FANCM

前言在过去的几十年中，对DNA损伤反应（DDR）途径的理解不断加深，拓宽了肿瘤学的治疗领域。越来越清楚的是，DNA损伤反应缺陷导致的细胞基因组不稳定性导致了癌症的发生。另一方面，这些缺陷也可以作为一个治疗机会。越来越多的DDR靶向药物已迅速扩展到参与DDR途径的多个成员的抑制剂，包括PARP、ATM、ATR、CHK1、WEE1和DNA-PK。目前，这些DDR成分的抑制剂，其中一些正处于临床研究中。此外，新的证据表明DDR抑制剂对传统癌症治疗的敏感性，以及DDR途径和免疫检查点抑制剂（ICI）反应之间的相关性，这些都促进基于DDR抑制剂的联合治疗。靶向DNA修复途径的药物正在肿瘤治疗领域显示出越来越大的作用。DNA损伤与DNA损伤反应为了保持基因组的完整性，复杂的DNA修复系统被用来对抗各种形式的DNA损伤，这些机制被称为DNA损伤反应。DDR通路分为三个功能上相互交织的部分：检测DNA损伤的传感器、触发信号级联的信号转换器和阻碍DNA修复的效应器。这些途径不是相互排斥的过程，而是相互协调，形成DNA修复的精确调控网络。             碱基切除修复（BER）和核苷酸切除修复（NER）所有生物体的基因组都在不断地经历微妙的变化，这是由于内源性产生的各种基因毒物，如活性氧（ROS）、电离辐射以及烷基化剂等环境损伤所致。DNA中的大多数细微变化，如单链断裂（SSB），都是通过BER途径修复的。BER首先由受损的碱基启动，然后切除碱基并用新合成的DNA替换。然后，脱嘌呤/脱嘧啶核酸内切酶（APE）切割AP位点，在损伤位点形成3′OH末端。最后，DNA聚合酶和DNA连接酶在去除损伤碱基产生的核苷酸缺口处被招募，从而封闭缺口。BER负责修复小损伤，而使DNA螺旋结构变形的较大的双链断裂（DSB）则需要NER途径修复。NER机制涉及一种关键蛋白质，即切除修复交叉互补蛋白1（ERCC1），它会清除断裂点附近的DNA，然后用正常的DNA复制进行替换。同源重组（HR）和非同源末端连接（NHEJ）在哺乳动物细胞中，HR和NHEJ是修复DSB的两条主要途径。由于同源姐妹染色单体是新DNA合成所需的模板，HR途径可以在S/G2细胞周期阶段修复DSB，而NHEJ在除M期外的所有细胞周期阶段都是活跃的。HR分析来自基因组其他部分的同源序列，收集断裂位点丢失的信息。HR首先切除断裂端，随后通过Brca2和Rad51形成Rad51核蛋白丝，开始检索同源序列，并促进断裂DNA和同源模板之间形成连接分子，完成修复。NHEJ比HR更简单一些，直接将断裂端重新连接在一起。NHEJ所需的基本因子是由Ku70/Ku80和DNA依赖性蛋白激酶的催化亚单位（DNA-PKcs）组成的异二聚体，其识别DSB并促进NHEJ的下游信号因子，如XRCC4、XLF和DNA连接酶IV。虽然NHEJ机制较为简单，但有时会导致重排，而HR被认为不会产生错误。除HR和NHEJ外，一种DSB修复途径与这两个主要DSB修复途径具有相似的机制，但在遗传上不同，称为替代末端连接（a-EJ）途径。a-EJ途径既可以与HR共享类似的起始过程，也可以与NHEJ一样组成无同源模板的DNA末端连接因子。目前，越来越多的研究开始关注a-EJ通路作为NHEJ或HR活性受损癌细胞的潜在治疗靶点。错配修复（MMR）除了暴露于基因毒素的细胞所产生的损伤外，DNA损伤也可能来自异常的DNA处理。针对复制相关错误的DNA修复途径称为MMR。在DNA合成过程中，MMR纠正核苷酸错误整合，从而防止分裂细胞中永久性的DNA改变。因此，基因突变或表观遗传沉默导致的MMR缺陷可能导致自发突变的发生率增加，这通常与遗传性和散发性癌症有关。跨损伤合成与模板置换DNA损伤耐受性（DDT）作为修复复制停滞DNA损伤的一种基本旁路机制，允许DNA复制穿过阻碍元件。跨损伤合成（TLS）是两种不同的DDT模式之一，取决于一种特殊的TLS聚合酶的功能，而不是复制性DNA聚合酶，其可以直接跨过损伤部位复制。由于TLS聚合酶的校对活性不足，TLS机制是容易出错的，这增加了突变的风险。毫不奇怪，TLS是细胞突变的主要来源。相反，DDT的另一种模式，即模板置换（TS），涉及在姐妹染色单体上重组到同源DNA模板，这类似于HR过程，被认为比TLS更准确。TLS和TS的修复活动开始于复制叉之后，这表明它们可能发生在DNA复制期间或之后，TS开始于S期早期，TLS开始于S期晚期。范可尼贫血（FA）途径范可尼贫血是一种罕见的遗传病，由范可尼基因的双等位基因突变引起，受影响的患者伴有对DNA损伤的反应不足。范科尼贫血已被确定为一种DNA修复途径，可清除阻碍DNA复制和转录的屏障，即DNA链间交联（ICL）。ICL可由醛类在多种代谢反应（如脂质过氧化和乙醇代谢）和化疗（如铂）期间形成。而链内交联通过NER途径修复，而ICL主要通过FA途径修复。通过UHRF1蛋白和FANCM–MHF1–MHF2复合物检测ICL后，FA核心复合物被招募到染色质中，并单泛素化底物FANCI和FANCD2。泛素化FANCD2-I为各种DNA内切酶招募支架蛋白，从而完成对交联处DNA的识别和核苷酸的切除，从而得到适合重组修复的DNA底物。O6-甲基鸟嘌呤-DNA甲基转移酶途径众所周知，DNA甲基化剂能够抑制DNA甲基化并产生广泛的DNA加合物，如O6-甲基鸟嘌呤（O6MeG）和O4-甲基胸腺嘧啶，这可能导致碱基错配和随后的点突变。其中，O6MeG被认为是甲基化剂诱导的DNA加合物的主要来源，可导致突变和致癌。O6MeG可以通过O6-甲基鸟嘌呤-DNA甲基转移酶（也称为MGMT）在单步自杀反应中修复。MGMT将受损鸟嘌呤O6位点的甲基转移到半胱氨酸残基，从而防止基因突变。可以想象，MGMT降低了烷化剂在癌细胞中的作用，可能导致化疗耐药。MGMT启动子的甲基化会阻碍其转录，因此可以用来提高细胞对烷化剂的敏感性。DDR治疗应用的机制与正常细胞相比，肿瘤细胞对DNA损伤敏感性增加的潜在机制在于三个主要方面：至少一条DDR途径的缺陷、复制应激的升高和内源性DNA损伤的增加。DDR缺陷尽管DDR缺陷与癌症的发生和发展有关，但DDR途径中的缺陷也为靶向肿瘤细胞提供了治疗机会。携带DDR缺陷的肿瘤细胞导致基因组不稳定性增强，并依赖剩余的DDR途径生存。作为一种治疗方法，剩余DNA修复途径的组合靶向产生了一种被称为“合成致死”的概念。合成致死的概念基于两个同时发生的功能丧失遗传事件，其中任何一个单独都不会导致损伤，而是共同作用导致细胞死亡。当癌细胞特有的DDR途径发生一种基因改变时，由DDR抑制剂引起的第二种功能丧失事件将在不影响正常细胞的情况下对癌细胞合成致死。复制应激真核细胞复杂的DNA复制系统在细胞分裂过程中受到细胞周期中各种蛋白质的严格调控。许多DNA核苷酸需要精确聚合以确保细胞内稳态。阻碍或终止复制叉进展的内源性或外源性障碍激活保守的细胞反应途径，称为复制应激。复制应激的分子机制是DNA聚合酶的进展停滞和随后DNA聚合与DNA解旋酶的解偶联。诱导复制应激的一个例子是G1/S细胞周期检查点缺陷，其原因可能是pRb功能丧失、CDKN2A缺失或细胞周期蛋白D1或细胞周期蛋白E扩增。 内源性DNA损伤一些内源性性DNA损伤是中性pH条件下低浓度氢离子和氢氧根离子的作用造成的，如脱嘌呤和脱嘧啶作用。细胞内环境对于染色体DNA来说，还具有其他危险，其中最严重的来自氧化过程，在线粒体产生的一些中间产物，如ROS，可能会从线粒体渗出，进入细胞质。这样的中间产物包括超氧离子、过氧化氢和羟自由基。在肿瘤代谢中，低PH值、缺氧和高水平的ROS在肿瘤微环境（TME）中普遍存在。靶向DNA修复途径的抑制剂目前利用DDR缺陷的抗癌策略在很大程度上是通过开发抑制DNA修复过程中分子的靶向药物来解决的。聚ADP-核糖聚合酶（PARP）抑制剂PARP抑制剂的发展是合成致死的典型代表。PARP1和PARP2是关键的DDR酶，通过带负电荷的聚ADP-核糖（PAR）链修饰靶蛋白，感知DNA损伤并传递信号。PARP1与受损DNA结合后的结构变化激活其催化功能，促进DNA修复效应分子的招募和DNA损伤部位周围染色质的结构重塑，而染色质的动态重塑将在很大程度上影响DNA修复的效率。                        鉴于PARP在促进DNA有效修复中的关键作用，PARP抑制剂可以选择性地杀死同源重组缺陷的肿瘤细胞。PARP抑制剂是BRCA突变肿瘤的一种很有前途的治疗策略。聚ADP-核糖水解酶（PARG）抑制剂PARG通过在DNA损伤后水解PAR核糖键来逆转PARP酶的作用。同样，PARG在DNA复制和修复中的积极作用导致PARG缺陷细胞对DNA损伤剂的敏感性增加。尽管大量研究表明PARP抑制剂与合成致死率之间存在相关性，但对PARG抑制剂治疗机制的研究却相对滞后。据报道，乳腺癌细胞中HR蛋白（如BRCA1/2）的缺失可刺激PARG抑制细胞的合成致死性，PARG抑制剂COH34可诱导BRCA突变或对奥拉帕利耐药的卵巢癌和乳腺癌细胞死亡。然而，在其他癌细胞中报告了相互矛盾的结果。在六个测试的乳腺癌细胞系中，只有一个BRCA缺陷的细胞系对PARG抑制剂PDD00017273敏感，而五个细胞系对PDD00017273（包括BRCA突变的细胞系）无效。共济失调毛细血管扩张突变蛋白（ATM）抑制剂DDR信号级联由一系列蛋白磷酸化驱动，ATM、ATR和DNA-PKs是参与该过程的关键激酶。被DNA双链断裂激活，ATM被MRE11-RAD50-NBS1（MRN）复合物招募到DSB位点。ATM底物包括p53、CHK1和CHK2，它们的磷酸化将导致S内或G2/M细胞周期阻滞。尽管ATM在DNA修复等多种分子过程中起着典型作用，但它也具有非典型功能，包括剪接体置换。ATM被认为是肿瘤抑制因子，ATM缺陷或突变在实体瘤和B细胞淋巴瘤中比较常见。ATM突变可能导致共济失调毛细血管扩张症，这是一种神经退行性疾病，其容易导致癌症。目前有几种ATM抑制剂正在研究用于癌症治疗。共济失调毛细血管扩张症和Rad3相关蛋白（ATR）抑制剂与由DSB触发的ATM不同，ATR被复制蛋白A（RPA）包裹的单链DNA激活并被招募。单链DNA可以通过DSB的核溶解处理以及复制DNA解旋酶与DNA聚合酶的解偶联产生。细胞内ATR信号涉及一系列下游分子的磷酸化，触发广泛的反应，包括阻断细胞周期检查点、DDR和细胞凋亡。与其他DDR蛋白如PARP相比，ATR抑制剂的开发相对滞后。原因可能包括ATR分子的大尺寸和对其晶体结构缺乏了解。此外，其在所有PIKK中的高度同源活性位点以及对共激活蛋白的需求进一步限制了其药物设计。CHK1抑制剂检查点激酶CHK1通过磷酸化和招募一系列调节蛋白，积极参与ATR和ATM启动的DNA损伤反应。CHK1通过磷酸化CDC25A来调节S期内检查点，导致CDC25A降解，随后S期细胞周期蛋白依赖性激酶2（CDK2）活性降低，CHK1对CDC25C和WEE1的磷酸化调节有丝分裂和G2/M检查点。此外，CHK1还磷酸化Thr-309上的RAD51，促进其在HR期间与BRCA2的相互作用。CHK1水平升高与更差的预后、疾病复发和治疗抵抗相关，这进一步支持CHK1抑制的治疗潜力。WEE1抑制剂作为对DNA损伤的反应，激活的ATR使Chk1磷酸化，Chk1又使WEE1和CDC25磷酸化。与活性被磷酸化抑制的CDC25相比，WEE1被激活，然后磷酸化下游CDK1上的Tyr15和Thr14以抑制其活性，导致G2/M周期阻滞，为DNA损伤修复留出时间。此外，通过磷酸化CDK1上的Tyr15，WEE1还可以在DNA复制完成之前阻止S期向G2期的进展。虽然WEE1抑制剂的原理是明确的，但其临床应用受到其治疗窗口的限制。目前，大多数临床研究集中于WEE1抑制与化疗药物的联合应用。DNA-PK抑制剂DNA依赖性蛋白激酶是一个由DNA激活的丝氨酸/苏氨酸蛋白激酶，大量表达在几乎所有哺乳动物的细胞中。DNA-PK是DNA修复的关键蛋白激酶， 参与了NHEJ的过程 。在各种肿瘤类型（包括胃肠道癌、肺癌和肝细胞癌）中都观察到DNA-PK表达上调，并且与较高的肿瘤分级和不良预后相关。DNA-PK抑制剂的开发主要集中在DNA-PKcs的催化活性上，而新的抗DNA-PKcs方法，如DNA-PKcs抑制性microRNA或靶向Ku异二聚体的抑制剂，则基于ATP结合位点的同源模型。目前，大多数DNA-PK抑制剂的临床研究集中在与癌症化疗或放疗联合使用的效果。小结细胞对DNA损伤的反应是一个复杂的过程，涉及各种信号网络和蛋白质，它们在特定的癌症类型中被差异激活或失活。肿瘤中增加的复制应激和DNA修复缺陷为我们治疗癌症提供了机会，使得癌细胞比正常细胞更容易受到DDR抑制。目前，以PARP抑制剂为典型的靶向DDR途径的药物已经走向临床应用，并且在肿瘤治疗中展现出令人鼓舞的前景。进一步，确定这些DDR抑制剂的最佳剂量、组合和时间表，减少不良反应，更理想地提高疗效将是未来的方向。此外，对每一种肿瘤进行表征，以确定其失控的DDR成分的具体特征，将有助于癌症患者的个性化治疗。参考文献：1.  Targeting DNA repair pathway in cancer:Mechanisms and clinical application. MedComm (2020). 2021 Dec; 2(4):654–691.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↓

AMSTERDAM and LONDON, Nov. 15, 2023 (GLOBE NEWSWIRE) -- Tessellate BIO, a preclinical stage biotechnology company with a focus on novel Synthetic Lethality approaches, today announces the appointment of multiple international experts to its Scientific Advisory Board. A key part of Tessellate BIO’s strategy is to source cutting-edge research from international world-renowned laboratories to bring into its drug discovery programs. The SAB plays an important role in building Tessellate BIO’s academic networks and in guiding the company’s scientific strategy. The SAB is composed of Drs. Roger Reddel, Hilda Pickett, Claus Azzalin, Andrew Deans, Christopher Lord, Rene Bernards, George Demetri, Giulio Draetta and Timothy Yap. It is chaired by Prof. Roger Reddel, Director of Children's Medical Research Institute (CMRI), and Sir Lorimer Dods, Professor, Faculty of Medicine and Health, University of Sydney. Prof. Reddel is the discoverer of the Alternative Lengthening of Telomeres (ALT) mechanism in human cancers, which is addressed by Tessellate BIO’s lead program, and a co-inventor of the ALT-specific companion diagnostic tool, the c-circle assay, which Tessellate BIO is co-developing as a companion diagnostic. Dr. Jurgen Moll, Tessellate BIO CSO, said, “Our goal is to redefine Synthetic Lethality, taking it beyond its proven potential in Homology Recombination Deficiency, and into areas where it can impact more cancers and more patients. Such a high-calibre SAB not only validates our approach but will play a vital role in ensuring we can identify the best in international science as we build our pipeline.” Prof. Roger Reddel, Tessellate BIO SAB chair, said, “I have been impressed with the Tessellate BIO team and believe they have a huge opportunity to move Synthetic Lethality beyond HRD, not only with their lead ALT program, but by applying the same approach more widely. The SAB has an exceptional depth of expertise, and I believe I speak for all the members in saying we are very excited to be involved in helping Tessellate BIO achieve its mission of turning cancer patients into cancer survivors.” The Tessellate BIO Scientific Advisory Board additional members (chaired by Prof. Roger Reddel) Hilda Pickett and Claus Azzalin are Tessellate BIO’s co-founders and SAB members. Prof. Hilda Pickett, BSc (Hons), PhD, is Head of the Telomere Length Regulation Unit at Children’s Medical Research Institute (CMRI) and Professor in the Faculty of Medicine and Health at the University of Sydney, Australia. Prof. Claus Maria Azzalin, MSc, PhD, is the Head of the Telomeres, Long Noncoding RNAs and Genome Stability Unit at the Instituto de Medicina Molecular João Lobo Antunes (iMM) and Invited Professor at the Faculty of Medicine at the University of Lisbon, Portugal. Prof. George D. Demetri, MD, is a Professor of Medicine at Harvard Medical School, Director at the Center for Sarcoma and Bone Oncology at the Dana-Farber Cancer Institute (DFCI), and Quick Family Chair, Medical Oncology at the DFCI in Boston, US. Prof. Giulio Draetta, MD, PhD, is Director at the Institute for Applied Cancer Science, and Chief Scientific Officer and Professor of Genomic Medicine at the University of Texas MD Anderson Cancer Center. Prof. Timothy Yap, MD, PhD, FRCP, is Professor in the Department for Investigational Cancer Therapeutics and the Department of Thoracic/Head and Neck Medical Oncology, as well as Vice President, Head of Clinical Development in the Therapeutics Discovery Division and Associate Director of Translational Research in the Institute for Personalized Cancer Therapy. Prof. Andrew Deans is Associate Professor and Head of the Genome Stability Unit at St. Vincent’s Institute for Medical Research in Melbourne, Australia. Prof. Christopher Lord, D.Phil., is Deputy Head of Division, Deputy Director of the Breast Cancer Now Toby Robins Research Centre, Group Leader of the CRUK Gene Function Laboratory and Professor of Cancer Genomics at The Institute of Cancer Research (ICR), in London, UK. Prof. Rene Bernards, PhD, is Group Leader at the Netherlands Cancer Institute (NKI) in Amsterdam and Professor of Molecular Carcinogenesis at Utrecht University, the Netherlands. For further information contact: Tessellate BIOAndree Blaukat, CEO - andree.blaukat@tessellatebio.com Media Enquiries Charles Consultants Sue Charles – Sue@charles-consultants.com +44 (0)7968 726585Chris Gardner - Chris@CGComms.onmicrosoft.com +44 (0)7956 031077 About Tessellate BIO Tessellate BIO discovers and develops novel precision oncology medicines with the mission to turn cancer patients into cancer survivors. A private preclinical stage biotechnology company, Tessellate BIO is redefining Synthetic Lethality by developing drugs that target unexplored or difficult to drug pathways beyond HRD. The company’s strategy is to drive small molecule drug discovery towards novel, validated oncology targets and, critically, the parallel development of associated companion diagnostics, including a potentially best-in-class diagnostic to detect ALT positive cancers for identification of treatment-eligible patients. The company also has follow-on programs in tumor suppressor Loss-of-Function (LoF) settings. Led by an experienced team of drug hunters, the company is building a pipeline of first-in-class medicines based on cutting-edge research sourced from international world-renowned laboratories including Children’s Medical Research Institute (CMRI), Australia and Instituto de Medicina Molecular (iMM), Portugal. Its lead program targets complexes that are critical for the ALT mechanism including the FANCM protein complex. Headquartered in the Netherlands and with research labs at the Stevenage Bioscience Catalyst, UK, Tessellate BIO is supported by top-tier life science investors BioGeneration Ventures (BGV) and Forbion. For more information, please visit: www.tessellatebio.com | follow us on LinkedIn

The Next Generation Synthetic Lethality Precision Oncology CompanyThe company aims to become a global leader in precision oncology by redefining Synthetic Lethality to treat large, currently unserved patient populationsLead program targets Alternative Lengthening of Telomeres (ALT) through the FANCM protein complexCompany backed by leading venture firms, BioGeneration Ventures (BGV) and ForbionWorld-class leadership team with proven experience as entrepreneurs and deep expertise in drug discovery and precision oncology AMSTERDAM and LONDON, Oct. 17, 2023 (GLOBE NEWSWIRE) -- Tessellate BIO, a preclinical stage biotechnology company with a focus on novel Synthetic Lethality approaches, has today emerged from stealth, with an initial €8m in seed funding backed by two leading European venture capital firms, BioGeneration Ventures (BGV) and Forbion. Its lead program targets the DNA damage response (DDR) and in particular cancers that depend on Alternative Lengthening of Telomeres (ALT). The company aims to become a global leader in precision oncology by redefining Synthetic Lethality. While Synthetic Lethality approaches targeting Homology Recombination Deficiency (HRD) have been successfully validated in the clinic by PARP inhibitors, there remains a vast and largely unexplored space in Synthetic Lethality beyond HRD that Tessellate BIO is pioneering. Tessellate BIO has attracted an impressive leadership team of seasoned entrepreneurs and industry-experienced drug hunters with proven track records, including: CEO, Andree Blaukat, previously SVP and Head of Oncology Research at Merck KGaA; CSO, Jürgen Moll, previously Head of Molecular Oncology Unit at Sanofi; and serial entrepreneur Andrew Lightfoot, as COO, who initially established the company. In addition, Eliot Forster, most recently former CEO of NASDAQ-listed F-star, has joined as Chair of the Board of Directors. Andree Blaukat, CEO, said, “Synthetic Lethality is a proven, but only partly explored concept, and there are large numbers of patients whose needs are not being met by current medicines. I believe applying Synthetic Lethality beyond HRD has the potential to open a new frontier in precision oncology by addressing a wide range of cancer types with highly tumor-targeted treatments.” Founding investor, board director and Partner at BGV, Daniela Couto, noted, “The know-how and data generated by the scientific founders Prof. Claus Azzalin and Prof. Hilda Pickett around FANCM and ALT got us really excited to kick-start Tessellate BIO. These foundations brought Forbion on board and allowed us to attract an excellent management team. Together, we are creating a very exciting first-in-class pipeline and looking for other like-minded investors to join us.” Board director and General Partner at Forbion, Rogier Rooswinkel, added, “We are delighted to have joined our partners at BGV and to have built together a company from the ground up. Developing innovative precision oncology drugs requires the right scientific and business leadership, and at Tessellate BIO we have built a world-class team.” Eliot Forster, Independent Director and Chair of the Board, said, “Novelty in the treatment of cancer is less and less common. Andree and his team are developing a novel approach beyond the already-exploited HRD. This is an enormous opportunity for patients. I have been hugely impressed by the ambition at Tessellate BIO and by the progress already made towards the vision of impacting patient care – turning cancer patients into cancer survivors.” For further information contact: Tessellate BIOAndree Blaukat, CEO - andree.blaukat@tessellatebio.com Media Enquiries Charles Consultants Sue Charles – Sue@charles-consultants.com +44 (0)7968 726585Chris Gardner - Chris@CGComms.onmicrosoft.com +44 (0)7956 031077 About Tessellate BIO Tessellate BIO discovers and develops novel precision oncology medicines with the mission to turn cancer patients into cancer survivors. A private preclinical stage biotechnology company, Tessellate BIO is redefining Synthetic Lethality by developing drugs that target unexplored or difficult to drug pathways beyond HRD. The company’s strategy is to drive small molecule drug discovery towards novel, validated oncology targets and, critically, the parallel development of associated companion diagnostics, including a potentially best-in-class diagnostic to detect ALT positive cancers for identification of treatment-eligible patients. The company also has follow-on programs in tumor suppressor Loss-of-Function (LoF) settings. Led by an experienced team of drug hunters, the company is building a pipeline of first-in-class medicines based on cutting-edge research sourced from international world-renowned laboratories including Children’s Medical Research Institute (CMRI), Australia and Instituto de Medicina Molecular (iMM), Portugal. Its lead program targets complexes that are critical for the ALT mechanism including the FANCM protein complex. Headquartered in the Netherlands and with research labs at the Stevenage Bioscience Catalyst, UK, Tessellate BIO is supported by top-tier life science investors BioGeneration Ventures (BGV) and Forbion. For more information, please visit: www.tessellatebio.com | follow us on LinkedIn About Tessellate BIO’s lead program - ALT ALT is a critical mechanism to maintain the integrity of telomeres, which is essential for the unlimited replicative potential of tumor cells that is a key hallmark of cancer. Many cancers with high unmet medical need and poor prognosis rely on ALT for proliferation. For example, several types of sarcomas have over 60% ALT dependency, and substantial subgroups of many solid tumors are ALT dependent. The lead program targets the FANCM protein complex and is based on the discoveries of Tessellate BIO co-founders Prof. Hilda Pickett (CMRI) and Prof. Claus Azzalin (iMM). About BGV BioGeneration Ventures (BGV) is a venture capital company, with a focus on early-stage European biotech companies. The Company has a strong track record of significant financial returns through investing in innovations in healthcare and providing the expertise to build world-class companies. BGV manages over EUR 400 million of funds investing in areas where true scientific innovations, the unmet medical need, and the potential to demonstrate a significant proof of concept all come together. BGV strives to work with founding teams to mature science and build companies. The Company uses its experience to guide progress into clinical trials, ultimately leading to successful drug development and value realization for its investors. BGV applies its expertise in a rigorous process to select the most compelling opportunities with the best prospects for exit. For more information, please visit: www.biogenerationventures.com About Forbion Forbion is a dedicated life sciences venture capital firm with offices in The Netherlands, Germany and Singapore. Forbion invests in life sciences companies that are active in the (bio-) pharmaceutical space. Forbion manages €3 billion across multiple fund strategies that cover all stages of (bio-) pharmaceutical drug development. Forbion’s current team consists of over 30 life sciences investment professionals that have built an impressive performance track record since the late nineties with investments in over 95 companies across 10 funds. Forbion’s record of sourcing, building and guiding life sciences companies has resulted in many breakthrough therapies and valuable exits. Portfolio company successes include NewAmsterdam Pharma (NASDAQ: NAMS), Gyroscope (acquired by Novartis) and Replimune (NASDAQ: REPL). Besides financial objectives, Forbion selects investments that will positively affect the health and well-being of patients. The firm is a signatory to the United Nations Principles for Responsible Investment. Forbion operates a joint venture with BGV, the manager of seed and early-stage funds, especially focused on Benelux and Germany. For more information, please visit: www.forbion.com