此外，ISM6166还保持了对其他RAS家族蛋白的高选择性，为降低脱靶毒性风险、减少潜在副作用提供了关键支撑。在四个临床前种属中，ISM6166均显示 出良好的血浆清除率和可接受的口服生物利用度，充分支持其作为同类最佳口服疗法的潜力。 KRAS隶属RAS原癌基因家族，是突变率最高的癌症驱动基因之一，但其表面异常光滑、缺乏药物结合口袋，且与GTP/GDP具有极高亲和力，长期被视 为"不可成药"靶点。通过靶向KRAS G12C等特定突变，现有KRAS抑制剂实现了一定程度上的进展，但仍然无法为携带其他KRAS突变类型的广大患者群体 提供有效治疗方案，长期用药容易产生获得性耐药也是难以逾越的障碍。 针对行业痛点难点，英矽智能(03696)靶向可以覆盖多种关键突变的泛KRAS抑制策略，提名可以同时靶向KRAS蛋白ON/OFF状态的口服小分子ISM6166，有 望覆盖肺癌、胰腺癌、结直肠癌、胃癌等多种KRAS驱动的实体瘤，具有巨大的适应症拓展潜力。 在肺癌模型中，ISM6166在10 mg/kg剂量下实现86.2%的肿瘤生长抑制率(TGI)，并在30 mg/kg剂量下实现55.1%的肿瘤消退。胃癌模型中的抗肿瘤药效更为显 ...

在肺癌模型中，ISM6166在10 mg/kg剂量下实现86.2%的肿瘤生长抑制率(TGI)，并在30 mg/kg剂量下实现55.1%的肿瘤消退。胃癌模型中的抗肿瘤药效更为显 著，ISM6166在5 mg/kg剂量下的TGI达到99.5%，更高剂量则诱导高达65.8%的肿瘤消退。上述数据表明，ISM6166不仅能够抑制肿瘤生长，还能在多种 KRAS变异的肿瘤模型中有效缩小肿瘤。 此外，ISM6166还保持了对其他RAS家族蛋白的高选择性，为降低脱靶毒性风险、减少潜在副作用提供了关键支撑。在四个临床前种属中，ISM6166均显示 出良好的血浆清除率和可接受的口服生物利用度，充分支持其作为同类最佳口服疗法的潜力。 智通财经APP获悉，KRAS隶属RAS原癌基因家族，是突变率最高的癌症驱动基因之一，但其表面异常光滑、缺乏药物结合口袋，且与GTP/GDP具有极高亲 和力，长期被视为"不可成药"靶点。通过靶向KRAS G12C等特定突变，现有KRAS抑制剂实现了一定程度上的进展，但仍然无法为携带其他KRAS突变类型 的广大患者群体提供有效治疗方案，长期用药容易产生获得性耐药也是难以逾越的障碍。 针对行业痛点难点，英矽智 ...

编者按：近年来，癌症药物研发的重心正悄然发生转变。与过去围绕成熟靶点持续进行优化迭代不同，新一轮创新更加聚焦于 如何突破长期被视为"不可成药"（undruggable）的靶点。在2025年欧洲肿瘤内科学会（ESMO）靶向抗癌治疗（TAT）大会 上，多项针对此类靶点的创新疗法首次人体研究结果相继公布，显示该领域正加速从基础探索迈向临床验证阶段。随后， Annals of Oncology对其中具有代表性的研究进行了系统梳理，重点介绍了已在人体中完成机制验证、展现出生物标志物相关信 号且具有可控安全性的候选药物，同时也涵盖多项仍处于临床前阶段、但有望突破"不可成药"限制的创新技术平台。 作为全球医药创新的赋能者，药明康德依托一体化、端到端的CRDMO平台，持续支持全球合作伙伴加速创新疗法研发进程， 致力于将更多突破性治疗方案带给癌症患者。本文将基于Annals of Oncology的相关内容，并结合公开资料，梳理当前"不可成 药"靶点领域涌现的早期突破及其潜在意义，呈现这一前沿方向的最新发展脉络。 靶点：MYC MYC长期被认为属于典型的"不可成药"靶点。其蛋白结构高度动态且缺乏稳定结合口袋，使传统小分子难以实 ...

Core Viewpoint - Targeted protein degradation represents a significant advancement in treating diseases previously deemed untreatable, particularly for traditionally "undruggable" targets such as transcription factors and scaffold proteins [2][6]. Group 1: Development of New Screening Methods - A novel high-throughput screening platform named DEFUSE (DE ath FUS ion E scaper) has been developed to identify small molecule protein degraders, enabling efficient degradation of oncoprotein SKP2 [3][10]. - The DEFUSE platform utilizes a fusion of target proteins with a rapidly activated death protein, allowing for a visual representation of cell survival or death based on the presence of degradation compounds [6][8]. Group 2: Discovery of New Degraders - The research team identified a small molecule, SKPer1, which specifically promotes the degradation of the oncogenic protein SKP2 and selectively kills SKP2-expressing cancer cells [8][10]. - SKPer1 functions as a novel molecular glue degrader, recruiting SKP2 to the ubiquitin ligase STUB 1, facilitating its ubiquitination and subsequent degradation [8][10]. Group 3: Implications for Cancer Treatment - SKPer1 demonstrated significant tumor-suppressive effects in vivo and exhibited good safety profiles, indicating its potential as a therapeutic agent [10]. - The study suggests that a 10-amino acid sequence derived from SKP2 can serve as a universal degradation tag, allowing other target proteins fused with this tag to be recruited for degradation by SKPer1 [10].

Core Viewpoint - Intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) represent about 60% of the human proteome and are crucial for various cellular functions and disease progression. Recent advancements in artificial intelligence (AI) have enabled the design of specific binding agents for these previously considered "undruggable" targets, unlocking new therapeutic possibilities [1][2][20]. Group 1: Importance of IDPs and IDRs - IDPs and IDRs play significant roles in cellular signaling, stress responses, and disease progression, making them valuable targets for clinical diagnostics and drug development [2][8]. - Traditional drug design struggles with IDPs due to their lack of stable structure, which complicates the development of targeted therapies [6][7]. Group 2: AI Breakthroughs in Drug Design - The research led by David Baker's team utilized generative AI to design proteins that can accurately bind to IDPs and IDRs, achieving atomic-level precision [2][11]. - The AI model, RFdiffusion, allows for dynamic matching without pre-setting structures, enabling the generation of binding proteins that can adapt to the flexible nature of IDPs [11][12]. Group 3: Experimental Results and Applications - The studies published in Nature and Science demonstrated the successful design of binding proteins for various IDPs, with binding affinities ranging from 3 to 100 nanomolar [15][18]. - These binding proteins have shown potential in therapeutic applications, such as inhibiting amyloid fiber formation related to type 2 diabetes and disrupting stress granule formation in neurodegenerative diseases [16][18]. Group 4: Future Implications - The new design strategies developed could lead to innovative treatment methods and diagnostic tools for diseases associated with IDPs and IDRs, marking a significant advancement in precision medicine [20][24]. - The complementary strategies of RFdiffusion and logos provide a robust framework for targeting both structured and unstructured protein regions, enhancing the versatility of drug design [21][22].

Core Viewpoint - The article discusses the breakthrough in targeting intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) using artificial intelligence (AI), specifically through the work of Professor David Baker and his team, which has made previously "undruggable" targets accessible for drug development [3][5][20]. Group 1: Research Breakthroughs - The research led by Professor David Baker utilizes generative AI to design proteins that can precisely bind to IDPs and IDRs, achieving atomic-level accuracy [3][5]. - The studies employed two complementary design strategies based on amino acid sequences, eliminating the need for structural information, thus enhancing the universality of drug discovery [7][22]. - The first study published in Science demonstrated the design of binding proteins for 43 diverse disordered protein targets, achieving tight binding for 39 of them, with affinities ranging from 100 picomolar to 100 nanomolar [14][20]. Group 2: Applications and Implications - The designed binding proteins show potential applications in various fields, including cancer treatment, disease diagnostics, and intervention in neurodegenerative diseases [14][20]. - Specific examples include a binding protein targeting enkephalin that successfully blocked pain signal transduction in human cells [14][21]. - The second study, available on bioRxiv, reported the design of binding proteins for various IDPs and IDRs, with affinities also in the range of 3-100 nanomolar [17][20]. Group 3: Methodology and Tools - The research utilized a protein design strategy called "logos," which created a library of binding pockets to recognize amino acid side chains, allowing for the assembly of binding proteins [9][11]. - The RFdiffusion model was employed to generate novel proteins that do not exist in nature, demonstrating its effectiveness in various therapeutic contexts [5][22]. - The strategies developed in these studies are now available online for researchers to use freely, promoting further exploration in the field [23][24].

Core Insights - Quantum physics, AI, and robotics drug and new materials development platform, CrystalTech (02228), has entered a strategic partnership worth billions with DoveTree LLC, founded by renowned chemist Gregory Verdine [1] - The agreement grants DoveTree exclusive global rights to multiple pipelines in oncology, autoimmune, and neurological diseases, with CrystalTech receiving a total of $100 million in upfront payments and potential milestone payments worth billions [1][10] Company Overview - Gregory Verdine is a pioneer in chemical biology and a successful entrepreneur, having founded over 12 biotech companies, with 7 going public and one being acquired [2][3] - Verdine's innovative "Stapled Peptides" technology has opened new pathways for targeting "undruggable" targets, creating a market valued in the billions [2][6] Financial Implications - CrystalTech will receive $51 million and $49 million in upfront payments within 10 and 180 days post-signing, respectively, along with potential milestone payments and royalties based on annual net sales [1][10] - The collaboration is expected to significantly enhance CrystalTech's financial returns and support ongoing R&D efforts [10] Market Potential - Verdine's work has led to the successful development of drugs targeting traditionally "undruggable" targets, generating over $30 billion in sales from three major drugs [6][8] - The partnership is seen as a model for combining U.S. intellectual property with Chinese efficiency, potentially unlocking a multi-billion dollar market for previously untargetable drug targets [10] Strategic Positioning - The collaboration elevates CrystalTech's status in the industry and may inspire further high-tech partnerships [10] - Verdine's extensive experience and network in the biotech sector, including roles with top venture capital firms, positions the partnership for success in the evolving landscape of drug development [9][10]