AbstractThe Werner syndrome RecQ helicase WRN was identified as a synthetic lethal target in cancer cells with microsatellite instability (MSI) by several genetic screens1,2,3,4,5,6. Despite advances in treatment with immune checkpoint inhibitors7,8,9,10, there is an unmet need in the treatment of MSI cancers11,12,13,14.

摘要Werner综合征RecQ解旋酶WRN被鉴定为具有微卫星不稳定性（MSI）的癌细胞中的合成致死靶标1,2,3,4,5,6。尽管免疫检查点抑制剂治疗取得了进展[7,8,9,10]，但MSI癌症的治疗需求尚未得到满足[11,12,13,14]。

Here we report the structural, biochemical, cellular and pharmacological characterization of the clinical-stage WRN helicase inhibitor HRO761, which was identified through an innovative hit-finding and lead-optimization strategy. HRO761 is a potent, selective, allosteric WRN inhibitor that binds at the interface of the D1 and D2 helicase domains, locking WRN in an inactive conformation.

在这里，我们报告了临床阶段WRN解旋酶抑制剂HRO761的结构，生化，细胞和药理学表征，该抑制剂是通过创新的命中发现和铅优化策略鉴定的。HRO761是一种有效的，选择性的变构WRN抑制剂，可结合D1和D2解旋酶结构域的界面，将WRN锁定在无活性构象中。

Pharmacological inhibition by HRO761 recapitulated the phenotype observed by WRN genetic suppression, leading to DNA damage and inhibition of tumour cell growth selectively in MSI cells in a p53-independent manner. Moreover, HRO761 led to WRN degradation in MSI cells but not in microsatellite-stable cells.

HRO761的药理学抑制概括了WRN遗传抑制观察到的表型，导致DNA损伤和以不依赖p53的方式选择性抑制MSI细胞中的肿瘤细胞生长。此外，HRO761导致MSI细胞中的WRN降解，但在微卫星稳定的细胞中却没有。

Oral treatment with HRO761 resulted in dose-dependent in vivo DNA damage induction and tumour growth inhibition in MSI cell- and patient-derived xenograft models. These findings represent preclinical pharmacological validation of WRN as a therapeutic target in MSI cancers. A clinical trial with HRO761 (NCT05838768) is ongoing to assess the safety, tolerability and preliminary anti-tumour activity in patients with MSI colorectal cancer and other MSI solid tumours..

在MSI细胞和患者来源的异种移植模型中，用HRO761口服治疗导致剂量依赖性的体内DNA损伤诱导和肿瘤生长抑制。这些发现代表了WRN作为MSI癌症治疗靶点的临床前药理学验证。HRO761（NCT05838768）的临床试验正在进行中，以评估MSI结直肠癌和其他MSI实体瘤患者的安全性，耐受性和初步抗肿瘤活性。。

MainLoss of DNA mismatch repair (MMR) by either germline or somatic mutations and epigenetic alterations occurs in 10–30% of colorectal, endometrial, ovarian, gastric and other cancer types15,16. Cancers that are MMR deficient have a high mutational burden and frequent insertion and/or deletion events in repetitive DNA tracts—a phenotype known as MSI17.

主要通过种系或体细胞突变和表观遗传改变导致的DNA错配修复（MMR）丢失发生在10-30%的结直肠癌，子宫内膜癌，卵巢癌，胃癌和其他癌症类型中15,16。MMR缺陷的癌症在重复的DNA片段（称为MSI17的表型）中具有高突变负担和频繁的插入和/或缺失事件。

Several large-scale functional genomics screens, including project DRIVE with 390 cell lines from the Cancer Cell Line Encyclopedia, have identified WRN as a synthetic lethal target in MSI cells1,2,3,4,5,6 (Extended Data Fig. 1a). Genetic depletion of WRN was shown to lead to DNA damage, anti-proliferative effects, mitotic defects with cell cycle arrest, chromosome shattering and apoptosis in MSI cancer models, but not in cancer cells with an intact MMR pathway.

几个大规模的功能基因组学筛选，包括来自癌细胞系百科全书的390个细胞系的project DRIVE，已经将WRN鉴定为MSI细胞中的合成致死靶标1,2,3,4,5,6（扩展数据图1a）。在MSI癌症模型中，WRN的遗传耗竭会导致DNA损伤，抗增殖作用，细胞周期停滞的有丝分裂缺陷，染色体破碎和细胞凋亡，但在具有完整MMR途径的癌细胞中则不会。

Moreover, WRN depletion in MSI cells reduced xenograft growth and tumour formation in mice6. Recent studies offered insights into the mechanism of WRN dependence. WRN dependence in MSI cells was linked to WRN helicase-mediated resolution of secondary DNA structures resulting from large-scale expansions of dinucleotide TA repeats that otherwise result in chromosome breakage18.

此外，MSI细胞中的WRN消耗减少了小鼠的异种移植物生长和肿瘤形成6。最近的研究提供了对WRN依赖机制的见解。MSI细胞中的WRN依赖性与WRN解旋酶介导的二级DNA结构的解析有关，二级DNA结构是由二核苷酸TA重复序列的大规模扩增引起的，否则会导致染色体断裂18。

Although MSI cancers have a high response rate to immune checkpoint inhibitors7,8,9,10, a substantial fraction of patients with MSI colon cancers does not benefit from current treatment regimens11,12,13,14.WRN is a multifunctional enzyme with both helicase and exonuclease activities and has roles in various cellular processes that are crucial for the maintenance of genome stability, including DNA replication, transcription, DNA repair and telomere maintenance19,20,21,22.

虽然MSI癌症对免疫检查点抑制剂有很高的反应率[7,8,9,10]，但相当一部分MSI结肠癌患者并未从目前的治疗方案中受益[11,12,13,14]。WRN是一种多功能酶，具有解旋酶和核酸外切酶活性，并在维持基因组稳定性至关重要的各种细胞过程中发挥作用，包括DNA复制，转录，DNA修复和端粒维持19,20,21,22。

Dissection of the helicase and exonuclease enzymatic activities of WRN using loss-of-function mutations showed that WRN de.

使用功能丧失突变解剖WRN的解旋酶和核酸外切酶活性表明WRN de。

Data availability

数据可用性

Atomic coordinates and structure factors for the co-crystal structures have been deposited in the PDB under accession codes 8PFP (WRN–ATPγS), 8PFL (WRN–3) and 8PFO (WRN–HRO761). The synthesis of compounds 2–6, including 1H and 13C NMR data, is described in the Supplementary Information. All raw sequencing data from this study have been deposited at the SRA under BioProject IDs PRJNA995921 and PRJNA995923.

共晶体结构的原子坐标和结构因子已以登录号8PFP（WRN–ATPγS），8PFL（WRN–3）和8PFO（WRN–HRO761）保存在PDB中。补充信息中描述了化合物2-6的合成，包括1H和13C NMR数据。这项研究的所有原始测序数据均已保存在SRA的生物项目ID PRJNA995921和PRJNA995923下。

The MSS proteomics data have been deposited to the ProteomeXchange Consortium through the PRIDE 56 partner repository under dataset identifier PXD044202. Source data are provided with this paper..

MSS蛋白质组学数据已通过PRIDE 56合作伙伴存储库以数据集标识符PXD044202保存到ProteomeXchange Consortium。本文提供了源数据。。

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Download referencesAcknowledgementsWe thank J. Loretan, M. Centeleghe, M. Grüninger and S. Ruetz for implementing and performing the routine cell proliferation assays; R. Newcombe for coordination of the Horizon OncoSignature screen; U. Naumann for the RNA-seq experiments; L. Barys for adding the methods of the Horizon OncoSignature screen and support uploading raw RNA-seq data; M.

下载参考文献致谢我们感谢J.Loretan，M.Centeleghe，M.Grüninger和S.Ruetz实施和执行常规细胞增殖测定；R、 Newcombe用于协调Horizon OncoSignature屏幕；U、 Naumann用于RNA-seq实验；五十、 Barys用于添加Horizon OncoSignature屏幕的方法，并支持上传原始RNA-seq数据；M。

Rapti for support on the bioinformatic analyses; M. Meyer, C. Be and F. Villard for technical support in protein production and protein crystallization; J. Brun, M. Furegati, A.-L. Garlot, F. Limam, S. Nocito, H. Schuetz and S. Plattner for compound synthesis; D. Gosling, D. Huber and S. Rodde for physicochemical profiling; the staff at Aurigene Discovery Technologies for synthetic support; C.

Rapti支持生物信息学分析；M、 Meyer，C。Be和F。Villard在蛋白质生产和蛋白质结晶方面提供技术支持；J、 Brun，M。Furegati，A.-L。Garlot，F。Limam，S。Nocito，H。Schuetz和S。Plattner用于化合物合成；D、 Gosling，D.Huber和S.Rodde进行物理化学分析；Aurigene Discovery Technologies的员工提供合成支持；C。

Hartwieg for material support; D. Erdmann, W. A. Rahman, P. Fontana, C. Zimmermann and M. Meyerhofer for protein production; S. Buhr, C. Genick, A. Wiget and W. Jahnke for contributions to hit finding and characterization; S. Hindupur for help with proteomics experiments; D. Gorses for making cell pellets for the proteomics experiments; F.

Hartwieg提供物质支持；D、 Erdmann，W。A。Rahman，P。Fontana，C。Zimmermann和M。Meyerhofer用于蛋白质生产；S、 Buhr，C。Genick，A。Wiget和W。Jahnke对命中发现和表征的贡献；S、 Hindupur帮助进行蛋白质组学实验；D、 Gorses用于制作用于蛋白质组学实验的细胞沉淀；F。

Gauter for contributing to the genetic validation work; R. Stump, D. Wyss, L. Holzer and L. Villemin for helping on pharmacology experiments; D. Sterker for MS/MS analysis of in vivo samples; P. Arabin, G. Chenal and M. Trunzer for in vitro and in vivo PK/ADME support; M. Moschetta for discussions on manuscript content; T.

戈特为基因验证工作做出了贡献；R、 Stump，D。Wyss，L。Holzer和L。Villemin帮助进行药理学实验；D、 Sterker用于体内样品的MS/MS分析；P、 Arabin，G。Chenal和M。Trunzer用于体外和体内PK/ADME支持；M、 Moschetta讨论手稿内容；T。

Schmelzle and M. Jensen for reviewing the manuscript; S. Chibout, B. Faller, F. Hourcade-Potelleret, S. Kakar and S. Malek for scientific guidance; L. Tordella for his guidance and input during the whole manuscript submission process; and all former team members for their contributions.Author informationAuthor notesEloísa Jiménez Núñ.

Schmelzle和M.Jensen审阅了手稿；S、 Chibout，B。Faller，F。Hourcade-Potelleret，S。Kakar和S。Malek提供科学指导；五十、 Tordella在整个稿件提交过程中的指导和投入；以及所有前团队成员的贡献。作者信息作者notesEloísa Jiménez Núñ。

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PubMed Google ScholarContributionsH.M. and M.C.-C. led the project and devised the drug discovery strategy. H.M. developed the medicinal chemistry strategy, analysed data and performed computational drug design. V.B., J. Hinrichs, J.S. and R.S. contributed to the medicinal chemistry, analysed data, designed compounds and devised the synthesis of the HRO761 series.

PubMed谷歌学术贡献。M、 M.C.-C.领导了该项目并设计了药物发现策略。H、 M.开发了药物化学策略，分析了数据并进行了计算药物设计。五、 B.，J.Hinrichs，J.S.和R.S.对药物化学做出了贡献，分析了数据，设计了化合物并设计了HRO761系列的合成。

J. Hinrichs was responsible for the material supply. J.B. oversaw the high-throughput screening and hit validation. E.J.N., F.H. and F.Z. contributed to scientific and strategic discussions in the HRO761 project. E.G. was responsible for the technical development of HRO761. N.D.N. and G.K. performed bioinformatic analyses and provided guidance for RNA-seq experimental design.

J、 Hinrichs负责材料供应。J、 B.监督高通量筛选和命中验证。E、 J.N.，F.H.和F.Z.为HRO761项目的科学和战略讨论做出了贡献。E、 G.负责HRO761的技术开发。D、 N.和G.K.进行了生物信息学分析，并为RNA-seq实验设计提供了指导。

C.S. solved and analysed all structures using X-ray crystallography methods. M.H. performed the proliferation assays, cell treatments and western blots, CFAs and developed the target engagement assay and made all measurements. M.D. performed the cell treatments and western blots. C.H. performed the cellular treatments and RT–qPCRs and prepared samples for RNA-seq experiments.

C、 S.使用X射线晶体学方法解决并分析了所有结构。M、 H.进行了增殖测定，细胞处理和蛋白质印迹，CFA，并开发了靶标接合测定并进行了所有测量。M、 D.进行细胞处理和蛋白质印迹。C、 H.进行了细胞处理和RT-qPCR，并制备了用于RNA-seq实验的样品。

A.D. developed the formulations for the PK–PD and efficacy experiments and was responsible for the solid-state characterization. S.F., M.R., S.B., L.L., F.S. and S.W. designed and performed PK–PD and efficacy experiments. S.F. and R.d.K. analysed PK data. S.F., M.R. and M.C.-C. analysed PK, PD and efficacy data.

A、 D.开发了PK-PD和功效实验的配方，并负责固态表征。S、 F.，M.R.，S.B.，L.L.，F.S.和S.W.设计并进行了PK-PD和功效实验。S、 F.和R.d.K.分析了PK数据。S、 F.，M.R.和M.C.-C.分析了PK，PD和疗效数据。

H.-J.M. was responsible for the toxicology and safety pharmacology investigations. H.V. performed and analysed the proteomics experiments. M.W. supervised and analysed the routine proliferation assays. M.C.-C. designed and analysed the cell biological experiments. J. Hamon was responsible for the set of biochemical and enzymatic assays.

H、 -J.M.负责毒理学和安全药理学调查。H、 V.进行并分析了蛋白质组学实验。M、 W.监督和分析常规增殖测定。M、 C.-C.设计并分析了细胞生物学实验。J、 哈蒙负责一系列生化和酶学检测。

Henrik Möbitz or Marta Cortés-Cros.Ethics declarations

Henrik Möbitz或Marta Cortés-Cros。道德宣言

Competing interests

相互竞争的利益

M.C.-C., H.V., C.Q., L.L., J.S., M.W., E.B., F.Z., E.G., E.D., S.W., S.B. and F.S. are employees of Novartis Pharma and hold stock in Novartis, Alcon and Sandoz. H.M., R.d.K., J.B., M.R., N.D.N., C.S., J. Hamon, M.S., A.H., S.F., M.H., R.A.-R., G.K., A.D., M.D., C.H., V.R., H.-J.M. and V.B. are employees of Novartis Pharma and hold stock in Novartis and Sandoz.

M、 C.-C.，H.V.，C.Q.，L.L.，J.S.，M.W.，E.B.，F.Z.，E.D.，S.W.，S.B.和F.S.是诺华制药的员工，持有诺华，爱尔康和桑德斯的股票。H、 M.，R.d.K.，J.B.，M.R.，N.d.N.，C.S.，J.Hamon，M.S.，A.H.，S.F.，M.H.，R.A.-R.，G.K.，A.d.，M.d.，C.H.，V.R.，H.-J.M.和V.B.是诺华制药的员工，持有诺华和桑德斯的股票。

I.J. and J. Hinrichs are employees of Novartis Pharma and hold stock in Novartis. R.S. is an employee of Novartis Pharma. F.H. and E.J.N. are employees of Pierre Fabre and hold stock in Novartis. HRO761 is covered by patent WO2022/249060 with the following co-authors listed as inventors: V.B., A.D., J.

一、 J.和J.Hinrichs是诺华制药的员工，持有诺华的股票。R、 美国是诺华制药的员工。F、 H.和E.J.N.是Pierre Fabre的员工，持有诺华的股票。HRO761被专利WO2022/249060涵盖，以下共同作者被列为发明人：V.B.，A.D.，J。

Hamon, J. Hinrichs, H.M., J.S., R.S. and F.Z. Additional patent applications related to WO2022/249060 are pending..

Hamon，J.Hinrichs，H.M.，J.S.，R.S.和F.Z.与WO2022/249060相关的其他专利申请正在申请中。。

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Peer review information

同行评审信息

Nature thanks Nicholas Larsen and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.

《自然》杂志感谢尼古拉斯·拉森（NicholasLarsen）和另一位匿名审稿人对这项工作的同行评审所做的贡献。同行评审报告可供查阅。

Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Extended data figures and tablesExtended Data Fig. 1 Genetic validation of WRN helicase dependence.a. WRN ATARIS dependency scores from DRIVE coloured by MSI (high-red and Low-orange) and MSS (blue) status.

Additional informationPublisher的注释Springer Nature在已发布的地图和机构隶属关系中的管辖权主张方面保持中立。扩展数据图和表扩展数据图1 WRN解旋酶依赖性的遗传验证。a.由MSI（高红色和低橙色）和MSS（蓝色）状态着色的驱动的WRN ATARIS依赖性得分。

b. Schematic representation of WRN helicase domains. Clonogenic assay (c) or immunoblot (d) of RKO cells doxycycline induction of a non-targeting negative control (sh2-NT), and one shRNA against WRN (sh19) without (-) or with a wild type (WT), exonuclease mutant (E84A) or helicase mutant (K577A) WRN cDNA.

b、 WRN解旋酶结构域的示意图。RKO细胞的克隆形成测定（c）或免疫印迹（d）强力霉素诱导非靶向阴性对照（sh2 NT）和一种针对WRN（sh19）的shRNA，不含（-）或野生型（WT），核酸外切酶突变体（E84A）或解旋酶突变体（K577A）WRN cDNA。

Clonogenic assay shown 15 days and immunoblot 4 days after dox induction. e. RKO xenograft growth ± doxycycline induction of WRN sh19 with WT or helicase dead (K577A) WRN cDNA. Mice were randomized (n = 6). Differences between the means of TVol were assessed on the endpoint ∆TVol using a two-tailed t-test (* P < 0.05, ** P < 0.01 and ns is non-significant).

克隆形成测定显示dox诱导后15天和免疫印迹4天。e、 RKO异种移植物生长±强力霉素诱导具有WT或解旋酶死亡（K577A）WRN cDNA的WRN sh19。小鼠随机分组（n = 6） 。使用双尾t检验在终点ΔTVol上评估TVol均值之间的差异（*P < 0.05，**P < 0.01，ns不显着）。

f. Ki67, p21 and cleaved caspase 3 (CC3) expression were evaluated on RKO xenograft sections by immunohistochemistry 7 and 14 days after treatment ± doxycycline and ± WT WRN cDNA. g. Quantification of Ki67, p21 and CC3 positive cells from FFPE sections. The white centre line denotes the median value, while the filled boxes contain the first quartile (25th) and third quartile (75th) percentiles of the dataset.

f、 在治疗±强力霉素和±WT WRN cDNA后7天和14天，通过免疫组织化学在RKO异种移植切片上评估Ki67，p21和切割的半胱天冬酶3（CC3）表达。g、 从FFPE切片定量Ki67，p21和CC3阳性细胞。白色中心线表示中值，而填充框包含数据集的第一个四分位数（第25个）和第三四分位数（第75个）百分位数。

The coloured whiskers mark the 5th and 95th percentiles. h. Immunoblot for WRN, pCHK2, ATM, p21 and actin of RKO tumour ± doxycycline and ± WT WRN cDNA. i. Immunoblot for WRN from samples from panel h treated for 7 and 14 days at different exposures. j. RTqPCR for WRN WT (endogenous) and WRN K577A mutant from tumours treated with doxycycline for 1 and 2 .

彩色胡须标记第5和第95百分位。h、 RKO肿瘤±强力霉素和±WT WRN cDNA的WRN，pCHK2，ATM，p21和肌动蛋白的免疫印迹。i、 来自在不同暴露下处理7天和14天的h组样品的WRN的免疫印迹。j、 来自用强力霉素治疗1和2的肿瘤的WRN WT（内源性）和WRN K577A突变体的RTqPCR。

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Reprints and permissionsAbout this articleCite this articleFerretti, S., Hamon, J., de Kanter, R. et al. Discovery of WRN inhibitor HRO761 with synthetic lethality in MSI cancers.

转载和许可本文引用本文Ferretti，S.，Hamon，J.，de Kanter，R。等人发现WRN抑制剂HRO761在MSI癌症中具有合成致死性。

Nature (2024). https://doi.org/10.1038/s41586-024-07350-yDownload citationReceived: 26 July 2023Accepted: 26 March 2024Published: 24 April 2024DOI: https://doi.org/10.1038/s41586-024-07350-yShare this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

《自然》（2024）。https://doi.org/10.1038/s41586-024-07350-yDownload引文接收日期：2023年7月26日接收日期：2024年3月26日发布日期：2024年4月24日OI：https://doi.org/10.1038/s41586-024-07350-yShare本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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