Cemsidomide

沙利度胺（Thalidomide），这个名字在医药史上承载着极其复杂的情感。20世纪50年代，它作为一款镇静剂和止吐药上市，因能有效缓解孕妇的晨吐反应而风靡全球。然而，残酷的现实很快击碎了美好的愿景——它导致了约一万名婴儿出现严重的先天性肢体畸形。这场“反应停惨剧”成为了制药史上最惨痛的教训之一。 然而，故事并未就此结束。几十年后，沙利度胺在抗癌领域迎来了戏剧性的“重生”。它被发现对多发性骨髓瘤有显著疗效，并于2006年获得FDA批准。这一“临床救赎”彻底改变了人们对它的认知，也开启了一个全新的研究领域：靶向蛋白质降解（Targeted Protein Degradation, TPD）。 2010年，科学家揭示了沙利度胺及其类似物来那度胺（Lenalidomide）、泊马度胺（Pomalidomide）的真正作用靶点——Cereblon (CRBN)，一种E3泛素连接酶复合物的底物受体。这些被称为免疫调节酰亚胺药物（IMiDs）的小分子，像“分子胶水”一样，将CRBN与原本不该被降解的靶蛋白（如转录因子IKZF1/3）粘在一起，给靶蛋白打上“泛素”标签，最终被蛋白酶体降解。 如今，CRBN配体的设计也从最早的邻苯二甲酰亚胺-戊二酰亚胺类，衍化出愈加精妙的结构。 经典骨架的传承与修饰：邻苯二甲酰亚胺-戊二酰亚胺类 这是最经典的沙利度胺骨架，其核心结构由一个邻苯二甲酰亚胺环和一个戊二酰亚胺连接而成。戊二酰亚胺负责与CRBN蛋白结合，而邻苯二甲酰亚胺环则像一个“适配器”，决定了招募哪些靶蛋白进行降解。 ·经典案例：泊马度胺（Pomalidomide）。作为沙利度胺的直接衍生物，在苯环上引入一个氨基（C4位）后，其降解效力显著增强。 ·新一代分子胶：Golcadomide (CC-99282)。在氨基上连接了一个含吗啉的侧链，是当前极具潜力的IKZF1/3降解剂，已进入多种淋巴瘤的临床试验。 PROTAC的“万能接头”。更重要的是，科学家们在沙利度胺的苯环上引入了氟原子（4-氟沙利度胺），它可以作为一个“抓手”，通过亲核取代反应轻松连接上各种化学 linker，从而构建出能降解任意目标蛋白的PROTAC分子。例如，通过这种方法，研究者成功合成了能降解CDK9、PARP、GPX4等重要靶点的PROTAC。 巧妙的“变体”：通过引入烷氧基或融合新的环系，科学家们可以调节降解谱，甚至避免降解致畸靶点SALL4。例如，化合物TX-16通过一个巧妙的铑催化[2+2+2]环加成反应构建了全新的三环骨架，其CRBN亲和力甚至超过了沙利度胺本身。 骨架的革新：异吲哚啉酮-谷酰亚胺类（来那度胺型） 来那度胺是沙利度胺的“升级版”，将邻苯二甲酰亚胺环替换为异吲哚啉酮环，并在C4位引入氨基。这一微小改变使其对CRBN的亲和力提高了10倍。 ·药物之星：来那度胺（Lenalidomide）。它已成为治疗多发性骨髓瘤的一线药物，并被列入世界卫生组织基本药物标准清单。 ·多样性源于5-氨基异构体。来那度胺的5-氨基异构体是一个极其重要的合成中间体。通过它，科学家们: o发现了全新的GSPT1降解剂（如ZXH1-16），该靶点在传统IMiD中不被降解。 o合成了光亲和探针（Photolenalidomide），发现新的靶蛋白。 o构建了庞大的化合物库，筛选出了能同时降解IKZF2和CK1α的双功能降解剂DEG-77。 ·临床在研新药： oIberdomide (CC-220)：因其延伸的化学结构能更好地与CRBN结合，展现出比来那度胺和泊马度胺更强的靶点降解能力。 oMezigdomide (CC-92480)：通过引入芳基哌嗪侧链，具有独特的降解谱和优异的体外选择性。 odWIZ-1/2：能选择性降解WIZ转录因子，从而诱导胎儿血红蛋白表达，为治疗镰状细胞病提供了全新策略。 ·合成策略的“军备竞赛”：为了高效构建这些复杂的分子，化学家们开发了多种策略。例如，在Vepdegestrant（ARV-471，一款进入临床的ERα PROTAC）的合成中，关键中间体3.11的公斤级制备就涉及了手性胺的还原胺化和酸催化环化等巧妙步骤。 跳出“沙利度胺”框架：多样化的杂环连接 这是目前CRBN配体创新最活跃的区域。科学家们大胆地用其他杂环（如喹唑啉酮、苯并三嗪酮、三唑等）替换了传统的邻苯二甲酰亚胺或异吲哚啉酮环。 ·Avadomide (CC-122)：一款“多效通路调节剂”，通过将邻苯二甲酰亚胺替换为喹唑啉二酮，展现出与经典IMiD不同的生物学活性，包括诱导干扰素反应。 ·Cemsidomide (CFT7455)：一款基于苯二氮䓬酮骨架的IKZF1/3降解剂，口服生物利用度高，已在复发/难治性多发性骨髓瘤的临床试验中显示出潜力。 ·GSPT1选择性降解剂：如TD-522，通过苯并三嗪酮骨架实现了对GSPT1的皮摩尔级高效降解，并在动物模型中显示出良好的肿瘤抑制效果。 ·“点击化学”的妙用：铜催化的叠氮-炔环加成反应（CuAAC） 在这一领域大放异彩。例如，FPFT-2116就是通过将3-叠氮基谷酰亚胺与不同的炔烃“点击”在一起，快速构建出含三唑环的新型CRBN配体。 ·合成方法学创新：为了快速获得这类化合物，科学家们开发了多种高效方法，如铑催化的N-H插入反应来构建苯并三唑类配体，以及光氧化还原C-H胺化反应来构建苯并咪唑类配体。 C-连接的芳香/杂芳基谷酰亚胺 传统的IMiD通过氮原子连接两个环，而这类化合物通过碳-碳键直接连接芳环和戊二酰亚胺。 ·优势：这种连接方式可能带来更好的代谢稳定性，因为C-C键比C-N键更难水解。 ·代表性化合物：4-氨基苯基谷酰亚胺（4.65）是一个“明星”分子，其CRBN结合亲和力与沙利度胺相当，并被成功用于设计能高效降解BET蛋白的PROTAC（SJ995973）。 ·高效的合成方法： oSuzuki偶联：利用二苄氧基吡啶硼酸酯作为“掩蔽的谷酰亚胺”，通过钯催化的Suzuki偶联，可以快速、模块化地构建这类C-连接的杂环化合物。 o电化学/镍催化偶联：2024年，Baran和Reisman课题组分别报道了使用廉价易得的α-溴代或α-氯代谷酰亚胺，通过镍催化的电化学或还原性交叉偶联，直接与芳基卤化物偶联，极大地简化了合成路线。 不直接连接芳环的谷酰亚胺 这类化合物的戊二酰亚胺与芳环之间通过一个或多个原子（如-CH₂-、-NH-、-O-）连接。 ·BTX306：含有一个独特的噻吩并环戊二烯稠环骨架，能强效降解GSPT1、eRF1、CK1α等多个靶点，并克服对来那度胺的耐药性。 ·化合物4.89：一类简单的苯甲酰胺衍生物，通过系统的结构优化，展现出优于传统IMiD的化学稳定性和选择性，并被用于设计靶向BRD4和HDAC6的PROTAC。 ·合成方法：Ugi四组分反应、硫代-Michael加成等策略被用于快速构建这类结构多样性的分子。 超越谷酰亚胺：新兴的骨架跃迁 为了彻底解决传统IMiD的稳定性（易水解、手性中心易消旋）和脱靶降解问题，科学家们开始寻找能替代戊二酰亚胺的全新骨架。 ·苯基二氢尿嘧啶：用二氢尿嘧啶环替换戊二酰亚胺，不仅消除了手性中心（避免了消旋问题），还显著提高了化学稳定性。基于此骨架设计的LCK PROTAC（SJ43489）展现出了优异的抗增殖活性。 ·硫代沙利度胺：将戊二酰亚胺上的羰基（C=O）替换为硫羰基（C=S），能够调节其TNF-α抑制活性。 ·螺环和桥环类似物：通过引入螺环或氮杂双环[3.1.1]庚烷等刚性骨架，可以改变分子的三维形状和构象，从而调节其与CRBN的结合模式和对不同靶点的选择性。 总结 从沙利度胺到纷繁复杂的CRBN配体库，这条演进之路不仅是化学家们精湛合成技艺的展示，更是药物设计理念的一次深刻变革。 现代合成方法学，如金属有机交叉偶联、C-H/N-H键活化、光氧化还原催化、不对称催化等，已经深度融入这一领域，使得科学家能够以前所未有的速度和精度，构建出结构复杂、功能多样的CRBN配体。 推文用于传递知识，如因版权等有疑问，请于本文刊发30日内联系医药速览。 原创内容未经授权，禁止转载至其他平台。 ©2021 医药速览 保留所有权利 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

iStock, lerbank Molecular glue degraders are gaining traction in the clinic as well as funding from Big Pharma, with their potential to treat previously “undruggable” cancers and immunological diseases. Here are five clinical programs worth keeping an eye on. Molecular glue degraders, known for their ability to break down disease-causing proteins, are gaining traction in the clinic and driving sizable Big Pharma deals that reflect the modality’s market potential. Pharma giants like Bristol Myers Squibb, Novartis, Eli Lilly and Roche have poured millions into acquiring assets and partnering with smaller biotechs to develop molecular glues into treatments in areas such as cancer and immunology. The promise of molecular glues comes down to selectivity and an ability to hit novel targets, said Robert Driscoll, senior vice president of equities research at Wedbush Securities. For drugmakers seeking pipeline prospects to make up for ongoing patent losses, these glues could pave the way to novel targets with limited market competition, he said. “When we look at the market potential of these molecular glues, the ability to potentially tackle undruggable targets unlocks some doors,” Driscoll told BioSpace . “If you have a novel target, you have a real advantage versus other folks out there who will be fast followers. The market potential there is huge.” Molecular glues were discovered essentially by accident in the 1950s when the morning sickness drug thalidomide—infamous for causing birth defects—was found, along with related molecules, to spur immuno-modulating interactions by degrading disease-causing proteins. One of those related molecules—lenalidomide—went on to become the blockbuster cancer drug Revlimid from Celgene, a company that was acquired by Bristol Myers Squibb in 2019 in one of the largest pharma deals in history. Thalidomide and its analogs are the only molecular glues currently approved by the FDA, all of them manufactured by Bristol Myers Squibb as the multiple myeloma treatments Revlimid, Thalomid and Pomalyst. Now, the molecular glue pipeline is brimming with potential, with Big Pharmas and smaller biotechs alike betting on the promise that these molecules can offer new approaches to difficult disease targets. Here, BioSpace takes a deep dive into five standout programs leading the way in molecular glue R&D. BMS’ multiple myeloma relapse renegade As the only drugmaker to have successfully developed and marketed a molecular glue protein degrader for multiple myeloma, BMS is ahead of the curve with its CELMoD program of oral therapies for blood cancers. Among the key molecules in the company’s pipeline is CC-92480, or mezigdomide. In a Phase 3 trial , the asset, when combined with Amgen’s Kyprolis and a corticosteroid, showed improvement in progression-free survival (PFS) in patients with multiple myeloma that has returned following previous treatment. The combination, nicknamed MeziKd, is “a follow-on from approved early-generation molecular glues” that offers an oral option for patients with multiple myeloma with potential to be best in class, according to Driscoll. Paul Richardson, director of clinical research and clinical program leader at Dana-Farber’s Jerome Lipper Multiple Myeloma Center, in a March press release touted the drug combination as an important new regimen for patients whose cancer doesn’t respond to treatments like Darzalex or BMS’s own Revlimid. “While treatment advances have been meaningful, far too many patients with multiple myeloma still relapse or stop responding—making the need for new options urgent,” Richardson said in a prepared statement. MeziKd “could address a key unmet need” for relapsing patients, he added. Monte Rosa’s AI-propelled assets caught Novartis’ notice Monte Rosa Therapeutics is among the smaller companies making a splash in this space, securing two deals with Novartis to develop molecular glues derived from the biotech’s AI discovery engine. Novartis paid $150 million up front with the potential for $2.1 billion in milestones in a licensing agreemen t with Monte Rosa in 2024 to advance the latter’s molecular glues targeting the VAV1 protein. The Swiss behemoth followed that up last year with another $120 million in upfront payments and milestones that could bring deal’s total to $5.7 billion. In clinical trials for immune-mediated and autoimmune conditions, MRT-6160 in a first-in-human trial showed VAV1 degradation greater than 90%, as well as T cell, B cell and cytokine inhibition. Monte Rosa has also demonstrated clinical effectiveness with another molecule called MRT-2359 in patients with metastatic castration-resistant prostate cancer via a Phase 1/2 study with interim results released in December 2025. MRT-2359 is being combined in this trial with the anti-androgen medicine enzalutamide. Monte Rosa’s AI discovery platform has allowed the company to work more quickly than basic screening approaches normally allow, Driscoll said. “The discovery of novel targets is expanding the target space here and allowing Monte Rosa to come up with new targets and apply that to selectivity challenges, adding efficiency to the process,” he continued. Collaboration Novartis Sticks With Monte Rosa in Second Molecular Glue Deal Worth up to $5.7B Novartis and Monte Rosa first partnered in October 2024 for a molecular glue asset for immune-mediated and autoimmune diseases. This time, the pharma is putting $120 million down upfront for more of the biotech’s AI-discovered degraders. September 15, 2025 · 2 min read · Tristan Manalac Read more C4 touts ‘best in class’ potential for DACs C4 Therapeutics has also caught Big Pharma’s attention with its molecular glue-based degrader-antibody conjugates (DACs) C4 pulled in a $73 million series A financing round almost a decade ago along with a strategic collaboration with Roche. The partners followed that up in April with another licensing deal worth $20 million upfront and up to $1 billion in milestones down the road. Together, the companies are developing cemsidomide, formerly known as CFT-7455, a molecular glue degrader that targets the proteins IKZF1 and IKZF3 to treat multiple myeloma. The drug candidate is in a Phase 2 trial following a successful early-stage study in which C4 touted high overall response rates. “C4 is claiming best-in-class potential, and that’s very exciting for the multiple myeloma space, which doesn’t have too many oral drugs,” Driscoll said. Neomorph and numerous partners target HIF Another biotech with deep Big Pharma connections, Neomorph is currently running a Phase 1/2 trial of its molecular glue degrader NEO-811 in patients with locally advanced or metastatic non-resectable clear cell renal cell carcinoma. The San Diego–based company calls the HIF signaling pathway inhibited by NEO-811 the “ Achilles heel ” of clear cell renal cell carcinoma, and the program has attracted collaborations with industry giants AbbVie , Biogen and Novo Nordisk , each with more than $1 billion in potential milestone payments. Similar to Monte Rosa, Neomorph has “gone all-in on molecular glues” and a platform that allows the company to discover novel signals in proteins that make them an ideal target for degradation, Driscoll said. Neomorph’s library of molecular glues is based on “rational design rather than random chance,” according to the company, which allows for more intentional targeting of disease as early as the discovery stage. Deals AbbVie Teams Up With Neomorph for Molecular Glue Collab Worth up to $1.64B Protein degradation–focused Neomorph nabs its third Big Pharma deal of around $1.5 billion in less than a year. January 23, 2025 · 1 min read · Annalee Armstrong Read more Degron, Takeda aim to stick it to solid tumors Degron Therapeutics’ lead molecular glue degrader DEG6498 entered the clinic late last year to treat advanced solid tumors using an RNA-binding protein that was considered “previously undruggable,” according to a May press release announcing the company’s $40 million series A extension. And the company, like many of its molecular glue peers, has picked up critical Big Pharma funding, this time from Takeda, which in 2024 signed a deal with Degron worth up to $1.2 billion. Most importantly, Takeda gained access to Degron’s discovery platform, called GlueXplorer, which uses AI to predict novel targets. Takeda CSO Chris Arendt at the time lauded the ability of molecular glues to aim at targets that had previously been undruggable and inaccessible by other treatments. AI’s application in finding new targets for molecular glues allows the field to advance at a faster clip than would otherwise be possible, Driscoll said. This strategy, he said, “is where the magic is happening.” Business Takeda Joins Hot Molecular Glue Market With $1.2B Deal Riding the growing wave of interest in molecular glue degraders, Takeda has partnered with Chinese biotech Degron Therapeutics to develop novel therapies for oncology, neuroscience and inflammation. May 23, 2024 · 2 min read · Tristan Manalac Read more