Brigimadlin

Boehringer expands oncology pipeline with Tessellate deal. Credit: Sundry Photography via Getty Images. Boehringer Ingelheim has signed a €500m ($572m) agreement with UK-based biotech Tessellate Bio to co-develop targeted cancer therapies for tumours that rely on the alternative lengthening of telomeres (ALT) mechanism – a lesser-known telomere maintenance process that supports the survival of certain hard to treat cancers. Under the terms of the deal, Tessellate Bio will receive an upfront licensing fee, research funding, and technical milestone payments, along with additional success-based development and commercial milestones. The total potential value of the agreement is more than $572m. Tessellate has developed small molecule inhibitors against an undisclosed target that plays a central role in enabling the replication and survival of ALT-positive cancer cells. According to the company, preclinical data shows that blocking this target leads to DNA damage and replication stress, selectively killing tumour cells dependent on the ALT mechanism while sparing healthy cells that do not use this pathway. The collaboration builds on Tessellate’s ongoing work to characterise ALT activity across tumour types, following a research initiative launched in September 2024 with Australian research institutes CMRI and Omico. Tessellate secured €8m in seed funding from BioGeneration Ventures and Forbion when it launched publicly in October 2023. This deal with Boehringer marks Tessellate’s first partnership with a biopharma company. For Boehringer, this deal aligns with its strategic expansion in oncology. Over the last few years, the German pharma company has pursued a series of R&D and licensing agreements to strengthen its cancer portfolio. In October 2024, it partnered with Circle Pharma to co-develop a first-in-class cyclin inhibitor, in a deal worth up to $607m in upfront and milestone payments. That same month, it opened a €60m ($66.8m) research building in Vienna, Austria , focused on advancing novel cancer therapies. Boehringer’s marketed oncology products include Giotrif (afatinib) for EGFR-mutated non-small cell lung cancer (NSCLC) and Vargatef (nintedanib) for specific types of lung cancer. The company is also advancing late-stage assets such as brigimadlin, an MDM2-p53 antagonist in a pivotal clinical trial for rare cancer dedifferentiated liposarcoma (DDLPS). Boehringer is also advancing zongertinib , a tyrosine kinase inhibitor being evaluated as a potential treatment for HER2-mutated NSCLC. GlobalData Strategic Intelligence US Tariffs are shifting - will you react or anticipate? Don’t let policy changes catch you off guard. Stay proactive with real-time data and expert analysis. By GlobalData Learn more about Strategic Intelligence In January 2025, Boehringer signed two further licensing agreements to deepen its pipeline. The first, with Synaffix, grants access to the company’s antibody-drug conjugate (ADC) platform in a deal worth up to $1.3bn , covering multiple undisclosed targets. The second was an extension of a long-standing partnership with Oxford BioTherapeutics, under which Boehringer exercised an option for a fourth novel target. Oxford BioTherapeutics will receive development milestones and royalties, while Boehringer takes over full development and commercial responsibilities.

上次谈到BI公司MDM2-p53 PPI抑制剂临床分子brigimadlin，其简略版发现过程如下图所示。但未详细交代最初螺环scaffold的由来。 这类scaffold其实最早由王少萌实验室报道。这在BI公司16年的文章中有提及，如下图所示。 其中蓝色箭头部分即王实验室早先开创性的工作，找到了这样一类新的比较优势的螺环母核。后来在此基础上，一部分人 (包括王实验室) 沿用这个母核继续优化，得到一些临床或临床前分子 (黑色箭头部分)。而BI公司，则对该类母核进行了结构微调，挪了一个N的位置，得到另一类化学更稳定的新母核，然后在此新母核基础上进行后面一系列优化 (绿色箭头部分)，并最终得到之前谈过的6连环临床分子brigimadlin。 之所以称N挪了位置的新母核化学更稳定，是因为之前的母核可能因为下图所示的机理发生差向异构化，包括部分临床分子也遗留了这个问题 (如下图SAR405838)。当然也有其它途径解决这个问题，如下图分子APG-115，相应位点做了对称双取代。 再看王少萌课题组当时如何找到这一类螺环scaffold。如下图所示，他们先锁定了p53结合MDM2的一个关键残基Trp23，然后就以此残基侧链做相似子结构搜索，锁定吲哚酮类结构。之后进一步子结构搜索，找到若干相关的螺环天然产物。 通过进一步modeling发现这些天然产物虽然本身不太可行，但相关scaffold可以通过进一步改造修饰，得到潜在的新型MDM2 PPI抑制剂。后来实验结果证实了这一想法。也算是CADD较早期的一个应用 (文章发于2005年，第一作者丁克，通讯王少萌)。 后来王课题组在此基础上进一步优化改造，得到临床候选分子，并与相关公司进行授权转让 (如SAR405838转让给赛诺菲)。这里不详细展开。 这里看一下p53 peptide结合MDM2的复合物结构 (下图左)，比较明显能看出p53上其中三个残基 (被加粗) 比较重要，其中居中的Trp23尤为关键，它不仅包埋得比较深，而且与MDM2形成一个氢键作用。这些在2005年王课题组那篇文章都有提到，也是他们后续成功找到hit的基础。 下图右是小分子共晶pose与图左三个p53关键残基的结构叠合。可以看到吲哚酮完美匹配Trp23侧链，余下两个hot spot残基也都被小分子不同程度mimic。与MDM2形成氢键作用的原子被高亮。 MDM2-p53的例子就谈到这儿。下面是更新的一个例子，诺华公司报道的first-in-class的YAP-TEAD PPI抑制剂。实际上这个例子之前也谈过多次，这里只就相关部分简单提及，有感兴趣可以移步往期。 诺华这个案例计算在其中发挥了比较关键的作用，包括hit finding，包括H2L/LO优化。而且相比于王课题组2005年报道的工作，诺华这个案例CADD的应用更典型。 但诺华这个案例的成功也离不开他们之前的一些研究工作。如下面截图所示，他们之前针对该PPI做过一些peptide抑制剂的研究，并找到一个对结合非常关键的残基，在YAP中该残基为M86，在TAZ (与YAP类似，也与TEAD作用) 中该残基为W43，而他们在YAP peptide上用Cl取代的Trp (非天然氨基酸) 替换该位点，可以将活性提高一个数量级 (相比YAP的M86)。 他们后续正是基于这一认识，选中氯苯或Cl取代吲哚作为基础pharmacophore锚定来做的虚拟筛选，并成功找到hit。尽管活性微弱 (优势异构体TR-FRET 267μM)，但经过一系列改造，活性有dramatically提升，并最终得到临床分子IAG933。 下图是之前谈诺华这个系列分子的文章截图，有当时的文字注释在，就不再赘述。 诺华这个系列分子相关往期 In silico driven诺华YAP-TEAD PPI抑制剂的发现 来自计算的临床分子，诺华YAP-TEAD PPI抑制剂IAG933 PPI抑制剂可以有一些共性 (比如本文两个例子都可以看出hot spot残基的重要性)，但也各有不同，还有一些不是directly PPI抑制，而是结合在其它口袋。开发难度上大多数PPI抑制剂比较有挑战，甚至相当有挑战，但也有成药性还好的，不能一概而论。具体问题具体看，这里只浅谈一鳞半爪，抛砖引玉。 往期还有几篇PPI相关的 浅谈近期获批的Menin抑制剂Revumenib 一类Aurora A-TPX2 PPI 抑制剂的发现 化大为小 - LEO Pharma IL-17A PPI modulator的发现 Discovery of Novel Spiro[3H‑indole-3,2′-pyrrolidin]-2(1H)‑one Compounds as Chemically Stable and Orally Active Inhibitors of the MDM2−p53 Interaction, JMC, 2016 Structure-based design of potent non-peptide MDM2 inhibitors, JACS, 2005 The First Class of Small Molecules Potently Disrupting the YAP-TEAD Interaction by Direct Competition, ChemMedChem, 2022 往期链接 “小小疫苗”养成记 | 医药公司管线盘点  人人学懂免疫学| 人人学懂免疫学（语音版）    综述文章解读 | 文献略读 | 医学科普|医药前沿笔记 PROTAC技术| 抗体药物| 抗体药物偶联-ADC 核酸疫苗 | CAR技术| 化学生物学 温馨提示 医药速览公众号目前已经有近12个交流群（好学，有趣且奔波于医药圈人才聚集于此）。进群加作者微信（yiyaoxueshu666）或者扫描公众号二维码添加作者，备注“姓名/昵称-企业/高校-具体研究领域/专业”，此群仅为科研交流群，非诚勿扰。 简单操作即可星标⭐️医药速览，第一时间收到我们的推送 ①点击标题下方“医药速览”   ②至右上角“...”  ③点击“设为星标