Eribulin mesylate

01 遇见/摘要 近日，Advanced Science《先进科学》在线发表了刘天罡教授团队联合王行环教授团队、刘然副研究员的最新研究成果。论文题为“Combinatorial biosynthesis creates a novel aglycone polyether with high potency and low side effects against bladder cancer《组合生物合成策略创造出一种高效且低副作用的新型抗膀胱癌糖基聚醚》”。该研究基于糖基聚醚化合物的构效关系和生物合成机理，利用组合生物合成策略，成功创制出一种新型糖基聚醚分子，其抗膀胱癌的有效性和安全性都优于临床一线抗膀胱癌药物顺铂。 02 遇见/内容 聚醚化合物是聚酮化合物的一类，具有高度的结构多样性和丰富的生物活性，广泛应用于兽医药和畜牧业，以控制球虫病以及作为反刍动物的生长促进剂。而聚醚化合物真正引起全世界范围的关注，是源于2009年Eric Lander在Cell上报道了盐霉素对乳腺癌肿瘤干细胞显著的抑制活性（Cell 2009, 138(4), 645–659）。尤其是，日本卫材制药公司研发的聚醚Eribulin（艾瑞布林）于2010年获批用于转移性乳腺癌的治疗（Nat. Rev. Drug Discov. 2011, 10: 173–174），成功将聚醚化合物推向了临床应用。从此，引发了聚醚化合物抗肿瘤活性研究的热潮。 刘天罡教授的博士研究课题就是聚醚化合物生物合成机理的解析（Chem. Biol. 2006, 13(9): 945–955; Chem. Biol. 2008, 15(5): 449–458），目的就是深入剖析聚醚分子的合成机制，为后续的高产和结构改造等研究工作奠定基础。在建立研究团队后，刘天罡教授课题组对聚醚化合物进行了系统的抗肿瘤活性研究，发现糖基聚醚化合物（Nanchangmycin、Endusamycin (End)，Lenoremycin (Len)和CP-80,219）对39种不同类型的癌细胞都有显著的抑制作用，尤其是对乳腺癌干细胞的抑制活性要优于盐霉素（ACS Pharmacol. Transl. Sci. 2018, 1(2), 84–95）。这展示出糖基聚醚化合物应用于肿瘤治疗的巨大潜力。但是这类化合物无论是在化学结构的新颖性还是在药物的安全性上面都有改善提升的空间。本研究则期望基于课题组前期工作总结出的构效关系，设计并通过合成生物学手段合成活性更好和毒性更低的新型糖基聚醚化合物。 图1.具有显著抗癌活性的代表性聚醚化合物 从糖基聚醚化合物的构效关系来看，图1中四个糖基聚醚的抗肿瘤效力从强到弱依次是Len、End、Nanchangmycin、CP-80,219，其中Len的抗肿瘤活性最为显著，但是毒性也最大。从结构来看，四种化合物的骨架相似，差异只在于修饰基团，包括糖基、甲基和羟基。可见，这些修饰基团的构成与药物发挥抗肿瘤效力和毒性作用密切相关。尤其是，作者发现糖基聚醚的抗肿瘤效力会随着糖基与羧基距离的缩短而增强，而最靠近羧基且适合加糖基的位置是C11位。这启发作者可以获得一系列C11位糖基化的结构类似物，有望从中筛选出疗效更高、毒性更低的抗癌药物。鉴于聚醚化合物化学和立体结构复杂，且聚醚环容易断裂，利用化学方法实现上述结构改造难度极大，而合成生物学技术驱动的组合生物合成策略则凸显出优势。 为了获得C11位糖基化的新结构聚醚衍生物，作者首先选择了C11位有羟基且活性较强的End，鉴定了其生物合成基因簇，并通过基因敲除策略获得了系列End结构类似物，它们和End在C11位都有羟基，有潜力进一步在C11位加载糖基，从而产生新的糖基化衍生物（图2）。 图2. 利用基因敲除策略获得系列End结构类似物 此外，作者鉴定了Len的生物合成基因簇，并阐明了其后修饰途径，成功找到了能够催化C11位糖基加载的糖基转移酶LenG5，且证明其具有一定的底物杂泛性（图3）。 图3. 鉴定负责C11位糖基化的糖基转移酶LenG5 随后，作者利用组合生物合成策略，对End和Len的生物合成途径进行了重组，合理地设计了新的生物合成途径。将负责End及其结构类似物生物合成的基因，分别与lenG5（编码糖基转移酶）进行组合表达，成功得到了一个新结构C11位糖基化衍生物End-16（图4）。 图4. 利用组合生物合成策略获得新结构C11位糖基化衍生物 接下来，作者在细胞层面检测了End-16对膀胱癌细胞多种生物学行为的影响。结果表明，End-16不仅能将膀胱癌细胞周期进程阻滞在G1期，从而抑制细胞增殖，还能干扰细胞伪足的形成和抑制上皮间质转化过程，从而抑制细胞的迁移和侵袭（图5）。 图5. End-16抑制膀胱癌细胞的周期进程和运动能力 最后，作者利用皮下荷瘤模型对End-16进行了体内的药效学研究。结果表明，与End和顺铂相比，End-16在体内抑制膀胱癌增殖的效果更显著，且毒性更低，引起的副作用更小（图6），具有应用于膀胱癌临床治疗的巨大潜力，值得进一步开展药效学、毒理学和药代动力学等临床前研究。 图6. End-16在体内展示出高效低毒的抗膀胱癌活性 本研究工作为利用组合生物合成策略创造具有更优药理特性的非天然产物提供了又一成功案例，提高了聚醚化合物成药的可能性，具有重要的理论研究与临床应用价值。 武汉大学药学院博士研究生闫盼、武汉大学中南医院王刚博士和武汉合生科技有限公司黄敏坚博士为共同第一作者。上海交通大学生命科学技术学院微生物代谢国家重点实验室刘天罡教授和刘然副研究员、武汉大学中南医院泌尿外科王行环教授为共同通讯作者。该项研究得到武汉合生科技有限公司、湖北省重点研发计划、湖北省楚天英才计划、国家重点研发计划合成生物学专项以及国家自然科学基金等项目资助。 文章题目：Combinatorial biosynthesis creates a novel aglycone polyether with high potency and low side effects against bladder cancer 全文链接：http://doi.org.libproxy1.nus.edu.sg/10.1002/advs.202404668 03 遇见/致谢 感谢刘天罡教授课题组对本号的支持，感谢文章作者闫盼提供本文稿件支持！ 关注我，更多资讯早知道↓↓↓

Strategic collaboration with Bristol Myers Squibb ended TOKYO, Japan I July 01, 2024 I Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, “Eisai”) announced today that it has agreed to end its global strategic collaboration with Bristol Myers Squibb for the co-development and co-commercialization of farletuzumab ecteribulin (FZEC), formerly known as MORAb-202, a folate receptor alpha (FRα)-targeting antibody drug conjugate (ADC) due to ongoing portfolio prioritization efforts within Bristol Myers Squibb. Based on the agreement, Eisai now owns all rights to FZEC and will solely conduct the global development and commercialization of the agent. Eisai will accelerate the development of the agent as a high priority with the hope to deliver it to patients as early as possible. Eisai plans to refund a part of the unused portion of the $200 million payment it received towards research and development expenses from Bristol Myers Squibb under the collaboration agreement and record the remaining as other income. FZEC is Eisai’s first ADC and is composed of Eisai’s in-house developed farletuzumab, a humanized IgG1 monoclonal antibody that binds to the FRα, and Eisai’s in-house developed anticancer agent eribulin, using an enzymatically cleavable linker. Currently, three clinical studies are ongoing: Eisai’s Phase 1/2 study for solid tumors (NCT04300556), and Bristol Myers Squibb’s Phase 2 studies for ovarian, peritoneal and fallopian tube cancers (NCT05613088) and non-small cell lung cancer (NCT05577715). Eisai positions oncology as a key franchise area and aims to contribute toward the cure of cancers by exploring the depths of human biology. FZEC development for refractory cancers is a testament of our dedication to addressing the unmet medical needs of patients with cancer. Eisai will make continuous efforts to increase the benefits provided to patients with cancer and their families. [Notes to editors] 1. Farletuzumab ecteribulin (FZEC, formerly known as MORAb-202) FZEC is Eisai’s first antibody drug conjugate (ADC) and that is composed of Eisai’s in-house developed farletuzumab, a humanized IgG1 monoclonal antibody that binds to the folate receptor alpha (FRα), and Eisai’s in-house developed anticancer agent eribulin, using an enzymatically cleavable linker. After FZEC enters the target FRα-positive cancer cells, it is thought that the linker is enzymatically cleaved, releasing eribulin from the antibody leading to its antitumor activity. When the anticancer agent and antibody components of an ADC are separated inside a targeted antigen-positive cancer cell, it is theorized that the released anticancer agent also has a bystander effect on neighboring antigen-negative cancer cells and the component cells of the tumor microenvironment. In pre-clinical studies, FZEC demonstrated a bystander effect*, with antitumor activity on the FRα-negative cancer cells surrounding the FRα-positive cancer cells. The payload eribulin was the first in the halichondrin class of microtubule dynamics inhibitor. Structurally, eribulin is a simplified and synthetically produced version of halichondrin B, a natural product isolated from the marine sponge Halichondria okadai, and functions by inhibiting the growth phase of microtubule dynamics which prevents cell division. Eribulin has been approved in countries including Japan, the United States, China, in Europe and in Asia for use in the treatment of advanced breast cancer and liposarcoma (soft tissue sarcoma in Japan). *Bystander effect: When the anticancer agent and antibody parts of an ADC are separated inside a targeted antigen-positive cancer cell, the released anticancer agent also affects neighboring antigen-negative cancer cells and the component cells of the cancer microenvironment. SOURCE: Eisai