合位点。然而，对于缺乏这种半胱氨酸残基的蛋白，这种方法难以奏效。最近，来自Scripps研究所的研究人员提出“Paralog-hopping”策略来识别缺乏半胱氨酸的同源亚型蛋白中的新配体结合位点。为了验证这个策略，他们选择Cyclin同源亚型蛋白CCNE2(Cyclin E2)和CCNE1(Cyclin E1)（二者都通过与CDK2的结合，调控细胞顺利的通过G1期，进入S期）作为对象开展位点探索。 CCNE1和CCNE2都是肿瘤细胞生长所必需的基因，但相比之下，更多的肿瘤细胞对CCNE1的依赖性更强，尤其是在卵巢癌中。研究人员基于前期发现的色氨酸丙烯酰胺（tryptoline acrylamide）立体探针在肿瘤细胞系中开展了ABPP（activity-based protein profiling）实验，结果表明(R,R)-WX-03-59和WX-03-348会与CCNE2的C109发生立体选择性的特异性反应，该半胱氨酸突变为CCNE2-C109A后，WX-03-348不再与突变体反应，表明CCNE2在C109附近具有可结合位点。为了促进CCNE1:CDK2抑制剂的开发，研究人员对两者结构进行分析发现，CCNE2的C109位点在CCNE1中对应为N112。为了明确CCNE1是否也可能拥有在CCNE2-C109对应位置的结合位点。通过评估炔烃修饰的色氨酸丙烯酰胺的扩展文库与纯化的CCNE1:CDK2和CCNE1-N112C的反应性。结果表明，WX-02-520优先与CCNE1-N112C反应，并可被WX-02-308阻断，表明CCNE1靠近N112和CCNE2靠近C109的位置均有小分子结合位点。接下来，他们建立一种更高通量的测定法来筛选与CCNE1-N112C结合的小分子。首先合成了WX-02308的衍生物，在色氨酸核心的不同位置连接PEG3-甲酯连接基，通过GEL-ABPP实验，发现WX-02-588及其对映体WX-02-589在C3位的PEG3-甲酯修饰具有更好的立体选择性；随后将荧光染料偶联至这两种化合物，生成YZ-01-A和YZ-01-B；利用GEL-ABPP验证了YZ-01-A与纯化的CCNE1-N112C:CDK2复合物的立体选择性反应的程度比纯化的野生型CCNE1:CDK2复合物的程度大得多。此外，他们还使用了NanoBRET（Nano Bioluminescence Resonance Energy Transfer）方法证实，YZ-01-A选择性地结合了CCNE1-N112C，但不结合野生型CCNE1。这表明NanoBRET和GEL-ABPP可用于精确评估化合物的靶标结合能力及抑制效果。通过NanoBRET测定技术，可以筛选出既能与CCNE1-N112C复合物可逆结合的小分子化合物，也能判断与野生型CCNE1复合物是否相互作用。为了再次确认这一能力，利用最近的专利，他们选择并合成了两种代表性分子I-125A和I-198；通过GEl-ABPP和NanoBRET实验测试，他们发现I-125A和I-198都能够浓度依赖性地阻断YZ-01-A与CCNE1-N112C的结合，并且I-125A表现出比I-198更强的抑制作用。它们的抑制作用是具有位点特异性和立体选择性的，它们仅对CCNE1-N112C产生抑制作用，而对野生型CCNE1不产生影响。进一步，他们发现I-125A不影响ATP位点NanoBRET示踪剂K-10与CCNE1 N112C或野生型CCNE1复合物的结合，与ATP位点竞争性抑制剂dinaciclib观察到的完全抑制活性形成对比，表明I-125A和dinaciclib的作用机制不同。尽管dinaciclib能阻断ATP结合位点的活性，它却不能影响YZ-01-A与CCNE1-N112C的相互作用，说明了YZ-01-A是通过不同于与ATP位点结合的方式与CCNE1-N112C复合物相互作用的。通过ABPP实验，发现探针WX-02-520在细胞中富集了约20种蛋白，其中6种蛋白（包括CCNE1-N112C）的立体选择性结合可被WX-02-308阻断。然而I-125A仅阻止了WX-02-520对CCNE1-N112C的富集，表明其高度选择性。通过解析野生型CCNE1和CDK2与I-125A和I-198复合物的共晶结构，发现这些化合物的结合口袋位于CDK2的C叶和A环附近，远离ATP结合位点，靠近CCNE1的α1、α7和α8螺旋。这表明它们并非通过直接与ATP口袋结合起作用，而是通过一个更隐蔽的、位于变构位点的口袋发挥作用。I-125A,I-198与CDK2的关键相互作用包括R122侧链胍基与I-125A和I-198的环丙基酰胺羰基之间的氢键，T182主链酰胺与噻唑或吡唑氮原子之间的氢键，此外还有疏水性和溶剂介导的相互作用。这些相互作用进一步增强了化合物与蛋白质的结合稳定性。I-198 结合口袋在Apo CCNE1:CDK2 结构中大部分不存在，通过分析这个口袋是通过CCNE1的α7和α8螺旋之间的环的运动形成的，并且还涉及CCNE1的α8螺旋（残基L244-P266）和CDK2的A环（helixA）的结构调整。进而干扰了CDK2的磷酸化位点和底物肽结合，最终抑制CDK2活性。这一研究为理解变构小分子如何调节CDK2的活性提供了重要的机制见解。通过ADP-Glo实验，他们测定这些化合物对激酶活性的抑制作用：使用RB1肽作为底物，实验结果表明I-125A作为CCNE1抑制剂比I-198更有效，两者的IC50值分别为0.13μM和0.75μM。对野生型CCNE1-CDK2复合物抑制的IC50分别为:17nM,0.35μM。使用另一种底物组蛋白H1测试时，发现I-125A和I-198的相对效力仍然相似。然而ATP位点CDK2抑制剂dinaciclib在这两个底物测定中都完全阻断了野生型CCNE1和CCNE1-N112C复合物的活性，表现出更强的抑制作用。 WX-02-308和WX-02-14是色氨酸丙烯酰胺类化合物，虽然它们能够在ABPP实验中完全结合N112C，但在底物测定中未表现出抑制CCNE1-N112C复合物的效果.研究还发现，I-125A和I-198对CCNE2复合物的激酶活性没有抑制作用，这进一步表明这些化合物具有特定的靶向性。研究人员试图进一步探索I-125A和I-198的细胞内活性。通过NanoBRET和纤维素GEL-ABPP实验测试，I-125A对CCNE1-N112C的TE50为1.0μM，I-198为10μM。进一步，他们开发了一种新的高通量筛选(High throughput screening，HTS)法，用于识别与复合物中的变构位点结合的其他化合物。为了实现这一目标，他们对NanoBRET测定进行了改进，使用稳定性更好的底物vivazine，以维持约10小时的稳定发光信号。通过将反应时间延长至185分钟，获得了强烈的立体选择性BRET信号。优化后的测定法在170分钟内表现出良好的实验性能（Z'值为0.85，信噪比约为30）。研究验证了化合物I-125A和I-198与CCNE1-N112C的结合效力，并对324种大环化合物进行了初步筛选，成功重新发现I-125A作为命中配体。这证明了该筛选方法的有效性，并认为可以用于更大规模的HTS，以发现更多结合CCNE1变构位点的化学物质，为药物发现提供工具。综上，本研究成功证明了 “Paralog-hopping” 策略的可行性。通过利用化学蛋白质组学中发现的亲电试剂-半胱氨酸相互作用，探索到蛋白质配体结合口袋，可以对不含半胱氨酸的同源亚型蛋白的对应活性口袋开发非共价配体。参考文献: Zhang Y, Liu Z, Hirschi M, et al. An allosteric cyclin E-CDK2 site mapped by paralog hopping with covalent probes[J]. Nature Chemical Biology, 2024: 1-12. 声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号粉丝群/投稿/授权/广告等请联系公众号助手觉得本文好看，请点这里↓

临床1期临床申请临床终止

2024-09-25

·生物制品圈

体外转录(IVT) mRNA再次牵手热门领域——PROTAC疗法

导读：基于“事件驱动”的药理学，蛋白水解靶向嵌合体（PROTAC）技术借助泛素-蛋白酶体系统（UPS）可以实现“不可成药”目标蛋白（POI）的降解，是药物开发的新兴技术。然而，当前在研的PROTAC技术主要有小分子药物和重组蛋白（bioPROTAC）两种类型。其中小分子药物存在靶蛋白结合部分优化异常困难的挑战，而重组蛋白面临着膜渗透性差等难题随着体外转录（IVT）mRNA和脂质纳米颗粒（LNP）技术的成熟和广泛应用，目前PROTAC的研究方向也采纳了IVT mRNA技术。本期文章，菌菌汇总了IVT mRNA-LNP技术在热门领域PROTAC疗法中的应用潜能。 01 mRNA PROTAC靶向PCNA 题目：Targeted degradation of PCNA outperforms stoichiometric inhibition to result in programed cell death 作者：默沙东（MSD）药物研发团队期刊： Cell Chemical Biology（IF: 6.6）链接： https://pubmed.ncbi.nlm.nih.gov/36318925/ 靶点介绍：他们选择增殖细胞核抗原（PCNA）这一肿瘤靶点。PCNA在DNA复制和细胞增殖中发挥关键作用。抑制PCNA能够使肿瘤细胞对化疗敏感，因此被认为是一种广谱抗肿瘤靶点。早期，MSD研发团队开发了靶向PCNA的bioPROTAC平台Con1-SPOP。Con1-SPOP是一种由靶点蛋白结合域和 E3 连接酶组成的融合蛋白，能够有效降解靶蛋白。该候选药物面临的主要挑战是药物递送问题。研究方法：本次研究由MSD多个药物研发部门合作在Cell Chemical Biology发表。他们尝试利用LNP递送Con1-SPOP mRNA并通过体内外试验评估了其作用效果。Con1-SPOP mRNA的制备过程包括质粒模板制备、体外转录（IVT）、LNP包封。研究通过细胞凋亡试验、蛋白组分析、流式分析、小鼠异种移植模型评估Con1-SPOP mRNA的抑制活性。研究结果：研究人员通过体内和体外试验表明，PCNA降解导致DNA损伤、p53激活和细胞凋亡，且PCNA的降解在整体蛋白质组学特征与PCNA抑制方面有所不同。PCNA在体内的降解导致肿瘤生长完全被抑制。整体而言，脂质纳米颗粒递送mRNA bioPROTAC分子能够快速降解PCNA蛋白。图示基于mRNA的bioPROTAC平台 02 mRNA PROTAC靶向ERα与BCL-xL 题目：mRNA PROTACs: engineering PROTACs for high-efficiency targeted protein degradation 作者：清华大学深圳国际研究生院谭英课题组期刊：MedComm (2020) （IF: 10.7）链接：https://pubmed.ncbi.nlm.nih.gov/38374873/ 靶点介绍：研究使用了两个靶蛋白验证mRNA PROTAC（m-PROTAC）的适用性：雌激素受体 α （ERα）和 B 细胞超大淋巴瘤蛋白（BCL-xL）。ERα在大多数类型的乳腺癌细胞中过表达，是乳腺癌治疗的一个重要靶点。BCL-xL是一种抗凋亡蛋白，在多种癌症细胞中过表达，是抗癌治疗的关键靶点。研究方法：研究中mRNA PROTAC同样编码靶点蛋白结合域（配体）和 E3 连接酶组成的融合蛋白，其中ERα涉及了两个配体序列，通过Linker（GSGS）连接，同时在上游添加了eGFP和P2A作为报告序列。图示基于mRNA的bioPROTAC平台研究结果：体外实验表明，m-PROTACs 可以成功降解不同细胞系中的靶蛋白，并且比传统的 p-PROTACs 更有效地抑制细胞增殖。体内实验表明，m-PROTAC 处理导致 4T1 小鼠异种移植模型中的肿瘤显著消退。 03 mRNA PROTAC靶向KRAS蛋白题目：Lipid-mediated intracellular delivery of recombinant bioPROTACs for the rapid degradation of undruggable proteins 作者：宾夕法尼亚大学Andrew Tsourkas课题组期刊：Nature Communications （IF: 14.7）链接：https://pubmed.ncbi.nlm.nih.gov/38987546/ 这项研究的初衷是解决bioPROTAC递送的难题，他们基于LNP递送平台，开发了一种模块化的重组bioPROTAC平台。其一是优化的bioPROTAC蛋白组成，包括三种必须元素：N 端 E3连接酶IpaH9.8、靶点蛋白结合配体DARPin和C 端的阴离子多肽标签ApP。其二是优化的LNP递送系统，在常规的可电离脂质（C12-200）、辅助磷脂DOPE、胆固醇、PEG脂质四组分LNP的基础上，添加了另一种阳离子脂质DOTAP，且磷脂占比大幅提高。这项研究中使用了bioPROTAC mRNA作为阳性对照，表明其在靶蛋白降解和肿瘤细胞抑制效应方面的作用与重组bioPROTAC类似，而蛋白质组学分析显示部分差异。图示基于蛋白的bioPROTAC平台 04 circRNA PROTAC靶向PCNA 题目：Circular mRNA encoded PROTAC (RiboPROTAC) as a new platform for the degradation of intracellular therapeutic targets 作者：苏州科锐迈德研发团队期刊：bioRxiv预印本链接：https://www.biorxiv.org/content/10.1101/2022.04.22.489232v1 靶点介绍：科锐迈德同样选择了一种广谱抗肿瘤靶点——增殖细胞核抗原（PCNA），这一点与上文中默沙东团队的选择一致。研究方法：科锐迈德团队使用了一种特殊结构的IVT mRNA——环状RNA（circRNA）编码 bioPROTAC 蛋白质降解剂，他们在文章中将其命名为RiboPROTAC。circRNA的制备步骤包括：质粒（IVT模板）合成、IVT反应、DNase I消化和HPLC纯化。circRNA的IVT模板序列包含PIE 元件、IRES、编码区等必要元件，其中编码区域由 PCNA 结合肽、柔性接头和 E3 连接酶 SPOP167-374 组成。研究通过细胞增殖实验、小鼠异种移植模型评估了PROTAC mRNA的抑制活性。研究结果：使用RiboPROTAC转染细胞后，高达75%的目的蛋白被降解。癌细胞系 B16F10 和 A549中PCNA蛋白水平降低，而且细胞增殖受到强烈抑制、细胞凋亡率增高、细胞周期停滞。体外结果表明RiboPROTAC 通过降解PCNA抑制癌细胞的增殖。小鼠体内实验表明，编码 PCNA 靶向降解剂的circRNA表现出显著的肿瘤抑制作用。图示基于circRNA的RiboPROTAC平台 05 总结蛋白水解靶向嵌合体（PROTAC）技术是一种新的治疗模式，通过将E3泛素连接酶受体工程募集到目标蛋白，诱导目标蛋白的多泛素化和降解，从而消耗“有害”蛋白，达到治疗疾病的目的。 mRNA介导的PROTAC策略整合了PROTAC蛋白和IVT-mRNA技术的优势： 1)相比RNAi等技术，bioPROTAC能够识别特定构象或翻译后修饰的蛋白，完全根除蛋白质及其相关的生物学功能； 2)相比小分子介导的PROTAC疗法，mRNA PROTAC具有更好的生物相容性、选择性和安全性，且具有更低的剂量和更好的催化性质； 3)相比蛋白介导的PROTAC疗法，mRNA及其LNP递送系统的安全性已在大规模人群中得到了验证，能够避免PROTAC蛋白的递送问题。识别微信二维码，添加生物制品圈小编，符合条件者即可加入生物制品微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

信使RNA蛋白降解靶向嵌合体

2024-06-18

·医药魔方

2例患者死亡，WEE1抑制剂3项临床研究遭FDA暂停，Zentalis股价大跌50%

6月18日，Zentalis Pharmaceuticals宣布，FDA已暂停该公司WEE1抑制剂azenosertib的3项临床研究，分别是：治疗实体瘤的I期剂量递增研究（ZN-c3-001），治疗铂耐药卵巢癌（PROC）的II期ZN-c3-005（DENALI）研究以及治疗子宫浆液性癌（USC）的II期ZN-c3-004（TETON）研究。FDA做出这一行动的原因是在DENALI研究中出现两例因疑似败血症而死亡病例。这一消息导致Zentali股价大跌50.66%。 Zentali表示已经完成了DENALI研究Ib期队列100多例受试者入组，公司将在今年晚些时候分享总体疗效和安全性数据。 Azenosertib是一款新型、选择性口服WEE1抑制剂。DNA损伤后，WEE1激酶在G1-S和G2-M检查点磷酸化并使Cyclin/CDK复合物失活，从而停止细胞周期并允许修复。通过抑制WEE1，azenosertib可激活CDKs使细胞周期在高水平DNA损伤的情况下继续进行，从而使癌细胞积累DNA损伤并最终死亡。 Zentali围绕azenosertib开展了数10项临床研究，部分临床研究是与辉瑞和GSK合作。好在此次仅暂停了3项试验，另外的几项还在正常推进。 Zentali表示，有望在今年晚些时候公布ZN-c3-001和I/II期ZN-c3-006 （MAMMOTH）研究的结果。将在解决部分临床暂停后提供azenosertib临床开发和其他数据时间表的额外更新。Zentalis还表示将仍然致力于azenosertib的开发，并将这种潜在的改变妇科恶性肿瘤的治疗方法带给患者。 Copyright © 2024 PHARMCUBE. All Rights Reserved. 欢迎转发分享及合理引用，引用时请在显要位置标明文章来源；如需转载，请给微信公众号后台留言或发送消息，并注明公众号名称及ID。免责申明：本微信文章中的信息仅供一般参考之用，不可直接作为决策内容，医药魔方不对任何主体因使用本文内容而导致的任何损失承担责任。

临床2期临床1期