NEK1

— Companies will co-develop inhibitors of a dark kinase target (NEK1) identified for cancer dependency by Turbine's Simulated Cell™ platform — LONDON and BUDAPEST, Hungary and NEW YORK, April 1, 2024 /PRNewswire/ -- Turbine, a company that is building the world's first predictive simulation of patient biology, and Harmonic Discovery (Harmonic), a therapeutics company building an integrated computational and experimental platform for kinase drug discovery and targeted polypharmacology, have entered into a collaboration to co-develop novel cancer therapies that will inhibit a dark kinase identified for cancer dependency using Turbine's Simulated Cell™ platform. "We believe that the dark kinase NEK1 holds great potential as a drug target for developing cancer therapies addressing important resistance challenges in the clinic," said Daniel Veres, M.D., Ph.D., Chief Scientific Officer and Co-Founder of Turbine. "Coupling Harmonic's deep expertise in multi-specific kinase-targeted drug design with our unique ability to guide drug discovery by running simulated experiments with causal interpretation in a vast biological search space will help realize a more innovative and efficient process than traditional approaches. We are excited for the opportunity to demonstrate the power of our platforms to collectively boost R&D success in the clinic." "Our fully integrated kinase drug discovery platform aims to challenge current drug discovery paradigms by building a machine learning-first infrastructure that integrates multiple aspects of kinase drug discovery," said Rayees Rahman, Ph.D., CEO and Co-Founder of Harmonic Discovery. "Turbine's exciting biological simulation technology is highly complementary to our approach. We are confident that integrating both companies' innovative platforms will yield a radically more effective approach to selecting and advancing kinase-targeted therapies that can substantially improve patient outcomes in oncology." The collaboration provides a framework in which biological and mechanistic insights from Turbine's simulations will directly inform Harmonic's generative chemistry models – with the goal of bringing forward new, differentiated, and effective kinase inhibitor therapies for the patients who need them most. Harmonic will assume responsibilities for computational chemistry and medicinal chemistry activities, while Turbine will be responsible for in silico simulations and wet-lab validation of target biology, including the identification of both synergistic kinase co-targets to NEK1 and patient populations most likely to benefit from therapies. Financial terms of the collaboration are not disclosed. About Turbine Countless resources and time get expended globally to research and advance novel therapies that end in clinical failure and no patient benefit. Imagine a world where it is possible to predict any potential drug's effect on translatable biological models – including those that may not even be available for lab-based testing – while accurately representing patient biology. Turbine is revolutionizing the status quo by working to ensure that we always run the right wet lab experiments. With machine learning that understands the logic by which human cells make decisions, Turbine has built the world's first predictive simulation of patient biology. The Simulated Cell™ platform models the protein signaling that decides cell fate and facilitates in silico experiments at scales that are impossible in the physical world, to empower the biopharma industry by guiding experiments that identify and confirm disease driving mechanisms. Turbine's platform has been validated with leading pharma companies such as AstraZeneca, Ono Pharmaceutical, Cancer Research Horizons, and Bayer. In addition, Turbine has received funding from industry leaders such as MSD (Merck & Co, Inc. Rahway NJ, USA) Global Health Innovation Fund, Accel, and MassMutual Ventures, among others. For more information, visit or follow Turbine on LinkedIn. About Harmonic Discovery Harmonic Discovery (the "Company") is a precision pharmacology company applying its generative chemistry platform to advance next-generation kinase inhibitors. The Company's platform is trained on multiple layers of proprietary data and is integrated with domain expertise to design safer and more efficacious kinase therapeutics. The Company's lead programs are focused on malignant hematology indications, with exploratory discovery efforts in additional therapeutic areas including immuno-oncology, immunology and inflammation. The Company has raised $8 million in Seed Financing to date from Innovation Endeavors, Fifty Years, Y Combinator and other select investment firms. The Company was founded in 2021 and is headquartered at Johnson & Johnson's JLABS ("JLABS@NYC") in New York City, New York. To learn more, visit SOURCE Harmonic Discovery Inc.

Scientists have uncovered how a newly discovered gene, NEK1, in which mutations have been linked to ALS cases, disrupts the function of the motor neuron and causes it to degenerate and die. The viral ALS Ice Bucket Challenge a few years ago raised major funding that resulted in the discovery of new genes connected to the disease. One of those genes is NEK1, in which mutations have been linked to as much as 2% of all ALS cases, making it one of the top-known causes of the disease. But it wasn't known how the mutated gene disrupts the function of the motor neuron and causes it to degenerate and die. Northwestern Medicine scientists have discovered for the first time how this mutated gene leads to ALS (amyotrophic lateral sclerosis). The investigators found the mutation causes two problems in the neuron. The first is that it causes the structures supporting the axon in the neuron to become less stable and susceptible to collapsing. (The axon is the thinner-than-a-human-hair cable leading from the cell that sends electrical messages to other neurons.) The second problem the scientists discovered is that the mutation disrupts the ability of the neuron to import cargo in the form of RNA or proteins into its nucleus, a process called nuclear import. Without the import of RNA -- which carries instructions from the DNA -- and critical proteins, the operational role of nucleus for the cell's function is disrupted. The paper will be published August 16 in Science Advances. "By illuminating these two pathways, we're suggesting these are great therapeutic targets for the disease," said study lead author Evangelos Kiskinis, assistant professor of neurology and neuroscience at Northwestern University Feinberg School of Medicine. "This discovery is important because a major breakthrough in ALS research in the last few years was discovering that nuclear import is disrupted in other forms of genetic ALS," Kiskinis said. "We are linking this new cause of ALS to other genetic causes in which the same process is disrupted." A major unaddressed question in the field is whether ALS is one disease or a collection of genetically distinct smaller versions under the "umbrella" of the same clinical problems, Kiskinis said. "Our discovery -- of the same destructive mechanisms in other genetic forms of ALS -- leads us to believe this is the same disease," Kiskinis said. "This new awareness is critical to developing treatments and for designing optimal clinical trials targeting specific ALS patient populations. ALS is a devastating neurodegenerative disease in which the upper and lower motor neurons in the brain and spinal cord dysfunction and die. It results in the loss of voluntary muscle movement, which leads to paralysis and eventual death. Treating human ALS brain cells with cancer drugs The structural components of the nerve's axon, which are destabilized in ALS, are microtubules. Kiskinis knew anti-cancer drugs such as paclitaxel, which target and stop the dividing of cancer cells, help stabilize the microtubules. So, the Northwestern team tested these anti-cancer drugs in ALS models of human neurons (made from ALS patients' stem cells). The drugs stabilized the microtubules in vitro and restored the ability of nerve cells with the ALS mutation to function. Kiskinis says it would be exceptionally challenging to use such anti-cancer drugs to treat ALS patients as they would likely have severe side effects, and a very narrow dose range as over-stabilizing microtubules can be toxic to neurons. However, the findings serve as proof of principle. "This suggests that stabilizing microtubules is a rational therapeutic approach in ALS," Kiskinis said. Kiskinis and his team are currently working on understanding more precisely how NEK1 regulates microtubules and nuclear import in human neurons. They also are developing approaches to increase the function of NEK1 to prevent the degeneration of the neurons in ALS. Other Northwestern authors include Elizabeth McKenna, Jacob Mann, Vasileios Papakis, Francesco Alessandrini, Ryan Mayers, Hannah Ball, Evan Kaspi, Katherine Lubinski and Liana Tellez. The title of the paper is "NEK1 Depletion Disrupts Microtubules and Nuclear Import." The study was supported by: National Institute on Neurological Disorders and Stroke grants R01NS134166, 5T32NS041234 and R21NS107761, National Institute on Aging grant T32AG20506, National Institutes of Health grant F31NS117084, all of the National Institutes of Health; Healey Center for ALS at Massachusetts General Hospital ALS Scholars in Therapeutics Fellowship, Les Turner ALS Foundation and New York Stem Cell Foundation.

曾经风行一时的“冰桶挑战”旨在唤起人们对“渐冻症”的关注。这种罕见病全名肌萎缩性脊髓侧索硬化症（Amyotrophic lateral sclerosis，ALS），属于神经退行性疾病。患者早期表现为肌肉萎缩、肌肉抽搐、肢体无力和语言不清，发病3-5年后常因全身肌肉无力导致瘫痪，以及因呼吸衰竭而死亡，只有10%的患者生存期超过10年，极少数生存期可超过50年，如著名的物理学家霍金。图1 冰桶挑战（图源：unsplash）导致ALS的大部分病因尚不明确，仅大约10%的病例是遗传性的。目前认为，多种相互关联的分子机制，包括蛋白质平衡、折叠和运输功能障碍，过度的神经元刺激，氧化应激，神经炎症等，导致了该疾病的发生。这些功能障碍导致了运动神经元的退化和死亡，引起逐渐蔓延至全身的肌肉萎缩。目前，已发现超过25个与ALS相关的基因。其中，C9ORF72、SOD1、TARDBP和FUS基因突变为最常见的遗传性ALS病因。其他已发现的还有ANG、VAPB、VCP、SQSTM1、DCTN1、DAO、SETX、ATXN2、OPTN、SCFD1、NEK1、C21ORF2等基因突变。利鲁唑是FDA批准的首个用于治疗ALS的药物。尽管在临床试验中，利鲁唑可以延长患者3-5个月的生存期，但对于已有的运动神经元损伤并不能修复。依达拉奉（Radicava）于2017年5月经FDA批准用于治疗ALS，其抗氧化作用被认为能够缓解氧化应激的影响，可延缓疾病发展或限制额外伤害。此外，还有一些对症治疗的药物可用于缓解ALS的症状。图2 利鲁唑和依达拉奉近日，根据发表于Neurobiology of Aging杂志上的一项新研究“Loss of amyotrophic lateral sclerosis risk factor SCFD1 causes motor dysfunction in Drosophila”，马耳他大学的研究人员关闭了果蝇的SCFD1基因，通过观察造成的后果，研究人员揭示了SCFD1功能丧失是如何引发ALS症状的，并提出了一个潜在的ALS新药靶点。图3 研究成果（图源：[1]）在一项招募了超过十万ALS患者和健康志愿者的国际性大型研究计划MinE项目中，SCFD1被识别为ALS的相关风险位点。马耳他大学神经遗传学副教授、最新研究的席研究员Ruben J. Cauchi博士解释说：“SCFD1基因是全球ALS患者最强的风险因素之一。然而，SCFD1与疾病之间联系的重要性仍然未知。这项大型研究能够发现那些ALS患者相对于健康志愿者而言突变频率更高的基因，但同时，他们所找到的基因与ALS的具体联系并不明确。”而在最新的研究中，马耳他大学的研究人员观察到，当果蝇的SCFD1基因被敲低时，成年果蝇出现了运动障碍，SCFD1基因的强烈敲低则导致果蝇幼虫出现了肌肉收缩障碍和神经肌肉接头障碍，化蛹时显得更加僵硬和伸长。图4 SCFD1基因强烈敲低影响果蝇幼虫化蛹（图源：[1]）对SCFD1基因强烈敲低的幼虫进行RNA测序，发现了585个差异表达基因。分析失调通路发现，围绕着蛋白质折叠或再折叠的通路下调最为显著。在过去的研究中，已经明确错误折叠和蛋白质聚集是ALS的标志性特征 。抑制运动神经元正确折叠蛋白的能力将会增加对于ALS的易感性，因此，修复或激活患者的SCFD1将有望减缓或阻止他们的疾病。研究团队相信他们的方向是正确的。去年9月，在患者群体的强烈游说下，已在加拿大获得有条件批准的新药AMX0035，在美国以商品名Relyvrio获得了类似的批准。AMX0035就对蛋白质折叠错误有所针对。AMX0035是两种已在使用药物苯丁酸钠（PB）和牛磺熊去氧胆酸（TUDCA）的专有口服组合，PB能够抑制内质网应激反应和由蛋白错误折叠或突变引起的神经元细胞死亡。TUDCA具有抗细胞凋亡和神经保护作用。但与单独使用PB或TUDCA相比，组合用药能够改变更多的基因表达。 责编|风立宵校对|风立宵End参考资料： [1]Rebecca Borg, Angie Purkiss, Rebecca Cacciottolo, et al, Loss of amyotrophic lateral sclerosis risk factor SCFD1 causes motor dysfunction in Drosophila, Neurobiology of Aging, 2023, ISSN 0197-4580, https://doi-org.libproxy1.nus.edu.sg/10.1016/j.neurobiolaging.2023.02.005.[2]van Rheenen, W., Shatunov, A., Dekker, A. et al. Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis. Nat Genet 48, 1043–1048 (2016). https://doi-org.libproxy1.nus.edu.sg/10.1038/ng.3622[3]https://www.biostock.se/en/2022/12/new-drugs-bring-hope-to-als-patients/ [4]https://www.alzforum.org/therapeutics/relyvrio 本文系生物探索原创，欢迎个人转发分享。其他任何媒体、网站如需转载，须在正文前注明来源生物探索。 往期精选 围观 ‍清洁用品中的这种常见化学物质，会使患上帕金森病的风险高出5倍！ 热文女性更要控盐！所有种族、年龄的女性更容易因盐得高血压，且绝经后风险更高！ 热文发现表观遗传学新机制，向战胜癌症和衰老更进一步！ 热文详解 “类器官智能”愿景路线图，用人脑细胞搭建生物计算机的未来会是怎样？ 热文 克服免疫系统限制：工程细菌引领新型癌症治疗策略点击“阅读原文”，了解更多~