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更新于：2025-05-07

SLFN12

更新于：2025-05-07

基本信息

别名

FLJ10260、Ribonuclease SLFN12、schlafen family member 12

+ [1]

简介

Ribonuclease which is part of an E2/17beta-estradiol-induced pro-apoptotic signaling pathway. E2 stabilizes the PDE3A/SLFN12 complex in the cytosol, promoting the dephosphorylation of SLFN12 and activating its pro-apoptotic ribosomal RNA/rRNA ribonuclease activity. This apoptotic pathway might be relevant in tissues with high concentration of E2 and be for instance involved in placenta remodeling (PubMed:31420216, PubMed:34272366, PubMed:34707099, PubMed:35104454). May play a role in cell differentiation (PubMed:30045019).

关联

项与 SLFN12 相关的药物

OPB-171775

靶点

SLFN12

作用机制

SLFN12抑制剂

在研机构

Otsuka Pharmaceutical Co., Ltd.

原研机构

Otsuka Pharmaceutical Co., Ltd.

在研适应症

胃肠道间质瘤

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

OST08267

靶点

PDE3A x SLFN12

作用机制

PDE3A抑制剂 [+1]

在研机构

盛睿泽华医药科技（苏州）有限公司

原研机构

盛睿泽华医药科技（苏州）有限公司

在研适应症

胃肠道间质瘤

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

CN117062819

专利挖掘

靶点

PDE3A x SLFN12

作用机制-

在研机构

清华大学 [+1]

原研机构

清华大学 [+1]

在研适应症

骨髓增生异常综合征 [+1]

非在研适应症-

最高研发阶段药物发现

首次获批国家/地区-

首次获批日期1800-01-20

项与 SLFN12 相关的临床试验

NCT04809805

/ Terminated临床1期

An Open Label, Phase 1, First-in-human, Study to Evaluate Safety, Tolerability, Maximum Tolerated or Administered Dose, Pharmacokinetics, Pharmacodynamics and Tumor Response Profile of Schlafen12 Complex Inducer (SLFN12 ci) BAY 2666605 in Participants With Metastatic Melanoma and Other Advanced Solid Tumors.

Researchers are looking for a better way to treat people who have advanced cancer.
In this study researchers want to learn more about a new substance called BAY2666605. BAY2666605 triggers the formation of a complex of two proteins called SLFN12 and PDE3A. This complex drive cancer cells into cell death by a mechanism called apoptosis. The complex is only formed in the cancers which contain both proteins.
This study is done in adult patients who have certain types of advanced cancers that cannot be cured by drugs that are currently available. The cancer types include skin cancer that has spread to other parts of the body and cancer that started in the bones or soft tissue, the ovaries, or the brain. Patients with these cancers are only included if the cells of the patient's cancer contain the building plan to produce SLFN12-phosphodiesterase 3A (PDE3A) complex. To confirm this, a specific test is performed with the cancer cells.
The researchers will study how BAY2666605 moves into, through and out of the body. Researchers will try to find the best dose that can be given, how safe BAY2666605 is and how it affects the body. Researchers will also study the action of BAY2666605 against the cancer. Part A will include about 36 participants and up to another 12 participants. Part B will include about 41 participants. All of the participants will take BAY2666605 by mouth as either a liquid or as tablets.
During the study, the participants will take the treatment in 4 week periods called cycles. In each cycle, the participants will in general take BAY2666605 once daily. The participants may also be asked to do overnight fasting before the intake of substance and to have standard high-fat, high-calorie breakfast on some days before taking the dose.
These 4 week cycles will be repeated throughout the trial. The participants can take BAY2666605 until their cancer gets worse, until they have medical problems, or until they leave the trial. Participants will have around 18 visits in each cycle. Some of the visits can also be done via Phone.
During the trial, the study team will take blood and urine samples, do physical examinations and check the participants' heart health using an electrocardiogram (ECG) and an ultrasound of the heart. The study team will also take pictures of the participants' tumors using CT or MRI scans. The study team will ask how the participants are feeling, if participants have any medical problems or if participants are taking any other medicine. About 1 month and 3 months after the last dose, the participants will have another visit and a phone call respectively where participants will be checked for and asked about medical problems. The researchers will then contact the participants every 3 months until the trial ends.

开始日期2021-04-15

申办/合作机构

Bayer AG

JPRN-jRCT2031200206

/ Completed临床1期IIT

An open-label, uncontrolled, dose-escalation, phase 1 trial to investigate the tolerability and safety of OPB-171775 in patients with advanced or metastatic malignant solid tumors

开始日期2020-11-06

申办/合作机构-

100 项与 SLFN12 相关的临床结果

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100 项与 SLFN12 相关的转化医学

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0 项与 SLFN12 相关的专利（医药）

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项与 SLFN12 相关的文献（医药）

2025-02-17·Human Molecular Genetics

Integrated multi-omics analysis revealed the molecular networks and potential targets of cellular senescence in Alzheimer’s disease

Article

作者: Liu, Shutong ; Zhang, Ge ; Han, Xinwei ; Xu, Yudi ; Zhang, Yuyuan ; Liu, Huimin ; Liu, Zaoqu ; Zhou, Zhaokai ; Ma, Hongxuan ; Qin, Hongzhuo

AbstractCellular senescence (CS) is a hallmark of Alzheimer’s disease (AD). However, the mechanisms through which CS contributes to AD pathogenesis remain poorly understood. We found that CS level in AD was higher compared with the healthy control group. Transcriptome-based differential expression analysis identified 113 CS-related genes in blood and 410 in brain tissue as potential candidate genes involved in AD. To further explore the causal role of these genes, an integrative mendelian randomization analysis was conducted, combining AD genome-wide association study summary statistics with expression quantitative trait loci (eQTL) and DNA methylation quantitative trait loci (mQTL) data from blood samples, which identified five putative AD-causal genes (CENPW, EXOSC9, HSPB11, SLC44A2, and SLFN12) and 18 corresponding DNA methylation probes. Additionally, integrative analysis between eQTLs and mQTLs from blood uncovered two genes and 12 corresponding regulatory elements involved in AD. Furthermore, two genes (CDKN2B and ITGAV) were prioritized as putative causal genes in brain tissue and were validated through in vitro experiments. The multi-omics integration study revealed the potential role and underlying biological mechanisms of CS driven by genetic predisposition in AD. This study contributed to fundamental understanding of CS in AD pathogenesis and facilitated the identification of potential therapeutic targets for AD prevention and treatment.

2024-12-16·Clinical Cancer Research

Article

2024-12-01·Journal of Cellular and Molecular Medicine

Deciphering the Role of SLFN12: A Novel Biomarker for Predicting Immunotherapy Outcomes in Glioma Patients Through Artificial Intelligence

Article

作者: Miao, Changfeng ; Li, Jiale ; Chen, Zigui ; Liu, Chao ; Luo, Qisheng ; Peng, Jun ; Zheng, Wei ; Zhang, He ; Qiu, Yingqi ; Fang, Yuhua ; Luo, Jiawei ; Xia, Ying

ABSTRACTGliomas are the most prevalent form of primary brain tumours. Recently, targeting the PD‐1 pathway with immunotherapies has shown promise as a novel glioma treatment. However, not all patients experience long‐lasting benefits, underscoring the necessity to discover reliable biomarkers for predicting treatment outcomes. This study applied a range of advanced artificial intelligence methods to identify a new biomarker linked to the effectiveness of anti‐PD‐1 immunotherapy in glioma patients. Through an extensive analysis of single‐cell RNA sequencing and bulk transcriptomic data from over 3000 patients, the gene SLFN12 emerged as a significant and independent predictor of immunotherapy response. Our results indicate that elevated SLFN12 expression is associated with worse overall survival across various glioma cohorts. Notably, we found that patients with high SLFN12 levels are less likely to respond favourably to anti‐PD‐1 treatment, positioning SLFN12 as a clinically valuable biomarker for personalised treatment decisions. Functional studies revealed that SLFN12 is involved in key immune‐related pathways, shedding light on its potential role in altering the tumour microenvironment and impacting immunotherapy outcomes. Additional laboratory experiments confirmed the role of SLFN12 in promoting glioma cell proliferation, migration and macrophage recruitment. In summary, this study identifies SLFN12 as a novel biomarker for predicting immunotherapy response in glioma patients, offering new insights for precision immunotherapy approaches.

项与 SLFN12 相关的新闻（医药）

2023-05-12

·生物谷

喜报 |科进生物完成近亿元新一轮融资、新艾滋病病毒限制因子确定

1、细胞治疗企业“先康达生命”获数千万元Pre-A轮融资细胞治疗企业「先康达生命」近日完成数千万元人民币的Pre-A轮融资，由广东联景投资集团有限公司（简称“联景投资”）旗下基金领投。新一轮融资主要用于推进实体瘤CAR-T细胞药物的临床研究及IND申报。先康达生命是先康达集团核心子公司，是一家专注于实体瘤细胞免疫疗法研究及产业化的国家高新技术企业，公司以CAR-T产品为先导，同步布局CAR-NK、IPS-T等国际前沿技术，开发了三个具有自主知识产权的技术平台——R-Star、Trans-CAR、Boost-CAR，推动细胞疗法在实体瘤治疗领域的应用。（先康达生命）2、普译生物完成近亿元A轮融资，加速新一代生物纳米孔基因测序产品量产近日，北京普译生物科技有限公司（以下简称“普译生物”）宣布完成近亿元A轮融资。本轮融资由万孚生物领投，三美投资、尚势资本跟投，老股东IDG资本、水木创投继续加码支持。所获资金将主要用于具有自主知识产权的纳米孔蛋白及配套测序试剂的持续优化，加速基于硅基半导体测序芯片的中高通量纳米孔基因测序仪系列产品的量产落地和商业化应用。（普译生物）3、君跻基因完成数千万元天使轮融资，东方嘉富、吴中生物医药产业发展基金共同投资5月11日消息，苏州君跻基因科技有限公司（以下简称“君跻基因”）近日宣布完成数千万元天使轮融资，本轮由东方嘉富、吴中生物医药产业发展基金共同投资。本轮募集资金将用于加速自动化实验平台产品及产线的研发以及CRO/CDMO产品市场化进程的快速推进，为全球生命科学研究和生物医药产业提供强有力的生态。（君跻基因）4、科进生物完成近亿元新一轮融资，助力解决细胞培养新材料的“卡脖子”问题2023年5月12日，国内高端实验室耗材和新材料领军企业—上海科进生物技术有限公司近日宣布完成近亿元新一轮融资，本轮融资由兴证资本领投，毅达资本和曜金资本共同参与。本轮融资将用于科进生物在高端实验室耗材和细胞培养新材料等“卡脖子”领域的持续研发投入，以及高端实验室耗材生产基地的扩建和相关产品的市场推广。（动脉网）5、新艾滋病病毒限制因子确定据《自然》旗下期刊《通讯·生物学》最新论文，西班牙庞培法布拉大学的一项研究将Schlafen 12（SLFN 12）鉴定并定性为一种新的艾滋病病毒（HIV）限制因子。SLFN 12可阻止病毒蛋白的产生，并帮助感染病毒的细胞逃避抗艾滋病病毒治疗和免疫反应。这些发现为改进HIV感染的治疗策略铺平了道路。（财联社）6、基因编辑小牛表现出抗病毒能力美国科学家首次培育出对牛病毒性腹泻病毒（BVDV）具有抗性的基因编辑小牛，小牛对病毒的易感性显著降低，并且没有表现出明显的副作用。研究发表在《美国国家科学院院刊·Nexus》上。（财联社）

细胞疗法临床申请免疫疗法

2022-04-15

·新浪医药新闻

AACR上首次公布结构的10款疗法

日前，美国癌症研究协会（AACR）2022年会落下帷幕。AACR是全球规模最大的癌症研究会议之一，聚集了来自全球各地高质量的肿瘤学研究和临床进展。在其“New Drugs on the Horizon”系列报告中，多家生物技术和医药公司首次公布了在研疗法的分子结构。 1、候选药物：BAY 2666605，首款抗癌PDE3A-SLFN12分子胶研发机构：拜耳，Broad研究所 BAY 2666605是由拜耳（Bayer）和Broad研究所的科学家联合开发的一款促进PDE3A和SLFN12构成复合体的分子胶。PDE3A和SLFN12是在多种癌症中过度表达的两种蛋白。PDE3A和SLFN12的结合会刺激SLFN12的RNA酶活性，导致其特异性底物tRNA-Leu-TAA的切割，而tRNA-Leu-TAA的切割导致核糖体停顿，抑制蛋白合成并导致癌细胞死亡。 BAY 2666605已经进入1期临床试验阶段，用于治疗同时表达PDE3A和SLFN12的晚期实体瘤患者，包括黑色素瘤、卵巢癌和肉瘤。 2、候选药物：CFT8634，靶向BRD9蛋白降解剂研发机构：C4 Therapeutics CFT8634靶向的BRD9蛋白是控制染色质重塑的SWI/SNF复合体的重要组分，这一复合体在多种癌症中经常出现突变。CFT8634是一款双特异性分子，它能够将BRD9和E3泛素链接酶CRBN连接在一起，在BRD9蛋白上添加泛素修饰，导致BRD9的特异性降解。在滑膜肉瘤的临床前模型中，CFT8634表现出持续降低肿瘤体积的效果。这款在研疗法已经获得美国FDA授予治疗滑膜肉瘤的孤儿药资格，其IND申请在今年2月底获得许可，预计在上半年开始针对滑膜肉瘤患者的1期临床试验。 3、C4 Therapeutics公司还在AACR大会上公布了在研CRBN E3连接酶调节剂（CELMoDs）CFT7455作为单药疗法，治疗复发/难治性多发性骨髓瘤患者的初步临床试验结果。CFT7455通过与E3泛素连接酶CRBN结合，促进IKZF1/3的降解。 4、候选药物：FHD-286，BAF复合体别构抑制剂研发机构：Foghorn Therapeutics FHD-286是一款潜在“first-in-class”，BAF复合体口服抑制剂。BAF复合体（又名SWI/SNF复合体）在对DNA的表观遗传学调控方面起到重要作用。在很多癌症中，表观遗传学调控的变化导致致癌基因的过度表达或者抑癌基因的表达受到抑制，从而引发细胞的癌变。FHD-286通过选择性别构抑制BAF复合体中的ATP酶成分SMARCA4和SMARCA2，抑制BAF的功能。临床前研究显示，葡萄膜黑色素瘤和血液癌症细胞系对BAF复合体抑制剂尤为敏感。目前，FHD-286正在两项1期临床试验中接受检验，用于治疗复发/难治性急性髓系白血病和转移性葡萄膜黑色素瘤。该公司还在利用靶向蛋白降解的策略来降解BAF复合体，其靶向降解BRD9的在研疗法FHD-609也已经进入临床试验阶段。 5、候选药物：EZM0414，组蛋白甲基转移酶SETD2抑制剂研发机构：Epizyme EZM0414和上面提到的FHD-286和CFT8634一样，都是旨在通过靶向表观遗传学机制来治疗癌症。Epizyme公司致力于靶向表观遗传学调控开发创新疗法。其EZH2抑制剂Tazverik是首款获得FDA批准的EZH2抑制剂，EZH2是组蛋白甲基转移酶PRC2的催化亚基。Tazverik的获批也为靶向表观遗传学机制治疗癌症的策略做出了临床验证。 EZM0414是一款潜在“first-in-class”SETD2抑制剂。SETD2是一种组蛋白甲基转移酶，与PCR2具有类似的作用。EZM0414已经获得美国FDA授予的快速通道资格，用于治疗复发或难治性弥漫性大B细胞淋巴瘤（DLBCL）。Epizyme已经启动1期临床试验，检验它在多发性骨髓瘤和DLBCL患者中的效果。 6、候选药物：ABBV-CLS-484，磷酸酶PTPN2/N1抑制剂研发机构：AbbVie，Calico，Broad研究所 PTPN2/N1是蛋白酪氨酸磷酸酶，它们的作用是去除酪氨酸上添加的磷酸基团。在癌症免疫反应的多个步骤中起到重要作用。比如PTPN2可以调节耗竭CD8阳性T细胞的产生。磷酸酶是很难于靶向的靶点，由于它的催化亚基部分高度保守，靶向催化亚基的药物很容易同时抑制其它磷酸酶的活性，导致毒副作用。ABBV-CLS-484是一款靶向PTPN2活性位点的抑制剂，能够在pM水平抑制其活性。目前艾伯维已经开展1期临床试验，检验它与免疫检查点抑制剂联用的效果。 7、候选药物：KSQ-4279，潜在“first-in-class”别构USP1抑制剂研发机构：KSQ Therapeutics KSQ-4279是一款强力选择性USP1别构抑制剂，USP1是泛素特异性加工（ubiquitin-specific processing）蛋白家族的一员，在DNA损伤反应中具有重要作用。KSQ Therapeutics公司使用其基于CRISPR筛选的CRISPRomics技术平台发现，USP1是靶向特定基因组不稳定癌症的创新合成致死靶点。 KSQ-4279的别构抑制的特征让它对USP1具有很高的选择性，显著优于其它USP蛋白家族。临床前研究显示它作为单药或者与PARP抑制剂联用，在多款携带BRCA突变或同源重组缺陷的癌症模型中显示出疗效。而且，功能性基因组耐药性筛选发现，驱动对USP1抑制剂耐药性的遗传因素与驱动PARP抑制剂耐药性的遗传因子并不重叠。这意味着这一组合可能延缓或预防耐药性的产生。目前KSQ Therapeutics已经启动1期临床试验，在晚期实体瘤患者中评估它的效果。 8、候选药物：MRTX0902，针对KRAS驱动癌症的SOS1抑制剂研发机构：Mirati Therapeutics 过去几年中，靶向KRAS G12C的努力获得重大突破，安进公司的sotorasib和Mirati公司的adagrasib（MRTX849）都在临床试验中表现出活性。SOS蛋白是一款鸟嘌呤核苷酸交换因子（GEF），它在激活RAS家族蛋白方面起到重要作用。 MRTX0902是一款强力选择性SOS1口服抑制剂。Mirati公司的科学家采用基于结构的设计，发现了一系列化合物可以扰乱SOS1和KRAS之间的相互作用，阻止SOS1介导GTP取代与KRAS结合的GDP。与GDP结合的KRAS处于失活状态，而adagrasib能够与处于失活状态的KRAS G12C结合，抑制它的活性。因此，MRTX0902与adagrasib联用有望进一步增强adagrasib的效果。 9、候选疗法：GDC-6036，口服KRAS G12C共价抑制剂研发机构：基因泰克罗氏旗下基因泰克公司开发的GDC-6036是一款KRAS G12C共价抑制剂，它与安进公司的sotorasib和Mirati公司开发的adagrasib具有相同的作用机制，通过与失活状态的KRAS G12C结合，将KRAS锁定在失活状态。目前它正在1期临床试验中作为单药，以及与其它抗癌疗法联用，治疗非小细胞癌、结直肠癌等携带KRAS G12C突变的癌症类型。 10、候选药物：NPX800，热休克因子1（HSF1）抑制剂研发机构：伦敦癌症研究所，Nuvectis Pharma HSF1是一款应激诱导的转录因子，在激发真核细胞热休克反应中起到关键性作用。在癌细胞中，HSF1被“劫持”用于激发与经典热休克反应类似的基因表达。HSF1信号通路在肿瘤发生中起到重要作用，是多项研究验证的抗癌药物靶点。伦敦癌症研究所的研究人员通过表型筛选，最初发现了抑制HSF1活性的化合物，并且与Nuvectis Pharma合作将其优化成为临床期候选药物。NXP800是一款潜在“first-in-class”，口服HSF1信号通路抑制剂。目前它正在1期临床试验中接受评估，治疗晚期实体瘤患者。参考资料： [1] New Drug Candidates at AACR New Orleans 2022. Retrieved April 11, 2022, from https://drughunter.com/new-drug-candidates-at-aacr-new-orleans-2022/ [2] KSQ Therapeutics To Present Data At The American Association For Cancer Research (AACR) 2022 Annual Meeting. Retrieved April 11, 2022, from https://ksqtx.com/news-events/ksq-therapeutics-to-present-data-at-the-american-association-for-cancer-research-aacr-2022-annual-meeting/ [3] NXP800: A first-in-class, orally active, smallmolecule HSF1* pathway inhibitor. Retrieved April 12, 2022, from https://nuvectis.com/wp-content/uploads/2022/04/NXP800-New-Drugs-on-the-Horizon_-AACR-2022.pdf 内容来源于网络，如有侵权，请联系删除，谢谢

AACR会议临床结果免疫疗法First in Class蛋白降解靶向嵌合体合作