更新于：2024-05-01

SETD2

SET domain containing 2, histone lysine methyltransferase

更新于：2024-05-01

基本信息

别名

FLJ23184、HIF-1、HIF1

+ [17]

简介

Histone methyltransferase that specifically trimethylates 'Lys-36' of histone H3 (H3K36me3) using dimethylated 'Lys-36' (H3K36me2) as substrate (PubMed:16118227, PubMed:19141475, PubMed:21526191, PubMed:21792193, PubMed:23043551, PubMed:27474439). It is capable of trimethylating unmethylated H3K36 (H3K36me0) in vitro (PubMed:19332550). Represents the main enzyme generating H3K36me3, a specific tag for epigenetic transcriptional activation (By similarity). Plays a role in chromatin structure modulation during elongation by coordinating recruitment of the FACT complex and by interacting with hyperphosphorylated POLR2A (PubMed:23325844). Acts as a key regulator of DNA mismatch repair in G1 and early S phase by generating H3K36me3, a mark required to recruit MSH6 subunit of the MutS alpha complex: early recruitment of the MutS alpha complex to chromatin to be replicated allows a quick identification of mismatch DNA to initiate the mismatch repair reaction (PubMed:23622243). Required for DNA double-strand break repair in response to DNA damage: acts by mediating formation of H3K36me3, promoting recruitment of RAD51 and DNA repair via homologous recombination (HR) (PubMed:24843002). Acts as a tumor suppressor (PubMed:24509477). H3K36me3 also plays an essential role in the maintenance of a heterochromatic state, by recruiting DNA methyltransferase DNMT3A (PubMed:27317772). H3K36me3 is also enhanced in intron-containing genes, suggesting that SETD2 recruitment is enhanced by splicing and that splicing is coupled to recruitment of elongating RNA polymerase (PubMed:21792193). Required during angiogenesis (By similarity). Required for endoderm development by promoting embryonic stem cell differentiation toward endoderm: acts by mediating formation of H3K36me3 in distal promoter regions of FGFR3, leading to regulate transcription initiation of FGFR3 (By similarity). In addition to histones, also mediates methylation of other proteins, such as tubulins and STAT1 (PubMed:27518565, PubMed:28753426). Trimethylates 'Lys-40' of alpha-tubulins such as TUBA1B (alpha-TubK40me3); alpha-TubK40me3 is required for normal mitosis and cytokinesis and may be a specific tag in cytoskeletal remodeling (PubMed:27518565). Involved in interferon-alpha-induced antiviral defense by mediating both monomethylation of STAT1 at 'Lys-525' and catalyzing H3K36me3 on promoters of some interferon-stimulated genes (ISGs) to activate gene transcription (PubMed:28753426). (Microbial infection) Recruited to the promoters of adenovirus 12 E1A gene in case of infection, possibly leading to regulate its expression.

关联

项与 SETD2 相关的药物

IPN-60210

靶点

SETD2

作用机制

SETD2抑制剂

在研机构

Epizyme, Inc.

原研机构

Epizyme, Inc.

在研适应症

弥漫性大B细胞淋巴瘤 [+4]

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

EPZ-719

靶点-

作用机制

SETD2抑制剂

在研机构

Epizyme, Inc.

原研机构

Epizyme, Inc.

在研适应症

多发性骨髓瘤

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 SETD2 相关的临床试验

NCT05121103 / Recruiting临床1期

A Phase 1/1b, Open-Label, Multi-Center, Two-Part Study of SETD2 Inhibitor EZM0414 in Subjects With Relapsed/Refractory Multiple Myeloma and Relapsed/Refractory Diffuse Large B-Cell Lymphoma

This study will include participants with relapsed/refractory (R/R) Multiple Myeloma (MM). MM is a type of cancer of the blood. This study will also include participants with relapsed/refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL).
DLBCL is also a type of cancer of the blood. They are referred to as 'relapsed' when the disease has come back after treatment and 'refractory' when treatment no longer works. The study has 2 main parts, called phase 1 and phase 1b. The main objective of both parts will be to evaluate the safety and tolerability of the study drug, called EZM0414.
The main objective of phase 1b will also be to determine the effectiveness of EZM0414. During phase 1 six dose levels will be tested to obtain the most tolerated dose. Participants will receive study drug at the assigned dose level every 28 days. During phase 1b participants will receive study drug at the maximum tolerated dose in 28-day cycles.

开始日期2021-11-11

申办/合作机构

Epizyme, Inc.

100 项与 SETD2 相关的临床结果

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100 项与 SETD2 相关的转化医学

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0 项与 SETD2 相关的专利（医药）

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6,836

项与 SETD2 相关的文献（医药）

2024-12-01·Annals of medicine

Substance basis and pharmacological mechanism of heat-clearing herbs in the treatment of ischaemic encephalopathy: a systematic review and network pharmacology.

Review

作者: Andong Zhao ; Qianqian Sun ; Jiahao Zhang ; Tian Hu ; Xuewei Zhou ; Chuan Wang ; Jiping Liu ; Bin Wang

BACKGROUND AND OBJECTIVE:

Ischaemic encephalopathy is a common cerebrovascular disease caused by insufficient blood supply to the cerebral vessels. The ischaemic encephalopathy is closely associated with the development of many chronic diseases such as obesity, hypertension and diabetes. Neurotrophic therapy has become the main therapeutic strategy for ischaemic encephalopathy. However, neurotrophic drugs only slightly recover the neurological function of patients, and their long-term efficacy is uncertain. Previous reports revealed that the active ingredients of natural medicines play important roles in the treatment of cerebral ischemia. In this study, we reviewed clearing herbs with anti-ischaemic encephalopathy functions using the data from quantitative statistical and network pharmacological exploration methods. We also discussed the different bioactive components and pharmacological effects of these herbs.

METHODS:

First, we collected Chinese herbal prescriptions against ischaemic encephalopathy in four databases. Then, we statistically analysed the frequency of application of heat-clearing herbs to obtain the commonly used heat-clearing herbs against ischaemic encephalopathy, and classified them according to their efficacy according to the statistical results, to summarize the mechanism of anti-ischaemic effects of different bioactive components; Second, the network database was used to obtain the above components of heat-clearing Chinese medicines and their corresponding targets of action, disease targets of ischaemic stroke; Venny 2.1.0 was used to obtain component-disease target intersections; Cytoscape was used to construct the 'Drug-Active Ingredient-Target Network Graph '; DAVID was used for GO and KEGG enrichment analysis.

RESULTS:

Literature and database screening involved 149 prescriptions, with a total of 269 flavours of Chinese medicines and 20 flavours of single-flavour heat-clearing Chinese medicines; The top nine in terms of frequency of use were Radix Paeoniae Rubra、Rehmanniae Radix Praeparata、Figwort Root、Cortex Moutan、Scutellariae Radix、Coptidis Rhizoma、Gardeniae Fructus、Cassiae Semen、Lonicerae Japonicae Flos. The common components obtained from network pharmacology were beta-sitosterol, quercetin, and stigmasterol, which mainly act on key targets such as RELA, AKT1, JUN, PRKACA, PTGS2, RAF1 and CHUK; and their active ingredients are mainly involved in signalling pathways such as Calcium, PI3K-Ak, MAPK, cAMP, IL-17, HIF-1, TNF, T-cell receptor, NF-kappa B and JAK-STAT.

CONCLUSIONS:

Heat-clearing herbs are useful and promising for the protection against and prevention of ischemic encephalopathy. The results of the network pharmacological studies are similar to the mechanisms of anti-ischemic encephalopathy of the active ingredients of the purgative herbs we have listed; Thin either directly protects cerebrovascular tissues by improving vascular permeability and reducing the area of infarcted tissues, or produces protective effects through molecular signaling pathways. It can be seen that the components of heat-clearing Chinese medicines can exert cerebroprotective effects through multiple pathways, which provides us with a reference for further development and study of heat-clearing Chinese medicines in the treatment of ischemic cerebrovascular diseases.

2024-12-01·Journal of enzyme inhibition and medicinal chemistry

Novel dual-targeting inhibitors of NSD2 and HDAC2 for the treatment of liver cancer: structure-based virtual screening, molecular dynamics simulation, and in vitro and in vivo biological activity evaluations.

Article

作者: Xing Jin ; Yuting Wang ; Jing Chen ; Miaomiao Niu ; Yang Yang ; Qiaoxuan Zhang ; Guangyu Bao

Liver cancer exhibits a high degree of heterogeneity and involves intricate mechanisms. Recent research has revealed the significant role of histone lysine methylation and acetylation in the epigenetic regulation of liver cancer development. In this study, five inhibitors capable of targeting both histone lysine methyltransferase nuclear receptor-binding SET domain 2 (NSD2) and histone deacetylase 2 (HDAC2) were identified using a structure-based virtual screening approach. Notably, DT-NH-1 displayed a potent inhibition of NSD2 (IC₅₀ = 0.08 ± 0.03 μM) and HDAC2 (IC₅₀ = 5.24 ± 0.87 nM). DT-NH-1 also demonstrated a strong anti-proliferative activity against various liver cancer cell lines, particularly HepG2 cells, and exhibited a high level of biological safety. In an experimental xenograft model involving HepG2 cells, DT-NH-1 showed a significant reduction in tumour growth. Consequently, these findings indicate that DT-NH-1 will be a promising lead compound for the treatment of liver cancer with epigenetic dual-target inhibitors.

2024-02-29·Heliyon

Identification of hypoxia- and immune-related biomarkers in patients with ischemic stroke.

Article

作者: Haofuzi Zhang ; Jidong Sun ; Peng Zou ; Yutao Huang ; Qiuzi Yang ; Zhuoyuan Zhang ; Peng Luo ; Xiaofan Jiang

Background:

The immune microenvironment and hypoxia play crucial roles in the pathophysiology of ischemic stroke (IS). Hence, in this study, we aimed to identify hypoxia- and immune-related biomarkers in IS.

Methods:

The IS microarray dataset GSE16561 was examined to determine differentially expressed genes (DEGs) utilizing bioinformatics-based analysis. The intersection of hypoxia-related genes and DEGs was conducted to identify differentially expressed hypoxia-related genes (DEHRGs). Then, using weighted correlation network analysis (WGCNA), all of the genes in GSE16561 dataset were examined to create a co-expression network, and module-clinical trait correlations were examined for the purpose of examining the genes linked to immune cells. The immune-related DEHRGs were submitted to gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. A protein-protein interaction (PPI) network was constructed by Cytoscape plugin MCODE, in order to extract hub genes. The miRNet was used to predict hub gene-related transcription factors (TFs) and miRNAs. Finally, a diagnostic model was developed by least absolute shrinkage and selection operator (LASSO) logistic regression.

Results:

Between the control and IS samples, 4171 DEGs were found. Thereafter, the intersection of hypoxia-related genes and DEGs was conducted to obtain 45 DEHRGs. Ten significantly differentially infiltrated immune cells were found-namely, CD56dim natural killer cells, activated CD8 T cells, activated dendritic cells, activated B cells, central memory CD8 T cells, effector memory CD8 T cells, natural killer cells, gamma delta T cells, plasmacytoid dendritic cells, and neutrophils-between IS and control samples. Subsequently, we identified 27 immune-related DEHRGs through the intersection of DEHRGs and genes in important modules of WGCNA. The immune-related DEHRGs were primarily enriched in response to hypoxia, cellular polysaccharide metabolic process, response to decreased oxygen levels, polysaccharide metabolic process, lipid and atherosclerosis, and HIF-1 signaling pathway H. Using MCODE, FOS, DDIT3, DUSP1, and NFIL3 were found to be hub genes. In the validation cohort and training set, the AUC values of the diagnostic model were 0.9188034 and 0.9395085, respectively.

Conclusion:

In brief, we identified and validated four hub genes-FOS, DDIT3, DUSP1, and NFIL3-which might be involved in the pathological development of IS, potentially providing novel perspectives for the diagnosis and treatment of IS.

项与 SETD2 相关的新闻（医药）

2024-04-06

·生物探索

Cancer Cell | 上海交通大学薛婧团队揭示表观遗传学失调如何塑造癌相关成纤维细胞的多样性

引言胰腺导管腺癌(PDAC)的肿瘤微环境(TME)涉及癌症相关成纤维细胞(CAFs)的显著积累，这是宿主对肿瘤细胞反应的一部分。在PDAC中，转录多样性CAF群体的起源和功能仍然知之甚少。肿瘤细胞内在基因突变和表观遗传失调可能重塑TME；然而，它们对CAF异质性的影响仍然难以捉摸。2024年4月4日，上海交通大学薛婧团队在Cancer Cell 在线发表题为“Tumor cell-intrinsic epigenetic dysregulation shapes cancer-associated fibroblasts heterogeneity to metabolically support pancreatic cancer”的研究论文，该研究通过单细胞RNA测序，在SETD2缺失的胰腺肿瘤中鉴定出一个由ABCA8a标记的脂质富集的CAF亚群。研究结果表明，肿瘤固有的SETD2缺失通过H3K27Ac的异位增益释放BMP2信号，导致CAFs向富脂表型分化。然后，脂质负载的CAFs通过ABCA8a转运体为线粒体氧化磷酸化提供脂质，从而促进肿瘤进展。总之，该研究将CAF异质性与肿瘤细胞的表观遗传失调联系起来，强调了CAF与胰腺肿瘤细胞之间以前未被认识的代谢相互作用。胰腺肿瘤，主要是胰腺导管腺癌(PDAC)，是一种高致死率的实体器官恶性肿瘤。胰腺肿瘤的发生是由肿瘤细胞的分子改变和相应的肿瘤微环境(TME)的变化复杂地控制的癌症相关成纤维细胞(Cancer-associated fibroblasts, CAFs)富含PDAC - TME，在肿瘤起始、转移、代谢重编程、免疫逃逸和耐药等过程中发挥着关键作用CAFs在起源、表型和功能上表现出显著的异质性，包括通过单细胞RNA-seq鉴定的肌成纤维CAFs (myCAF)、炎性CAFs (iCAF)和抗原呈递CAFs (apCAF)。不同的CAF亚群通过细胞因子和代谢物的分泌影响肿瘤和免疫细胞，形成其致瘤或抗肿瘤功能。尽管来自肿瘤细胞和TME的信号对CAF异质性进行了空间调节，肿瘤内在因素，特别是表观遗传失调，对CAF表型和功能多样性的影响仍不清楚。肿瘤细胞的表观遗传改变广泛存在，并影响肿瘤的发生。除了它们在肿瘤细胞中的作用外，新出现的证据强调了表观遗传失调对TME的影响，包括基质细胞和免疫细胞。SETD2是一种原发性组蛋白H3K36三甲基转移酶，在各种肿瘤类型中普遍存在突变和/或拷贝数变异(CNV)。因此，开发针对SETD2突变或缺乏患者的个体化治疗方案具有广泛的翻译意义。模式图（Credit: Cancer Cell）该研究探讨了了SETD2-H3K36me3表观遗传失调对肿瘤代谢和基质异质性的影响，揭示了氧化磷酸化(OXPHOS)主导的代谢特征，并确定了一个脂质负载的CAF亚群。该CAF亚群以ABCA8a为标记，向肿瘤细胞提供脂质，增强线粒体OXPHOS，促进肿瘤进展。该研究阐明了SETD2缺失在重塑CAFs以支持肿瘤能量需求中的作用，表明OXPHOS靶向治疗SETD2缺陷PDAC患者是一种潜在的策略。原文链接https://www.cell.com/cancer-cell/abstract/S1535-6108(24)00090-4责编|探索君排版|探索君文章来源|“iNature”End往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文Nature | 破除传统：为何我们需要重新思考肿瘤的命名方式热文Nature | 2024年值得关注的七项技术热文Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文CRISPR技术进化史 | 24年Cell综述

临床研究

2024-04-01

·CPHI制药在线

从Odevixibat在国内报产，浅谈益普生管线布局

关注并星标CPHI制药在线近日，Albireo/益普生（Ipsen）递交的「Odevixibat胶囊」的5.1类进口申请获CDE受理。Odevixibat是一种每日一次的强效非体循环回肠胆汁酸转运蛋白（IBAT）抑制剂，可以阻断肠胆汁酸经过肠肝循环回流入肝，从而减轻肝脏内及循环内的胆汁酸浓度。目前，Odevixibat（商品名：Bylvay）已在美国获批2项适应症：3个月以上所有亚型的进行性家族性肝内胆汁淤积（PFIC）患者的瘙痒（2021.07）；12个月龄及以上Alagille综合征(ALGS)患者的胆汁淤积性瘙痒症（2023.12）。此外，该药还被开发用于治疗胆道闭锁。 PFIC和ALGS均属于罕见病，Odevixibat是首个获批治疗PFIC的药物，其市场表现并不亮眼，2022年销售额仅有2400万美元。不过随着对罕见病的重视，Odevixibat被企业看好。 Odevixibat由Albireo开发。2021年10月，Jadeite Medicines超1.35亿美元获得该药在日本的开发和商业化授权。2023年3月，益普生通过收购Albireo将该药纳入囊中，收购金额约为9.52亿美元。今年2月，益普生与Jadeite Medicines签订协议，获得Odevixibat在日本的开发和商业化授权。在国内，Odevixibat于2023年11月被CDE纳入优先审评，用于治疗6个月或以上患者的进行性家族性肝内胆汁淤积症（PFIC）。PFIC是由于编码胆汁转运蛋白的基因发生不同突变导致的罕见常染色体隐性遗传病，典型表现是胆汁淤积引起的黄疸和瘙痒。根据编码胆汁转运蛋白基因的不同,PFIC可分为6个亚型,分别由ATP8B1、ABCB11、ABCB4、TJP2、NR1H4和MY05B基因突变引起。目前国内PFIC治疗缺乏特异性药物，临床上首选促胆汁酸排泄药熊去氧胆酸。利福平、消胆胺、胆汁酸螯合剂考来烯胺等也可用于治疗PFIC。期待Odevixibat早日在国内获批，给PFIC患者提供一种新选择。此外，Odevixibat还在国内被开发用于治疗胆道闭锁，目前针对该适应症的临床试验已进入3期阶段。 Odevixibat并不是全球获批的唯一一款IBAT抑制剂，目前全球还批准了另外两款，即氯马昔巴特（maralixibat）和依洛昔巴特(elobixibat)。其中氯马昔巴特于2021年9月被FDA批准用于治疗一岁及以上ALGS患者的胆汁淤积性瘙痒，2024年3月又被FDA批准用于五岁及以上PFIC患者的胆汁淤积性瘙痒症状。依洛昔巴特于2018年1月在日本获批治疗便秘。此外，目前全球还有几款在研IBAT抑制剂，如GSK的linerixibat。linerixibat被开发用于治疗原发性胆汁性胆管炎（PBC）的胆汁淤积性瘙痒，目前已进入3期临床。益普生的罕见病布局益普生是一家专注于肿瘤、罕见病和神经科学领域的全球生物制药公司，在罕见病领域已斩获多款药物，如Increlex（美卡舍明）、Somatuline（兰瑞肽，治疗肢端肥大症和垂体巨人症）、Sohonos（palovarotene，治疗进行性骨化性纤维发育不良）。其中Increlex被批准用于治疗儿童和青少年的严重原发性胰岛素生长因子1缺乏症导致的生长障碍。Sohonos是益普生超13亿美元收购Clementia获得，2023年8月被FDA批准用于减少8岁及以上女性和10岁及以上男性进行性骨化纤维发育不良(FOP)成人和儿科患者的新异位骨化体积。近年来，益普生不断扩张其在罕见病领域的布局： 2021年7月，益普生与IRLAB签署一项授权协议，引进创新多巴胺D3受体拮抗剂mesdopetam的全球开发和推广权益。该药用于治疗帕金森病患者在接受左旋多巴治疗之后出现的运动障碍。 2021年8月，益普生与Exicure就新型球形核酸（SNA）达成合作，共同研究、开发和商业化用于治疗亨廷顿病和天使综合征的SNA。 2021年12月，益普生与GENFIT达成4.8亿欧元的长期战略合作协议，获得后者治疗原发性胆汁性胆管炎（PBC）潜在首创PPAR-α/δ双重激动剂Elafibranor的全球独家开发、生产、商业化权益。目前，Elafibranor治疗二线治疗原发性胆汁性肝硬化（PBC）的新药申请正在欧美接受审查。 2023年1月，益普生斥资9.52亿美元收购Albireo，获得包括Bylvay®（odevixibat）在内的多款药物。益普生的肿瘤领域布局肿瘤药是制药领域最大的细分市场，也是药企积极布局的热门方向。除了罕见病，益普生近年来也积极拓展肿瘤管线： 2021年7月，益普生和BAKX Therapeutics签署8.52亿美元的独家全球合作协议，获得后者Bcl-2抑制剂BKX-001的研究、开发、制造和商业化授权。BKX-001被开发用于治疗白血病、淋巴瘤及实体瘤。 2021年10月，益普生和Accent Therapeutics (Accent)签署一项全球独家合作协议，共同研究、开发、生产和商业化后者的METTL3项目。METTL3是一种RNA修饰蛋白 (RMP)，已被临床前验证是AML的新治疗靶点。 2022年6月，益普生斥资2.47亿美元收购Epizyme，获得包括EZH21抑制剂Tazverik(tazemetostat)和 SETD2抑制剂EZM0414在内的多款药物。 2022年8月，益普生和Marengo Therapeutics达成战略合作，共同将Marengo公司的两款临床前选择性T细胞受体（TCR）激活剂推进临床，交易金额达16亿美元。而且，今年益普生肿瘤领域已迎来新突破，其肿瘤药物Onivyde（伊立替康脂质体注射液）于2024年2月被FDA批准联合5-氟尿嘧啶/亚叶酸+奥沙利铂（NALIRIFOX方案），一线治疗成人转移性胰腺导管腺癌（mPDAC）。总结罕见病是医药领域的小钢炮市场，是益普生等国内外药企布局的热门方向。不过整体来看，益普生在罕见病领域的斩获并不多，且其罕见病产品Increlex、Somatuline销售额持续下滑。肿瘤业务是益普生最大的收入来源，但2023年其前三季度营收也较2022前三季度有所降低。期待益普生斥巨资在罕见病、肿瘤领域的布局早日见到成效，有更多的新产品获批上市。【智药研习社近期课程预告】来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~

临床3期并购优先审批引进/卖出申请上市

2024-03-26

·PRNewswire

Research published in Journal of the American Chemical Society highlights potential of HIF Inhibition as a therapeutic approach for cancers

Research led by Curve CSO Professor Ali Tavassoli's laboratory at University of Southampton Landmark paper on dual HIF-1 and HIF-2 inhibitor that works by inhibiting the interaction of both HIF-1α and HIF-2α with HIF-1β SOUTHAMPTON, England, March 26, 2024 /PRNewswire/ -- Curve Therapeutics ("Curve" or the "Company"), a private biotechnology company pioneering a revolutionary intracellular screening platform addressing complex and challenging disease targets, today announces the publication of an article in the Journal of the American Chemical Society (JACS). The paper entitled 'Identification and Development of Cyclic Peptide Inhibitors of Hypoxia Inducible Factors (HIF) 1 and 2 That Disrupt Hypoxia-Related Signalling in Cancer Cells' can be viewed here.1 Curve's Chief Scientific Officer, Professor Ali Tavassoli, co-authored the article and leads the academic group at the University of Southampton where the work was undertaken. Professor Ali Tavassoli, Chief Scientific Officer of Curve Therapeutics, said: "It is well recognised that HIF plays a key role in the survival and growth of solid tumours. The compounds we report in this paper inhibit the protein-protein interaction of the two subunits that form the HIF transcription factor. We show that these compounds prevent the hypoxia-induced activity of this transcription factor, stopping hypoxia-response in cell-based assays. This paper underlines the promising therapeutic potential of dual HIF inhibition as an approach for the treatment of a variety of cancers." Curve Therapeutics is a leader in the discovery of innovative therapeutics to address disease targets which are difficult to target using conventional drug discovery methods. Through the utilisation of its world leading Microcyle® discovery platform, Curve can screen directly inside mammalian cells, allowing for the identification of biologically active library members within an intracellular environment where both the library and the target are present in their native conformations. Curve is developing a non-peptidic, small-molecule dual inhibitor of HIF-1 and HIF-2 with first-in-class potential. This is the first report of a dual HIF-1 and HIF-2 inhibitor which functions by inhibiting the interaction of both HIF-1α and HIF-2α with HIF-1β. The Microcycles discovered by Prof. Tavassoli were identified using his SICLOPPS screening platform and show good cellular activity. Patents and patent applications describing these HIF inhibitory Microcycles are exclusively licensed to Curve. About Curve Therapeutics Curve Therapeutics is a private biotechnology company pioneering a revolutionary intracellular screening platform to enable the discovery of innovative therapeutics that address complex and challenging disease targets with the potential to transform the lives of patients. Curve originated from world-leading Microcycle® research conducted by Professor Tavassoli's group in the Department of Chemistry at the University of Southampton, UK. Curve is backed by blue chip investors including Advent Life Sciences, Epidarex Capital, Pfizer Ventures, Columbus Venture Partners and British Patient Capital. Curve has a US$1.7bn global research collaboration with MSD the trade name of Merck & Co., Inc., Kenilworth, NJ USA, to discover and validate modulators of up to five therapeutic targets using its Microcycle® technology, initially for oncology and neurology indications. For more information visit: . About Curve's Microcycle® platform Curve has developed an IP-protected, mammalian cell platform technology for functional screening and enrichment of diverse hexameric cyclic peptide Microcycle® libraries to identify those library members that have the desired biological activity against a therapeutic target. Curve's platform allows direct screening for biologically active library members inside mammalian cells and facilitates small molecule hit-to-lead programmes. A key advantage of the technology is that both the library and the target are present in all of their native conformations within a cell. Uniquely, the compact size and rigid structure of Microcycles® enables the design of non-peptide small molecule leads. The platform can be used for a wide range of therapeutically relevant targets, including protein-protein and protein-DNA interactions and has been used by Curve to develop a pipeline of cancer programmes against targets including a dual HIF-1/HIF-2 inhibitor and an inhibitor of ATIC homodimerization. [1] Andrew T. Ball, Soran Mohammed, Cyrielle Doigneaux, Reece M. Gardner, James W. Easton, Steven Turner, Jonathan W. Essex, Garry Pairaudeau, Ali Tavassoli, Identification and Development of Cyclic Peptide Inhibitors of Hypoxia Inducible Factors 1 and 2 That Disrupt Hypoxia-Response Signaling in Cancer Cells, Journal of the American Chemical Society (19 March 2024) DOI: 10.1021/jacs.3c10508 SOURCE Curve Therapeutics