PDXP

▎药明康德内容团队编辑 编者按：染色体不稳定性（CIN）是癌细胞的一个普遍特征，这一特性不仅驱动了肿瘤的异质性和进化，也成为了其特有的弱点。然而，尽管这一特性在癌症生物学中具有重要意义，其在临床治疗中的应用潜力尚未得到充分开发。近期，来自Volastra Therapeutics的研究团队在《自然-通讯》（Nature Communications）发表研究论文，开发了一种靶向小分子抑制剂VLS-1272，为针对CIN的新型抗癌策略提供了重要的理论依据和治疗工具。在该论文中，药明康德为研究团队提供了体内药理分析服务。KIF18A：癌症治疗潜在靶点在细胞分裂过程中，遗传物质的精确分离对生物体的生存至关重要。然而，染色体分离错误会导致遗传物质分配不均，这种现象被称为染色体不稳定性（CIN）。CIN在大多数人类癌症中普遍存在，与多种实体瘤和血液肿瘤的发生发展密切相关。具体而言，CIN不仅增加了肿瘤的异质性，还可能导致肿瘤对标准治疗药物产生耐药性，并促进癌症的转移进程。因此，开发针对CIN的治疗策略具有重要的临床意义，不仅有望延长患者的生存期，还可能通过克服药物耐药性为癌症治疗带来广泛的益处。在这项研究中，研究人员利用癌症依赖性图谱（DEPMAP）数据库，对细胞系的CIN进行量化并分级。基于这一分析，研究团队发现，KIF18A在高CIN细胞中表现出更高的必需性。结合本研究的数据以及既往发表的机制研究和实验证据，KIF18A被确立为CIN相关癌症的潜在治疗靶点。为了评估CIN细胞对KIF18A的依赖性，研究人员构建了CIN细胞系模型，并且敲除了KIF18A。实验结果显示，KIF18A缺失显著抑制了高CIN细胞的增殖，且这种抑制作用在高CIN细胞中更为明显。这一结果与DEPMAP数据库的分析一致，进一步证实了高CIN细胞对KIF18A缺失的高度敏感性。为了验证这一发现的普适性，研究人员在乳腺癌细胞系中进行了进一步实验。结果表明，在不同CIN水平的乳腺癌细胞中，降低KIF18A表达均能抑制细胞增殖，且抑制程度与细胞的CIN基线水平呈正相关。在高CIN水平的乳腺癌细胞中，KIF18A敲低不仅显著抑制细胞增殖，还导致G2/M期细胞比例增加。这些数据表明，细胞通过在有丝分裂期停滞来响应KIF18A的缺失。图片来源：123RF为了进一步评估KIF18A在肿瘤生长中的作用，研究人员将表达对照质粒或KIF18A shRNA质粒的肿瘤细胞植入免疫缺陷小鼠体内，这些肿瘤细胞分别接受或不接受强力霉素（Dox）处理。实验结果显示，与植入转染对照质粒的细胞或未接受Dox处理的小鼠相比，经Dox处理且KIF18A shRNA诱导的肿瘤细胞的生长显著延迟。此外，对肿瘤样本的分析证实了KIF18A的有效敲低。这些体内实验结果表明，CIN肿瘤细胞在体内生长过程中高度依赖KIF18A，进一步支持了KIF18A作为CIN相关癌症治疗靶点的潜力。VLS-1272：新型KIF18A靶向抑制剂为了进一步评估KIF18A作为治疗靶点的潜力，研究人员开发并运行了一个高通量筛选平台，旨在寻找能够抑制KIF18A的ATP酶活性的小分子化合物。通过对一个包含5万种类先导化合物的库进行筛选，研究人员重点针对KIF18A马达结构域（氨基酸1-374）的微管依赖性ATP酶活性进行抑制剂的筛选。经过多轮药效学和药代动力学性质的优化，最终获得了候选化合物VLS-1272。▲VLS-1272的分子结构（图片来源：参考资料[1]）VLS-1272具有一系列优异的特性，包括口服生物利用度高、效力强、非ATP竞争性、微管依赖性以及对KIF18A的高度选择性（相较于其他驱动蛋白）。该化合物能够强效抑制KIF18A的ATP酶活性，并阻止KIF18A在有丝分裂纺锤体上的转移，从而导致染色体集合缺陷、诱导有丝分裂停滞与细胞死亡。这些作用机制表明，VLS-1272是一种具有潜力的KIF18A靶向抑制剂，为CIN相关癌症的治疗提供了新的方向。基于在100多种癌细胞系中对VLS-1272的分析结果，VLS-1272展现出对CIN癌细胞的特异性抑制作用，这一特性显著区别于其他处于临床开发阶段的抗有丝分裂药物。在肿瘤异种移植模型中，VLS-1272治疗诱发了显著的有丝分裂缺陷，并以剂量依赖的方式抑制了肿瘤生长。研究人员进一步证明，无论是通过遗传学手段敲低KIF18A，还是通过药物抑制其活性，均能有效抑制肿瘤生长。这些数据共同揭示了KIF18A抑制剂在临床治疗中的潜在价值。综上所述，本研究揭示了KIF18A抑制剂通过靶向CIN来抑制肿瘤生长的新策略。作为一种广泛存在于恶性肿瘤中的特征，CIN通过克隆异质性驱动癌症转移并加速耐药突变演化。靶向抑制KIF18A能够选择性清除具有高水平CIN的肿瘤细胞，破坏其适应性生存优势，从而延缓耐药表型产生。作为一款新型KIF18A抑制剂，VLS-1272在临床前模型中展示出了显著的抗癌效力。其独特优势在于不影响T细胞增殖，这为其与免疫检查点抑制剂的联合应用提供了可能。展望未来，研究人员将进一步探索KIF18A抑制的临床潜力，为CIN相关癌症的治疗开辟新的方向。参考资料：[1] Phillips, A.F., Zhang, R., Jaffe, M. et al. Targeting chromosomally unstable tumors with a selective KIF18A inhibitor. Nat Commun 16, 307 (2025). https://doi-org.libproxy1.nus.edu.sg/10.1038/s41467-024-55300-z本文来自药明康德内容微信团队，欢迎转发到朋友圈，谢绝转载到其他平台。如有开设白名单需求，请在“学术经纬”公众号主页回复“转载”获取转载须知。其他合作需求，请联系wuxi_media@wuxiapptec.com。免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。更多推荐点个“在看”再走吧~

A low vitamin B6 level has negative effects on brain performance. A research team has now found a way to delay the degradation of the vitamin. Vitamin B6 is important for brain metabolism. Accordingly, in various mental illnesses, a low vitamin B6 level is associated with impaired memory and learning abilities, with a depressive mood, and even with genuine depression. In older people, too little vitamin B6 is linked to memory loss and dementia. Although some of these observations were made decades ago, the exact role of vitamin B6 in mental illness is still largely unclear. What is clear, however, is that an increased intake of vitamin B6 alone, for example in the form of dietary supplements, is insufficient to prevent or treat disorders of brain function. Publication in eLife A research team from Würzburg University Medicine has now discovered another way to increase vitamin B6 levels in cells more effectively: namely by specifically inhibiting its intracellular degradation. Antje Gohla, Professor of Biochemical Pharmacology at the Department of Pharmacology and Toxicology at Julius-Maximilians-Universität Würzburg (JMU), is responsible for this. Other participants come from the Rudolf Virchow Center for Integrative and Translational Bioimaging at JMU, the Leibniz-Forschungsinstitut für Molekulare Pharmakologie-FMP Berlin and the Institute for Clinical Neurobiology at Würzburg University Hospital. The team has now published the results of their investigations in the scientific journal eLife. Enzyme Blockade Improves Learning Ability "We were already able to show in earlier studies that genetically switching off the vitamin B6-degrading enzyme pyridoxal phosphatase in mice improves the animals' spatial learning and memory capacity," explains Antje Gohla. In order to investigate whether such effects can also be achieved by pharmacological agents, the scientists have now looked for substances that bind and inhibit pyridoxal phosphatase. With success: "In our experiments, we identified a natural substance that can inhibit pyridoxal phosphatase and thus slow down the degradation of vitamin B6," explains the pharmacologist. The working group was actually able to increase vitamin B6 levels in nerve cells that are involved in learning and memory processes. The name of this natural substance: 7,8-Dihydroxyflavone. New Approach for Drug Therapy 7,8-Dihydroxyflavone has already been described in numerous other scientific papers as a molecule that can improve learning and memory processes in disease models for mental disorders. The new knowledge of its effect as an inhibitor of pyridoxal phosphatase now opens up new explanations for the effectiveness of this substance. This could improve the mechanistic understanding of mental disorders and represent a new drug approach for the treatment of brain disorders, the scientists write in their study. The team also considers it a great success that 7,8-Dihydroxyflavone has been identified as an inhibitor of pyridoxal phosphatase for the first time -- after all, this class of enzymes is considered to be particularly challenging for drug development. A Long Way to a Drug When will people benefit from this discovery? "It's too early to say," explains Marian Brenner, a first author of the study. However, there is much to suggest that it could be beneficial to use vitamin B6 in combination with inhibitors of pyridoxal phosphatase for various mental disorders and neurodegenerative diseases. In a next step, Gohla and her team now want to develop improved substances that inhibit this enzyme precisely and highly effectively. Such inhibitors could then be used to specifically test whether increasing cellular vitamin B6 levels is helpful in mental or neurodegenerative diseases.

Volastra Chief Executive Officer Charles Hugh-Jone Bristol Myers Squibb Company forged an oncology drug discovery and development deal valued at more than $1 billion with Volastra Therapeutics. Volastra Chief Executive Officer Charles Hugh-Jones/Courtesy Volastra Therapeutics Hot off the heels of its milestone approval for the unique checkpoint inhibitor Opdualag , Bristol Myers Squibb Company forged an oncology drug discovery and development deal valued at more than $1 billion with Volastra Therapeutics . BMS will leverage Volastra’s proprietary CINtech platform to identify CIN-related, synthetic lethal targets as drug candidates. In its announcement, New York-based Volastra noted that synthetic lethality is a well-established genetic approach to target discovery. The approach involves the exploitation of the vulnerabilities in the cells of cancerous tumors in order to safely induce cell death while sparing normal cells. Volastra noted that its pre-clinical research has shown that synthetical lethal approaches can be particularly effective in tumors with high levels of CIN, which has been identified as a key driver of metastatic cancer. Volastra is developing proprietary computational and experimental approaches to understand CIN biology and drive drug discovery. The company’s CINtech platform marries proprietary imaging technologies, model cell line systems and computational analytics. Rupert Vessey, executive vice president of research & early development at BMS, expressed excitement about the collaboration with Volastra and the company’s chromosomal instability targeting platform. Vessey said new therapies targeting CIN have the potential to enhance treatment selectivity and improve patient outcomes. The two companies are keeping the oncology targets close to the vest. Under the agreement terms, Volastra is expected to conduct research activities through the selection of developmental candidates. From there, BMS may take on all subsequent development, regulatory and commercialization activities. Volastra stands to make a significant amount of money from the partnership but the financial terms are heavily weighted on the back end of the deal. Volastra will receive an upfront payment of $30 million and stands to make an additional $1.1 billion from potential development, regulatory and commercial milestone payments. Volastra will also be eligible for royalties on any sales. Volastra Chief Executive Officer Charles Hugh-Jones, a Pfizer veteran, said his company has a significant understanding of chromosomal instability, which he called the “Achilles heel” of cancer. The oncology expertise of BMS combined with Volastra’s platform is an ideal partnership to develop and advance novel therapies, he said. “Through this collaboration, Volastra will apply our innovative platform towards the creation of effective CIN-targeted medicines. We look forward to working together with Bristol Myers Squibb to transform cancer treatment,” Hugh-Jones said in a statement. In addition to BMS, Volastra has also partnered with Dewpoint Therapeutics to discover novel molecules capable of blocking immuno-suppressive signaling in CIN-high tumors. The company also entered into a big data partnership with Microsoft to develop algorithms capable of identifying markers that correlate with tumor metastatic behaviors. Oncology is a key focus for BMS. While the company celebrated the regulatory win for its LAG-3-aimed Opdualag for melanoma, the company also saw a setback in Melanoma with the failure of the Phase III PIVOT IO-001 study. That trial saw the pairing of Nektar Therapeutics’ immunotherapy drug bempegaldesleukin in combination with BMS’ anti-PD-1 drug Opdivo compared to Opdivo alone in metastatic melanoma. As BioSpace previously reported , the trial failed to meet two of the endpoints: progression-free survival and objective response rate. Featured Jobs on BioSpace