GABA transporter subfamily

A New York City drug developer led by well-known executives and backed by some of the top names in biotech investing is shutting down, a blow to a company that was prepping for a pivotal trial in colorectal cancer. Inspirna is “winding down” after “10 years as a fantastic biotech company,” CEO Oz Azam wrote in a LinkedIn post on Monday morning. The cell and gene therapy veteran joined Inspirna in 2023 after leading Empyrean Neuroscience and Tmunity Therapeutics. Inspirna’s team decided to close the company after a Phase 2 trial of its oral small molecule, called ompenaclid, “did not read out positively” in KRAS colorectal cancer, according to a source familiar with the decision, who agreed to speak on the condition of anonymity. Merck KGaA paid $45 million upfront last year for the ex-US rights to the SLC6A8 inhibitor and had the option to co-develop and co-promote it in the US. The companies were also working on follow-up SLC6A8 compounds. Merck KGaA will “not pursue further development of ompenaclid” and will not exercise its option in the US, a spokesperson for the drugmaker told Endpoints News via email. Azam did not immediately respond to an inquiry from Endpoints. Inspirna is at least the seventh biotech to shutter so far in 2025, following last week’s news about Lyndra Therapeutics . Inspirna was putting together a global pivotal study of ompenaclid for patients with certain forms of colorectal cancer, but the trial “requires additional funding and is dependent on further FDA feedback,” according to the company’s first-quarter presentation . Inspirna last disclosed a $50 million Series D in July 2022. Its backers included blue-chip investors like Vivo Capital, Sands Capital, Novo Holdings, and Sofinnova Partners. The financing was expected to keep the R&D engine humming until the second half of 2024, a spokesperson told Endpoints at the time of the Series D. Inspirna also had a small molecule called abequolixron in its pipeline. The LXR-beta selective agonist was being tested in Phase 1b/2 for certain forms of lung cancer. GSK discovered the asset and originally intended for it to treat cardiovascular disease before licensing it out to Inspirna. Inspirna was formed more than a decade ago as Rgenix from the Tavazoie Lab at The Rockefeller University. The biotech’s platform focused on microRNA, or miRNA, dysregulation, which is thought to contribute to the development of cancer and its progression. Dieter Weinand, a former CEO of Bayer’s pharma division, chaired Inspirna’s board.

撰文丨王聪 编辑丨王多鱼 排版丨水成文 牛磺酸（Taurine），是一种由含硫氨基酸转化而来的氨基酸，广泛分布于体内各个组织和器官，主要以游离状态存在于组织间液和细胞内液中，因最先于牛胆汁中发现而得名。常见的功能饮料中就添加有牛磺酸，以补充能量，改善疲劳。 更重要的是，最近关于牛磺酸的研究接连登上三大顶刊 Science、Cell 和 Nature，这些研究揭示了牛磺酸的新功能——抗衰老【1】、提高癌症治疗效果【2】，以及抗肥胖【3】。 2025 年 3 月 20 日，中国科学院上海药物所徐华强团队与上海交通大学医学院附属仁济医院马雄教授团队合作，在 Cell Research 期刊发表了题为：Structural basis of augmenting taurine uptake by the taurine transporter in alleviating cellular senescence 的研究论文【4】。 该研究解析了牛磺酸转运体（TauT）的冷冻电镜结构，揭示了它精准转运牛磺酸并逆转细胞衰老的机制，这项发现不仅解答了多年科学难题，更为抗衰老和疾病治疗提供了全新方向。 牛磺酸：身体中的“多面手” 牛磺酸虽然最初在牛胆汁中发现，但却是人体不可或缺的“全能选手”：保护心脏、维持肝功能、助力生殖健康、延缓衰老……它就像细胞里的“充电宝”。然而，人体自身合成牛磺酸的能力有限，主要依赖饮食吸收。细胞中负责运输牛磺酸的正是位于细胞膜上的牛磺酸转运体（TauT，其由SLC6A6基因编码）。一旦 TauT “罢工”，牛磺酸缺乏会引发肝损伤、心肌病、视网膜退化甚至加速衰老。 然而，TauT 与牛磺酸的结合以及对牛磺酸的转运机制等基本问题，尚未得到解答。 冷冻电镜下的“分子特写”：TauT如何工作？ 研究团队利用冷冻电镜技术，首次以原子级分辨率解析了牛磺酸转运体（TauT）的多个工作状态：从“空载待命”（apo状态）到“装载牛磺酸”的动态过程。 研究发现： 1、精准识别：牛磺酸的磺酸基像“钥匙”一样插入 TauT 的特定凹槽，与多个氨基酸形成氢键和盐桥，确保结合专一性（图1a-b）。 2、多重关卡：除了核心结合位点（S1），TauT 还设有“中转站”（S2-S3位点），形成一条从细胞外到细胞内的连续运输通道（图1d-g）。 3、门控开关：TauT 通过结构变形实现“内向开放”和“外向封闭”，好比一道旋转门，防止牛磺酸“倒流”（图1h）。 4、增强秘诀：突变实验发现，破坏 TauT 的“额外门锁”（例如S464位点），可大幅提升运输效率，为药物设计提供靶点（图1i-j）。 对TauT的结构认识及其在减轻细胞衰老中的作用 抗衰老实锤！TauT如何逆转细胞“老化”？ 研究团队用阿霉素诱导的胆管细胞衰老模型验证发现：增强 TauT 功能可显著缓解细胞衰老！  具体机制在于，TauT 高效运输牛磺酸，维持细胞内充足浓度，对抗氧化应激和 DNA 损伤。该研究还发现，临床中观察到的 TauT 致病突变（例如 A78E、G399A 位点突变）会破坏 TauT 结构，导致其牛磺酸运输能力暴跌，引发视网膜退化等疾病。 这些发现为开发“激活TauT”的抗衰疗法（例如小分子药物、基因治疗）奠定了基础。 总的来说，这项研究首次完整描绘了牛磺酸转运体（TauT）的“工作蓝图”，不仅解答了底物识别与跨膜运输的核心问题，更揭示了其在细胞保护中的关键角色。未来，科学家或可通过： 药物开发：设计 TauT 激动剂，提升牛磺酸吸收，治疗衰老相关疾病。 精准医疗：针对 TauT 基因突变患者，开发个性化干预方案。 健康应用：优化饮食中牛磺酸摄入（例如海鲜、红肉），或开发功能性补充剂。 从分子结构的“惊鸿一瞥”到逆转衰老的“生命密码”，这项研究让我们离“健康长寿”的梦想更近一步。或许在不久的将来，激活 TauT 会成为对抗衰老、守护器官健康的“超级武器”！ 论文链接： 1. https://www.science.org/doi/10.1126/science.abn9257 2. https://www.cell.com/cell/abstract/S0092-8674(24)00303-9 3. https://www.nature.com/articles/s41586-024-07801-6 4. https://www.nature.com/articles/s41422-025-01090-y 设置星标，不错过精彩推文 开放转载 欢迎转发到朋友圈和微信群  微信加群  为促进前沿研究的传播和交流，我们组建了多个专业交流群，长按下方二维码，即可添加小编微信进群，由于申请人数较多，添加微信时请备注：学校/专业/姓名，如果是PI/教授，还请注明。 点在看，传递你的品味

Merck KGaA on Thursday reported its annual results for 2024, although investors eager for an update on a potential deal with SpringWorks Therapeutics were left frustrated. The German drugmaker simply reaffirmed that it is in advanced discussions about a possible acquisition of SpringWorks, although there is no certainty that an agreement will be signed. Rumours of a transaction between the parties first surfaced on February 10, with Merck confirming later the same day that talks were ongoing. A purchase of SpringWorks would give Merck the oral gamma secretase inhibitor Ogsiveo (nirogacestat), which is approved for desmoid tumours, as well as the MEK inhibitor mirdametinib, currently under review by the FDA for neurofibromatosis type 1-associated plexiform neurofibromas.The acquisition of SpringWorks would revitalise Merck's pipeline, following a number of recent setbacks, including the failure of a pair of Phase III studies for its lead oncology candidate xevinapant. While the company's healthcare segment posted 5% growth last year to €8.5 billion ($9.2 billion), driven by oncology — which was up 10.5% to €2 billion — it is heavily reliant on its 20-year-old drug Erbitux.Erbitux biosimilars on the horizonThe anti-EGFR monoclonal antibody generated sales in 2024 of €1.2 billion, up 13.3% over the prior year. Merck noted that growth for Erbitux was led by Latin America, particularly Mexico, as well as Europe and China, tempered by negative pricing effects in Japan.Asked on an analyst call about the growth potential of Erbitux, particularly in China, Peter Guenter — CEO of Merck's healthcare unit — noted that sales of the product are forecast to increase this year, with biosimilars not expected to launch before 2026. Guenter indicated that China, which accounts for about 25% of Erbitux revenue, is "an important growth driver, but actually the brand is very dynamic across the world."While Erbitux faces competition in China from Simcere Pharmaceutical's Enlituo, Guenter clarified that the product — approved last June — is not classified as a biosimilar, but rather a non-comparable biologic. "And that has, of course, relatively important implications in terms of, you know, lack of substitution," Guenter explained, as well as inclusion on the reimbursement drug list and volume-based procurement programme.Merck's other key drug, the multiple sclerosis (MS) therapy Mavenclad, achieved blockbuster status in 2024 for the first time, posting an 11.1% increase in revenue to €1.1 billion. Meanwhile, its older MS treatment Rebif declined 11.6% to €626 million in line with the wider interferon market.For the current year, the firm expects sales in its healthcare unit to be between €8.3 billion and €8.9 billion, representing organic growth of up to 5%.Pipeline questions continueMerck also disclosed Thursday that the oral TLR7/8 inhibitor enpatoran failed to meet the primary endpoint of the systemic lupus erythematosus cohort of the mid-stage WILLOW study. Despite what Guenter called "a near miss" in the trial, the company plans further development of the drug, given "promising responses" in patient subgroups and the totality of data, including positive results from the cutaneous lupus erythematosus arm of WILLOW.Guenter explained "the good news is that we see clear responses in predefined subpopulations. So we can really say that the drug clearly hits the target." These subgroups include patients with skin manifestations within the lupus cluster, those with a strong interferon gene signature and also those with high steroid use at baseline.Meanwhile, chief financial officer Helene von Roeder noted that Inspirna "informed [us] about negative top-line data" from an ongoing Phase II trial of ompenaclid in RAS-mutated advanced or metastatic colorectal cancer. The SLC6A8 inhibitor — also known as RGX-202 — was the focus of a licensing agreement between the parties last year. However, von Roeder indicated that the mid-stage failure means "we will not exercise the US option" on the drug, but will instead record an impairment charge of around €15 million in the current quarter.