KRAS G12D, the most common oncogenic mutation of KRAS, represents a promising therapeutic target for solid tumors. Herein, we report the discovery of 16k, a novel KRAS G12D inhibitor based on a 6-methoxyquinazoline scaffold, identified through the scaffold hopping and structural optimization strategies. The compound 16k exhibited significant antiproliferative effects against KRAS G12D mutant tumor cells, specifically the AGS and GP2D cell lines (IC₅₀ = 0.18 and 0.21 μM, respectively), with minimal cytotoxicity toward normal cells and effectively inhibited colony formation. Preliminary mechanistic investigations revealed that 16k markedly elevated the levels of ROS, disrupted the balance of mitochondria-associated apoptotic proteins, and induced MMP collapse by inhibiting the downstream ERK/AKT signaling pathways of KRAS in AGS and GP2D cells. Molecular dynamics simulations confirmed that 16k binds stably to KRAS G12D, with hydrogen bond interactions observed with residues His 95, Arg 68, and Asp 12, further supporting the consistency of the docking results. 16k also demonstrated favorable drug-like properties, including good hepatic microsomal metabolic stability and a safer toxicity profile in vivo. In conclusion, this work expands the structural diversity of KRAS G12D inhibitors and highlights 16k as a promising lead compound for the development of targeted therapies against G12D-mutant cancers.

2024-08-02·EXPERT OPINION ON THERAPEUTIC PATENTS

Inhibition of GTPase KRAS ^G12D : a review of patent literature

Review

作者: Li, Xiaoran ; Li, Yuhang ; Zhang, Xiaojin ; Yang, Le

INTRODUCTION:

KRAS is a critical oncogenic protein intricately involved in tumor progression, and the difficulty in targeting KRAS has led it to be classified as an 'undruggable target.' Among the various KRAS mutations, KRAS^G12D is highly prevalent and represents a promising therapeutic target, yet there are currently no approved inhibitors for it.

AREA COVERED:

This review summarizes numerous patents and literature featuring inhibitors or degraders of KRAS^G12D through searching relevant information in PubMed, SciFinder and Web of Science databases from 2021 to February 2024, providing an overview of the research progress on inhibiting KRAS^G12D in terms of design strategies, chemical structures, biological activities, and clinical advancements.

EXPERT OPINION:

Since the approval of AMG510 (Sotorasib), there has been an increasing focus on the inhibition of KRAS^G12D, leading to numerous reports of related inhibitors and degraders. Among them, MRTX1133, as the first KRAS^G12D inhibitor to enter clinical trials, has demonstrated excellent tumor suppression in various KRAS^G12D-bearing human tumor xenograft models. It is important to note, however, that understanding the mechanisms of acquired resistance caused by KRAS inhibition and developing additional combination therapies is crucial. Moreover, seeking covalent inhibition of KRAS^G12D also holds significant potential.

npj Precision Oncology

High-throughput screening identifies NT-1 that synergizes with MRTX1133 against acquired resistant KRASG12D colorectal cancer

Article

作者: Thielen, Natalie ; Ha, Grace ; Rustgi, Anil K ; LaFave, Lindsay M ; Kitamura, Seiya ; Houston, Michele ; Nagai, Emiko ; Shin, Alice E ; Gabre, Joel T ; Augenlicht, Leonard H ; Wei, Ning ; Chu, Edward ; Kuang, Chaoyuan

Metastatic colorectal cancer (mCRC) remains a significant clinical challenge, with a 5-year survival rate of 10%. Approximately 40% of CRCs harbor mutations in the KRAS gene, leading to poor response to standard therapy. This underscores the crucial need for novel therapeutics targeting KRAS and overcoming the growing barrier of resistance. To address these critical challenges, we conducted a high-throughput screen to identify small molecules that synergize with the KRAS^G12D inhibitor MRTX1133 against CRC. Through screening a 2,652-kinase inhibitor library, we discovered that Osimertinib, an EGFR tyrosine kinase inhibitor, and its analogs strongly synergize with MRTX1133 against both parental and MRTX1133-resistant cells. The top compound from the screen, NT-1, is a chemical analog of Osimertinib. NT-1 strongly synergized with MRTX1133 to suppress EGFR/MAPK signaling and induce apoptosis in an MRTX1133-resistant patient-derived organoid model of CRC. We present novel small molecule combinations with the potential to overcome the limitations of KRAS inhibitors with direct clinical translational applications.

项与 KRAS G12D/G12V抑制剂(百济神州) 相关的新闻（医药）

2026-05-19

·MA天天进步

2026ASCO肺癌口头报告日程速览

2026 ASCO 肺癌口头报告日程 📍 2026 ASCO Annual Meeting · Chicago 将于北京时间2026年5月29日（星期五）至2026年6月3日（星期三）期间召开召开 🕐 以下所有时间均为北京时间（BJT，UTC+8） 📋 含肺癌专场及相关转化研究专场（含 Plenary）。小编为大家准备了精美的可打印版2026ASCO肺癌相关口头报告日程，公众号内回复“2026ASCO肺癌日程下载”即可获得下载链接。大会总览（仅肺癌相关口头报告）项目数量会议天数 4天（5月30日—6月2日）相关专场 7 个口头报告 59 项 LBA 重磅报告 9 项Day 1 · 5月30日（周六）Session 17108 · Lung Cancer—Non-Small Cell Metastatic 🕑 2026-05-30 02:00–05:00（北京时间）🎙 主持：Nasser H. Hanna; Jonathan W. Riess第一组 · EGFR 🎯 分组主持：Daniel Shao-Weng Tan 〔LBA8500〕口头报告Sunvozertinib monotherapy versus platinum-based chemotherapy as first-line treatment for advanced NSCLC with EGFR exon20ins: Primary analysis of a multinational phase 3 randomized study (WU-KONG28)— John V. Heymach（MD Anderson） 💡 迪哲舒沃替尼用于EGFR 20ins的3期临床结果，开始挑战埃万妥单抗+化疗的地位。〔8501〕口头报告Overall survival of first-line amivantamab plus lazertinib in atypical EGFR-mutated advanced NSCLC: Updated results from the CHRYSALIS-2 study— Joel W. Neal（Stanford） 💡 埃万妥单抗+拉泽替尼用于非典型EGFR突变2期CHRYSALIS-2的OS结果〔8624〕口头报告Wait or treat? Managing asymptomatic brain metastases in oncogene-mutated NSCLC: Results of a phase-III randomized controlled trial— Anil R. Tibdewal（Tata Memorial） 💡 驱动基因阳性无症状脑转移的处理方案3期研究〔263183〕讨论Cracking the Rare Code: New Advances for Uncommon EGFR Mutations— Daniel S.-W. Tan（NCCS Singapore）〔267075〕 Panel Q&A — Heymach / Tibdewal / Tan / Neal第二组 · ALK / RET 🎯 分组主持：Angel Qin 〔8502〕口头报告Lorlatinib vs crizotinib as first-line treatment for advanced ALK+ NSCLC: 7-year update from the phase 3 CROWN study— Tony S.K. Mok（CUHK） 💡 洛拉替尼CROWN研究7年数据随访更新〔8503〕口头报告ALKOVE-1: Efficacy and safety of neladalkib in patients with advanced ALK+ NSCLC— Jessica J. Lin（Mass General） 💡 第4代ALK抑制剂neladalkib的1期结果更新〔8504〕口头报告Efficacy and safety of pralsetinib as first-line treatment of RET fusion–positive advanced NSCLC: The phase 3 AcceleRET-Lung study— Sanjay Popat（Royal Marsden） 💡 RET抑制剂普拉替尼一线3期研究结果〔8505〕口头报告Efficacy and safety of lunbotinib (A400/EP0031), a next-generation selective RET inhibitor, from a pivotal phase II study in patients with advanced RET fusion–positive NSCLC— Qing Zhou（Guangdong PPH） 💡 科伦RET抑制剂2期临床结果〔263182〕讨论Raising the Bar in ALK and RET— Angel Qin（U Michigan）〔267076〕 Panel Q&A — Mok / Lin / Qin / Popat第三组 · 免疫+化疗联合 🎯 分组主持：Natalie I. Vokes 〔8506〕口头报告Sacituzumab tirumotecan + pembrolizumab versus pembrolizumab as first-line treatment for PD-L1–positive advanced NSCLC: Results from the randomized phase 3 OptiTROP-Lung05 study— Caicun Zhou（Shanghai East Hospital） 💡 芦康沙妥珠+K药 vs K药在晚期一线PD-L1阳性NSCLC中的3期结果〔LBA8507〕口头报告A randomized, open-label, parallel-controlled phase 3 trial of benmelstobart plus chemotherapy and anlotinib for first-line treatment of advanced non-squamous NSCLC— Yuankai Shi（CAMS Beijing） 💡 贝莫苏拜单抗+安罗替尼+化疗 vs 替雷利珠单抗+含铂化疗在晚期一线NSQ-NSCLC的3期TQB2450-III-11结果〔263181〕讨论First But Not Alone: Novel Frontline Combinations With Checkpoint Inhibitors— Natalie I. Vokes（MD Anderson）〔267077〕 Panel Q&A — Shi / Vokes / Caicun ZhouDay 3 · 6月1日（周一）Session 17097 · Plenary Session 🕑 2026-06-01 02:00–05:00（北京时间）🎙 主持：Eric J. Small, MD, FASCO; Jo Chien, MD 〔—〕口头报告 02:00-02:05Welcome and Introduction— Jo Chien, MD（University of California San Francisco）Prostate Cancer–Local-Regional Disease 〔LBA1〕口头报告 02:05-02:17Perioperative (neoadjuvant and adjuvant) apalutamide (APA) + androgen deprivation therapy (ADT) vs placebo (PBO) + ADT with radical prostatectomy (RP) in high-risk localized or locally advanced prostate cancer (HR LPC/LAPC): Final analysis of the PROTEUS phase 3 study.— Mary-Ellen Taplin, MD, FASCO（Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute） 💡 前列腺癌〔—〕摘要讨论 02:17-02:29Discussion of LBA1— Declan G. Murphy, MD（Peter MacCallum Cancer Centre）〔—〕 Panel Q&A 02:29-02:39— （全体）Soft Tissue Tumors 〔LBA2〕口头报告 02:39-02:51SARC041: A phase 3 randomized double-blind study of abemaciclib versus placebo in patients with advanced dedifferentiated liposarcoma.— Mark A. Dickson, MD（Memorial Sloan Kettering Cancer Center） 💡 肉瘤〔—〕摘要讨论 02:51-03:03Discussion of LBA2— Paolo Giovanni Casali, MD（Fondazione IRCCS Istituto Nazionale dei Tumori di Milano）〔—〕 Panel Q&A 03:03-03:13— （全体）Neoadjuvant, Perioperative, and Adjuvant Therapy 〔LBA3〕口头报告 03:13-03:25Event-free survival with adjuvant selpercatinib in stage IB-IIIA RET fusion-positive NSCLC: Primary results of the phase 3 LIBRETTO-432 trial.— Jonathan W. Goldman, MD（University of California Los Angeles） 💡 RET塞普替尼辅助治疗3期研究结果〔—〕摘要讨论 03:25-03:37Discussion of LBA3— Christine M. Lovly, MD, PhD, FASCO（City of Hope National Medical Center Department of Medical Oncology and Therapeutics Research）〔—〕 Panel Q&A 03:37-03:47— （全体）Immunotherapies 〔LBA4〕口头报告 03:47-03:59Ivonescimab plus chemotherapy versus tislelizumab plus chemotherapy in previously untreated advanced squamous non–small cell lung cancer: Overall survival results of the phase 3 HARMONi-6 trial.— Shun Lu, MD, PhD（Shanghai Chest Hospital, Shanghai, Jiao Tong University, School of Medicine） 💡 H6 依沃西单抗+化疗 vs 替雷利珠单抗+化疗用于SQ-NSCLC一线3期OS数据〔—〕摘要讨论 03:59-04:11Discussion of LBA4— Julie R. Brahmer, MD, MSc, FASCO（The Bloomberg–Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University School of Medicine）〔—〕 Panel Q&A 04:11-04:21— （全体）Pancreatic Cancer - Advanced/Metastatic Disease 〔LBA5〕口头报告 04:21-04:33Daraxonrasib, a RAS(ON) multi-selective inhibitor vs chemotherapy in previously treated metastatic pancreatic adenocarcinoma (mPDAC): Primary and final analysis from the phase 3 RASolute 302 study.— Brian M. Wolpin, MD, MPH（Dana-Farber Cancer Institute, Gastrointestinal Cancer Center） 💡 pan-RAS抑制剂（Daraxonrasib）vs化疗用于胰腺癌一线3期结果〔—〕摘要讨论 04:33-04:45Discussion of LBA5— Jennifer J. Knox, MD, MSc, FRCPC（Princess Margaret Cancer Centre, University Health Network）〔—〕 Panel Q&A 04:45-04:55— （全体）Session 17109 · Lung Cancer—Non-Small Cell Metastatic 🕑 2026-06-01 02:15–03:45（北京时间）🎙 主持：Brian S. Henick, MD; Guilherme Harada, MDAntibody-Drug Conjugates and Other Novel Therapies 〔8512〕口头报告 02:15-02:21Efficacy and safety of HLX43 (anti–PD-L1 ADC) in patients with advanced non–small cell lung cancer.— Jie Wang, MD, PhD（Cancer Hospital, Chinese Academy of Medical Sciences） 💡 HLX43 (anti–PD-L1 ADC) 的早期数据Other Lung Cancers 〔8513〕口头报告 02:21-02:27Phase 2 data from ROSETTA Lung-02, a global randomized phase 2/3 trial of pumitamig (PD-L1 × VEGF-A bsAb) + chemotherapy in 1L NSCLC.— Solange Peters, MD, PhD（Centre Hospitalier Universitaire Vaudois） 💡 pumitamig联合化疗一线2期结果Immunotherapies 〔8514〕口头报告 02:27-02:33Updated results from a phase 2 trial of SSGJ-707 (PF-08634404), a PD-1/VEGF bispecific antibody, as monotherapy in patients with advanced non-small cell lung cancer (NSCLC).— Lin Wu, Sr., MD（Hunan Cancer Hospital） 💡 SSGJ-707单药2期结果〔—〕 Panel Q&A 02:33-02:45— （全体）〔8515〕口头报告 02:45-02:51Tremelimumab (T) + durvalumab (D) + chemotherapy (CT) vs pembrolizumab (P) + CT in 1L non-squamous (NSQ) metastatic NSCLC (mNSCLC) with STK11, KEAP1, and/or KRAS mutations (mut): Interim analysis (IA) of the phase 2b TRITON study.— Ferdinandos Skoulidis, MD, PhD（The University of Texas MD Anderson Cancer Center） 💡 D+T+CT对比K药+化疗在特定突变人群2期研究期中分析结果Targeted (Non-Immunotherapy) 〔8516〕口头报告 02:51-02:57A phase 1/2 study of TSN1611, a highly selective oral KRAS G12D inhibitor, in solid tumors: Efficacy and safety in KRAS G12D–mutated NSCLC patients.— Siqing Fu, MD, PhD（The University of Texas MD Anderson Cancer Center） 💡 KRAS G12D（TSN1611）1期结果〔—〕 Panel Q&A 02:57-03:09— （全体）Immunotherapies 〔8517〕口头报告 03:09-03:15Prophylactic peptide vaccine targeting resistance mutations in advanced ALK-positive lung cancer: Primary analysis from the ARCHER trial.— Vincent K. Lam, MD（Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine） 💡 ALK阳性靶向耐药中蛋白质多肽疫苗研究结果Targeted (Non-Immunotherapy) 〔LBA8518〕口头报告 03:15-03:21Phase 3 clinical trial of the combination of erlotinib plus ramucirumab compared with osimertinib in untreated advanced or recurrent non-small cell lung cancer with EGFR L858R mutation: The REVOL858R trial (WJOG14420L).— Naoki Haratake, MD, PhD（National Hospital Organization, Kyushu Cancer Center） 💡 对EGFR L858R人群采用厄洛替尼+雷莫西尤单抗 vs 奥希替尼一线治疗的3期结果〔8519〕口头报告 03:21-03:27Safety and efficacy results of the phase 2 study of silevertinib (BDTX-1535) in treatment-naïve patients with non-small cell lung cancer with non-classical EGFR mutations.— Julia K. Rotow, MD（Dana-Farber Cancer Institute） 💡 EGFRi（silevertinib）用于非经典突变2期结果〔8520〕口头报告 03:27-03:33DZD6008, a fourth-generation EGFR TKI, in pretreated NSCLC patients with EGFR C797X mutations: Results from phase 1/2 studies.— Mengzhao Wang, MD（Peking Union Medical College Hospital） 💡 迪哲第4代EGFRi（DZD6008）用于C797X突变的1期研究结果〔—〕 Panel Q&A 03:33-03:45— （全体）Session 17112 · Lung Cancer—Non–Small Cell Local-Regional/Small Cell/Other Thoracic Cancers 🕑 2026-06-01 05:30–07:00（北京时间）🎙 主持：C. S. Pramesh, FRCS, MBBS, MS; Melina Elpi Marmarelis, MDLocal-Regional Non–Small Cell Lung Cancer 〔8009〕口头报告 05:30-05:36Complex segmentectomy versus lobectomy in small-sized peripheral non–small cell lung cancer: A post-hoc supplemental analysis of a multicenter, open-label, phase 3 trial (JCOG0802/WJOG4607L).— Atsushi Kamigaichi, MD（Hiroshima University） 💡 小尺寸周围型非小细胞肺癌的复杂肺段切除术与肺叶切除术对比：一项多中心、开放标签、3期临床试验（JCOG0802/WJOG4607L）的事后补充分析Neoadjuvant, Perioperative, and Adjuvant Therapy 〔8010〕口头报告 05:36-05:42Perioperative toripalimab in non-small cell lung cancer: Clinical outcomes and safety from a large prospective real-world study.— Pingping Song（Cancer Hospital of Shandong First Medical University (Shandong Cancer Institute, Shandong Cancer Hospital)） 💡 特瑞普利单抗围术期大型回顾性研究数据Small Cell Lung Cancer 〔8011〕口头报告 05:42-05:48LuSato-1: Phase I study of 177Lu-SSO110 with 68Ga-SSO120 companion imaging in patients with extensive stage small cell lung cancer (ES-SCLC) on maintenance treatment with immune checkpoint inhibition (ICI).— Surein Arulananda, PhD, MBBS（Monash Health） 💡 SCLC中的核素显像应用〔—〕 Panel Q&A 05:48-06:00— （全体）〔8012〕口头报告 06:00-06:06Preliminary results from an ongoing phase 1 study of LB2102, a dnTGFBR2-armored DLL3-targeted autologous CAR-T cell therapy, in patients with relapsed or refractory SCLC or LCNEC.— Zhonglin Hao, MD, PhD（Markey Cancer Center）〔8013〕口头报告 06:06-06:12Autologous natural killer cell infusion as consolidation therapy after first-line chemoradiotherapy for limited-stage small-cell lung cancer: A randomized, controlled, open-label, single-center phase II clinical study.— Jiuwei Cui, MD, PhD（The First Hospital of Jilin University）〔8014〕口头报告 06:12-06:18Transcriptomic analyses of molecular subsets and correlations with clinical outcomes from the phase 3 IMforte study of lurbinectedin (lurbi) + atezolizumab (atezo) maintenance treatment (Tx) in extensive-stage small-cell lung cancer (ES-SCLC).— Luis G. Paz-Ares, MD, PhD（Hospital Universitario 12 de Octubre, Universidad Complutense and Ciberonc） 💡 Imforte A药+卢比替丁维持3期研究的转录组事后分析〔—〕 Panel Q&A 06:18-06:30— （全体）Local-Regional Non–Small Cell Lung Cancer 〔8015〕口头报告 06:30-06:36Impact of neoadjuvant durvalumab (D) on tumor microenvironment (TME) features and their association with event-free survival (EFS) in patients with resectable NSCLC (R-NSCLC) from the phase 3 AEGEAN trial.— John V. Heymach, MD, PhD（Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center） 💡 AEGEAN围术期额研究肿瘤微环境与预后的分析Outcomes/Quality 〔8016〕口头报告 06:36-06:42Tumor-naïve multimodal cfDNA MRD assay to predict recurrence in a prospective cohort of patients undergoing curative-intent lung cancer resection.— Di Lu（Department of Thoracic Surgery, Nanfang Hospital, Southern Medical University） 💡 MRD预测术后复发Biologic Correlates 〔8017〕口头报告 06:42-06:48Clinical validity of ultrasensitive single-digit parts per million ctDNA detection in non–small cell lung cancer.— Jonathan Wan, PhD, MBBChir（Francis Crick Institute） 💡 MRD技术更新〔—〕 Panel Q&A 06:48-07:00— （全体）Day 3–4 · 6月1–2日（周一深夜）Session 17135 · Developmental Therapeutics—Molecularly Targeted Agents and Tumor Biology 🕑 2026-06-01 21:00 – 2026-06-02 00:00（北京时间）🎙 主持：Shivaani Kummar, MD, FACP, MBBS; Collin M. Blakely, MD, PhDChemotherapy and Antibody-Drug Conjugates 〔3000〕口头报告 21:00-21:12DXC006, a first-in-class CD56-targeting antibody-drug conjugate, in advanced solid tumors: A first-in-human, phase I dose escalation clinical trial.— Hongyun Zhao, PhD（Cancer center, Sun Yat-sen University） 💡 杭州多禧生物的CD56 ADC药物1期（DXC006）〔3001〕口头报告 21:12-21:24Phase I study of BL-M14D1, a novel DLL3-directed antibody-drug conjugate (ADC), in patients with locally advanced or metastatic small-cell lung cancer (SCLC), neuroendocrine carcinoma (NEC), and other solid tumors.— Wei Li, MD（Shanghai East Hospital） 💡 百利天恒的DLL3 ADC药物1期（BL-M14D1）〔3002〕口头报告 21:24-21:36First-in-human study of SYS6043, a novel B7-H3–targeting antibody-drug conjugate, in patients with advanced pan-tumor malignancies.— Li Zhang, MD（Department of Medical Oncology, Sun Yat-sen University Cancer Center） 💡 石药的B7H3 ADC药物1期（SYS6043）〔3003〕口头报告 21:36-21:48T-Bren (BL-M07D1) in patients with recurrent or metastatic (R/M) ovarian cancer: Results from two phase II studies.— Gong-Yi Zhang, MD（Cancer Hospital Chinese Academy of Medical Sciences） 💡 百利天恒的HER2 ADC药物2期（BL-M07D1）〔—〕摘要讨论 21:48-22:00Making Sense of Antibody-Drug Conjugate Trials: Efficacy, Toxicity, and Patient Selection— Paolo Tarantino, MD, PhD（Department of Medical Oncology, Dana-Farber Cancer Institute; Harvard Medical School）〔—〕 Panel Q&A 22:00-22:12— （全体）Tissue-Based Biomarkers 〔3004〕口头报告 22:12-22:24Analysis of spatial atlas of ADC targets in immunotherapy-treated NSCLC to link compartment-specific target expression with tumor immune contexture, clinical outcome, and on-treatment remodeling.— Antoine Italiano, MD, PhD（Gustave Roussy, Department of Medical Oncology, IHU-National PRecISion Medicine Center in Oncology）〔3005〕口头报告 22:24-22:36Clinical utility of discordances between histomorphology and molecular biomarkers in precision oncology.— gil shamai, PhD（Technion Israel Institute of Technology）〔—〕摘要讨论 22:36-22:48Artificial Intelligence and Spatial Profiling: Redefining Predictive Biomarkers— David L. Rimm, MD, PhD（Department of Pathology, Yale School of Medicine）〔—〕 Panel Q&A 22:48-23:00— （全体）Small Molecules 〔3006〕口头报告 23:00-23:12Clinical activity and safety of RNK08954 in advanced non–small cell lung cancer (NSCLC) patients with KRAS G12D mutation (NCT06667544).— Zhengbo Song, MD（Phase I Clinical Trial Ward, Zhejiang Cancer Hospital） 💡 珃诺生物的KRAS G12D药物早期研究结果（RNK08954）New Targets and New Technologies (non-IO) 〔3007〕口头报告 23:12-23:24Phase I/IIa study of DN022150, a novel selective noncovalent small molecule KRAS G12D inhibitor in patients with advanced KRAS G12D–mutant solid tumors.— Yiyi Yu, PhD（Zhongshan Hospital, Fudan University） 💡 青峰医药集团旗下的江西科睿药业有限公司开发的KRAS G12D早期研究结果（DN022150）Small Molecules 〔3008〕口头报告 23:24-23:36Preliminary efficacy of GFH375 in patients with advanced cholangiocarcinoma or colorectal cancer harboring KRAS G12D mutation.— Zhengbo Song, MD（Phase I Clinical Trial Ward, Zhejiang Cancer Hospital） 💡 劲方医药研发的口服KRAS G12D (ON/OFF）抑制剂GFH375。携带 KRAS G12D 突变的晚期胆管癌或结直肠癌患者中 GFH375 的初步疗效。〔—〕摘要讨论 23:36-23:48"Kracking" KRAS G12D— Kathryn C. Arbour, MD（Memorial Sloan Kettering Cancer Center）〔—〕 Panel Q&A 23:48-00:00— （全体）Day 4 · 6月2日（周二）Session 17111 · Lung Cancer—Non–Small Cell Local-Regional/Small Cell/Other Thoracic Cancers 🕑 2026-06-02 02:15–05:15（北京时间）🎙 主持：Laura Alder, MD; Patrick M. Forde, MD, PhDNeoadjuvant, Perioperative, and Adjuvant Therapy 〔8000〕口头报告 02:15-02:27Randomized phase III study of nivolumab after surgery and adjuvant chemotherapy in NSCLC (ECOG-ACRIN EA5142, ALCHEMIST).— Jamie E. Chaft, MD, FASCO（Memorial Sloan Kettering Cancer Center） 💡 辅助化疗后采用O药辅助维持 vs 标准随访（类似IMpower010或KEYNOTE-091）设计的3期结果〔8001〕口头报告 02:27-02:39Adjuvant erlotinib versus observation after complete resection of EGFR-mutant NSCLC: Final overall survival results of Alliance A081105.— Ramaswamy Govindan, MD, FASCO（Alvin J Siteman Cancer Center at Washington University School of Medicine in St. Louis） 💡 EGFR阳性辅助治疗厄洛替尼 vs 观察〔8002〕口头报告 02:39-02:51Neoadjuvant lorlatinib in stage III NSCLC harboring ALK fusion: A phase 2 multicenter study (LORIN).— Chao Zhang, MD, PhD（Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital） 💡 洛拉替尼新辅助2期研究结果〔—〕摘要讨论 02:51-03:03Signals, Surprises, and Subtleties: Lessons From Early-Stage Lung Cancer Trials— Mariano Provencio, MD, PhD（Hospital Universitario Puerta de Hierro）〔—〕 Panel Q&A 03:03-03:15— （全体）Outcomes/Quality 〔8003〕口头报告 03:15-03:27Pollution and progression: Air quality and stage of lung cancer diagnosis across the U.S.— Raheem Bell, MD, MS（Northwestern University Feinberg School of Medicine, Department of Surgery）〔8004〕口头报告 03:27-03:39Redefining lung cancer screening eligibility: Smoking duration vs. pack-years in a national VA cohort of nearly 1 million patients.— Brendan Heiden, MD, MS, MBA（Division of Cardiothoracic Surgery, Department of Surgery, Washington University School of Medicine）〔—〕摘要讨论 03:39-03:51From Air to Awareness: Pollution and the Path to Early Detection— Katharine A. Rendle, PhD, MPH, MSW（Perelman School of Medicine, University of Pennsylvania）〔—〕 Panel Q&A 03:51-04:03— （全体）Small Cell Lung Cancer 〔LBA8005〕口头报告 04:03-04:15Concurrent thoracic radiotherapy (TRT), platinum/etoposide chemotherapy, and durvalumab immunotherapy in extensive-stage (ES) small cell lung cancer (SCLC): A phase III trial.— Bjorn Henning Gronberg, MD, PhD（Department of Oncology, St. Olavs hospital） 💡 ES-SCLC患者中进行胸部放疗（TRT）+化疗+度伐利尤单抗的3期临床研究〔8006〕口头报告 04:15-04:27Intracranial efficacy of tarlatamab versus chemotherapy (CTx) as second-line (2L) treatment for small cell lung cancer (SCLC): DeLLphi-304 phase 3 post hoc analysis.— Giannis S. Mountzios, MD（Fourth Department of Medical Oncology and Clinical Trials Unit, Henry Dunant Hospital Center） 💡 塔拉妥单抗 vs 化疗二线治疗ES-SCLC 3期研究的事后分析（脑部疗效）〔8007〕口头报告 04:27-04:39Efficacy and safety of ivonescimab combined with liposomal irinotecan in patients with small-cell lung cancer (SCLC) progressing after first-line chemoimmunotherapy: A multicenter, phase 2 study.— Yun Fan, MD（Department of Thoracic Oncology, Zhejiang Cancer Hospital） 💡 免疫耐药ES-SCLC中采用依沃西单抗+脂质体伊立替康的2期研究〔8008〕口头报告 04:39-04:51ABBV-706 as monotherapy and in combination with budigalimab in patients with relapsed/refractory (R/R) small cell lung cancer (SCLC).— Lauren Averett Byers, MD, MSc（The University of Texas MD Anderson Cancer Center） 💡 艾伯维的SEZ6 ADC药物ABBV-706单药或联合PD-1抑制剂（budigalimab）在复发/难治的SCLC 〔—〕摘要讨论 04:51-05:03Bright Spots and Blind Alleys in Small Cell Lung Cancer Therapy— Misty Dawn Shields, MD, PhD（Indiana University Melvin and Bren Simon Comprehensive Cancer Center）〔—〕 Panel Q&A 05:03-05:15— （全体）Day 4–5 · 6月2–3日（周二深夜）Session 17136 · Developmental Therapeutics—Molecularly Targeted Agents and Tumor Biology 🕑 2026-06-02 22:45 – 2026-06-03 00:15（北京时间）🎙 主持：Cynthia X. Ma, MD, PhD; Christos Vaklavas, MDRadiopharmaceuticals 〔3009〕口头报告 22:45-22:51Integrin αvβ3-targeted radionuclide therapy with 177Lu-AB-3PRGD2 in multiple advanced metastatic solid tumors: A prospective, single-arm, single-center, investigator-initiated clinical trial.— Hao Fu, PhD（The First Affiliated Hospital of Xiamen University）〔3010〕口头报告 22:51-22:57Phase Ib results from the phase Ib/II study of [177Lu]Lu-DOTA-TATE in combination with standard of care as a first-line treatment for pts with extensive-stage small cell lung cancer.— Stephen V. Liu, MD（Department of Medical Oncology, Lombardi Comprehensive Cancer Center, Georgetown University）Chemotherapy and Antibody-Drug Conjugates 〔3011〕口头报告 22:57-23:03An open-label, first-in-human study of SKB500 in patients with locally advanced or metastatic solid tumors.— Haifeng Liu（Clinical Research Ward, Jilin Provincial Cancer Hospital） 💡 科伦博泰的B7H3药物（SKB500）1期临床〔—〕 Panel Q&A 23:03-23:15— （全体）〔3013〕口头报告 23:15-23:21First-in-human study of BG-C9074 (B7-H4–targeting ADC) in advanced solid tumors: Dose escalation and safety expansion.— Binghe Xu, MD, PhD（Cancer Hospital Chinese Academy of Medical Sciences） 💡 百济引进映恩生物的B7H4 ADC药物（BG-C9074）1期临床Small Molecules 〔3014〕口头报告 23:21-23:27First-in-human trial of BH-30643, a novel macrocyclic, non-covalent, mutant-selective OMNI-EGFR inhibitor, in EGFR-mutant (EGFRm) NSCLC.— Xiuning Le, MD, PhD（The University of Texas MD Anderson Cancer Center） 💡 BlossomHill Therapeutics（由知名新药发明家崔霁松博士及团队创办）研发的一代拟称为“OMNI-EGFR™”的创新大环、非共价、突变选择性小分子激酶抑制剂（BH-30643）〔—〕 Panel Q&A 23:27-23:39— （全体）Tissue-Based Biomarkers 〔3015〕口头报告 23:39-23:45Genomically personalized radiation dose de-escalation: A phase II basket radiation study in patients with pathogenic mutations in ATM.— Amy Xu, MD, PhD（Memorial Sloan Kettering）Chemotherapy and Antibody-Drug Conjugates 〔3016〕口头报告 23:45-23:51A phase 1 study of BGB-B2033 (GPC3 x 4-1BB bispecific antibody) monotherapy in patients with selected advanced or metastatic solid tumors: First disclosure of clinical data.— Hong Jae Chon, MD, PhD（CHA Bundang Medical Center）Small Molecules 〔3017〕口头报告 23:51-23:57Luvometinib in adults with neurofibromatosis type 1 and symptomatic, inoperable plexiform neurofibromas: A randomized, double-blind, placebo-controlled, phase 3 trial.— Wenbin Li（Department of Neuro-Oncology, Cancer Center, Beijing Tiantan Hospital, Capital Medical University）〔—〕 Panel Q&A 23:57-00:09— （全体）声明：以上材料来自笔者从公开来源整理资料，仅供个人学习分享使用，不构成任何投资或诊疗建议。如有错误请联系笔者修改。

2026-04-30

·PRNewswire

D3 Bio Presents KRAS Pipeline Updates at AACR 2026; Elisrasib (D3S-001), a Next-Generation KRAS G12C Inhibitor, Shows Strong Phase 2 Efficacy Across Multiple Tumor Types

Elisrasib monotherapy demonstrates notable efficacy in three major tumor types at its recommended phase 2 dose (RP2D , 600 mg QD). Phase 2 clinical outcomes include: 2L+ KRAS G12Ci–naïve NSCLC: ORR of 58.8%, mPFS of 12.2 months 2L+ colorectal cancer (CRC): ORR of 46.9%, mPFS of 9.5 months 2L+ pancreatic ductal adenocarcinoma (PDAC): ORR of 65.0%, mPFS of 13.5 months Additionally, meaningful efficacy was observed in KRAS G12C inhibitor-pretreated and refractory NSCLC, with an ORR of 32.3% and mPFS of 8.1 months, and significant activity in patients with CNS metastases. SHANGHAI, April 29, 2026 /PRNewswire/ -- D3 Bio Inc., a global clinical-stage biotechnology company dedicated to developing innovative oncology therapeutics, today announced new phase 2 clinical data from its lead asset elisrasib (D3S-001), a next-generation KRAS G12C inhibitor, alongside additional clinical and preclinical results from its KRAS-focused pipeline. The phase 2 studies demonstrate that elisrasib delivers broad antitumor activity across multiple KRAS G12C-mutant solid tumors, including NSCLC, CRC, and PDAC. Phase 2 data for elisrasib were shared as oral presentations at the American Association for Cancer Research (AACR) Annual Meeting 2026 during both the Clinical Plenary Session (Abstract CT020) and the Clinical Trials Mini-Symposium (Abstract CT303) in San Diego, CA. Extensive and Durable Clinical Activity Observed Across Indications In 2L+ KRAS G12Ci-naïve NSCLC (n=68), elisrasib demonstrated robust efficacy at the RP2D (600 mg QD) with an ORR of 58.8%, median duration of response (mDoR) of 16.5 months, and mPFS of 12.2 months. Among late-line NSCLC patients refractory to prior KRAS G12C inhibitor therapy (n=31), an ORR of 32.3%, mDoR of 15.6 months, and mPFS of 8.1 months were recorded. In previously treated CRC, elisrasib showed significant efficacy as both monotherapy (n=32, ORR 46.9%, mDoR 13.1 months, and mPFS 9.5 months) and in combination with cetuximab (n=29, ORR 62.1%, mDoR 7.0 months, and mPFS 8.2 months). Further studies are planned to evaluate optimized combination strategies to enhance the durability of response in CRC. For late-line PDAC, monotherapy (n=20) achieved an ORR of 65.0%, mDoR of 10.8 months, and mPFS of 13.5 months. Favorable Safety Profile Elisrasib was well-tolerated across NSCLC, CRC, and PDAC populations. Grade 3 or higher treatment-related adverse events (TRAEs) ranged between 8.7% and 15.6% across these indications. Combination therapy with cetuximab was associated with a higher incidence of Grade 3 TRAEs, which were manageable and largely attributed to cetuximab. Only one transient, asymptomatic Grade 4 hypokalemia event was reported, with no other Grade 4 or 5 TRAEs observed. Expert Commentary "Elisrasib demonstrates the ability to provide deeper, longer-lasting tumor responses, even in cases where first-generation KRAS G12C inhibitors failed. Overall, these findings indicate that elisrasib may significantly improve treatment for lung cancer patients with KRAS G12C mutations," stated Professor Byoung Chul Cho, MD, PhD, Yonsei Cancer Center, Yonsei University College of Medicine, Korea, and lead study investigator. "Among patients whose disease progressed on first-generation inhibitors, we found five cases of KRAS gene amplification, an important mechanism of evasion of KRAS G12C inhibitor efficacy. Out of those five KRAS amplification cases, four experienced tumor shrinkage, three showed a clinical response, and the disease control rate was 100%, indicating elisrasib's effectiveness in this biomarker-defined group." Additional D3 Bio Presentations at AACR 2026 D3 Bio also presented advancements in its KRAS program, notably: First-in-human phase 1 investigation of D3S-002, a selective ERK1/2 inhibitor, in advanced solid tumors with MAPK pathway mutations — Poster (Abstract CT060) Clinical pharmacokinetic modeling of D3S-003, an oral dual-state KRAS G12D inhibitor — Poster (Abstract 1831) D3S-003: An allele-specific, orally available KRAS G12D (OFF/ON) inhibitor with best-in-class potential — Poster (Abstract 4569) "We are encouraged by the consistent and robust clinical activity exhibited by elisrasib across various KRAS G12C–mutant tumors, reinforcing the strength and momentum of D3 Bio's expanding KRAS pipeline," commented Dr. George Chen, Founder, Chairman and Chief Executive Officer of D3 Bio. "These data suggest elisrasib may become a foundational therapy for KRAS G12C mutant cancers." About Elisrasib (D3S-001) Elisrasib is a next-generation KRAS G12C inhibitor designed for rapid, complete, and selective target engagement. It covalently binds the GDP-bound (OFF) form of KRAS G12C, effectively blocking nucleotide cycling and suppressing oncogenic signaling. Preclinical studies show robust potency, complete KRAS G12C engagement at clinically relevant exposures, and CNS penetration capability. Elisrasib is currently being evaluated globally in a Phase 2 monotherapy and combination trial across KRAS G12C–mutant solid tumors including NSCLC, CRC, and others. Key Publications: Cancer Discovery Nature Medicine (2025) 31(8):2768–2777 About D3S-002 D3S‑002 is a selective ERK1/2 inhibitor purposely designed for combination approaches, providing vertical MAPK‑pathway inhibition to enhance efficacy and overcome acquired resistance, particularly in tumors previously treated with KRAS G12C inhibitors. Key Publication: Cancer Res 1 April 2023; 83 (7_Supplement): 5501. About D3S-003 D3S‑003 is a differentiated KRAS G12D inhibitor targeting both active (ON) and inactive (OFF) conformations, addressing one of the most common KRAS mutations. This program expands D3 Bio's multi-allele KRAS portfolio, aiming to provide innovative therapies for diverse KRAS-driven malignancies. About D3 Bio D3 Bio is a global biotechnology company focused on the discovery, development, and registration of novel oncology and immunology therapies with first or best in class potential. Guided by deep clinical insight and biomarker-driven‑strategies, the Company is advancing a pipeline of programs targeting key oncogenic drivers and immune pathways. D3 Bio owns global rights to all its programs. For further information, please visit SOURCE D3 Bio 21% more press release views with Request a Demo

临床结果临床2期临床1期AACR会议

2026-04-16

·幻想者笔记

分子胶的发现历史：从悲剧到突破

作为学习免疫学背景的中国制药行业的一员，曾经从事于临床前药物毒理学和安全药理学评价的工作，也从事于药物生产数字化的工作，而现在投身于临床试验这片汪洋大海，每月参加数次行业的前沿会议听取各位新药研发创业老板们的进展，听行业的热点频频转向。PD-1不用多说已经过气，双抗和ADC也不是什么新故事了，GLP-1竞争格局基本上形成了，去年今年小核酸、TCE、分子胶、PROTAC、大环肽以及夹杂的各种AI制药在各个会场十分热闹。我还稍微有点免疫背景，对于这些热点背后的MoA，成药性，安全性风险和患者获益也是似是而非。因此花点时间借助AI来学习并记录和追踪一下中国新药研发的新热点，也算凑个热闹吧。今天先从分子胶开始吧。其机制一句话粗浅概括:外源小分子进入体内，结合变构体内的蛋白后与原本不能结合的靶蛋白结合，从而发挥生物学效应。引用最近最火的Daraxonrasib的机制图做个参考。 1957-1961年：沙利度胺悲剧意外的开始 1957年，德国Grünenthal公司推出沙利度胺（Thalidomide）作为镇静剂和止吐药，被广泛用于缓解孕妇晨吐症状。然而到1961年，发现其导致严重出生缺陷（海豹肢畸形），全球约1万名婴儿受害，迅速从市场撤出，成为医药史上最大的灾难之一。1965-1998年：意外的治疗价值绝处逢生 1965年，以色列医生Jacob Sheskin偶然发现沙利度胺对麻风病结节性红斑有效。1990年代，发现其对多发性骨髓瘤有显著疗效。1998年FDA批准沙利度胺用于麻风病结节性红斑，2006年批准用于新诊断的多发性骨髓瘤。衍生物开发来那度胺（Lenalidomide）于2005年获FDA批准，泊马度胺（Pomalidomide）于2013年获批。这些免疫调节药物（IMiDs）成为多发性骨髓瘤的基石疗法。2010年：分子胶机制的重大发现历史性突破 2010年，日本东京工业大学的Hiroshi Handa团队和Takumi Ito在《Science》杂志发表里程碑研究，鉴定出Cereblon（CRBN）是沙利度胺的直接结合靶点，发现CRBN是CRL4 E3泛素连接酶复合物的底物受体。机制阐明沙利度胺结合CRBN后，改变其底物识别特异性，诱导CRBN与新的靶蛋白（如Ikaros、Aiolos等转录因子）形成相互作用，促使这些靶蛋白被泛素化标记并通过蛋白酶体降解。这种"分子胶"机制首次被系统性阐述。2014-2015年：分子胶概念正式确立从偶然到理性 2014年，多项研究确认IMiDs通过诱导新底物（neo-substrate）降解发挥作用，明确了Ikaros家族转录因子（IKZF1/3）是关键降解靶点。2015年，Benjamin Ebert等人在《Nature》发表研究，详细解析CRBN-IMiD-Ikaros三元复合物的结构基础。"分子胶降解剂"作为独立的药物发现策略被广泛认可。2016-2020年：理性设计时代开启技术突破这一时期，结构生物学通过X射线晶体学和冷冻电镜解析三元复合物结构，化学生物学开发新型化学探针和筛选方法，计算建模利用分子动力学模拟预测三元复合物形成。新靶点探索研究从CRBN扩展到其他E3连接酶（VHL、IAP等），发现新型分子胶降解靶点（GSPT1、CK1α等）。2021-2026年：临床应用爆发期 KRAS突破 2021年，Revolution Medicines公开RAS(ON) Inhibitor平台。2023年，RMC-6236（Daraxonrasib）进入临床，成为首个KRAS G12D分子胶。2024-2026年，多项II期临床试验显示令人鼓舞的数据。管线扩张超过20个分子胶降解剂进入临床试验，3个进入Phase III阶段，适应症从血液瘤扩展到实体瘤、神经退行性疾病、自身免疫病。二、全球进度前五的分子胶管线（2026年更新版）1. Daraxonrasib (RMC-6236) - Revolution Medicines 基本信息适应症：KRAS G12D突变实体瘤（胰腺癌、结直肠癌、NSCLC）临床阶段：Phase II（多项试验） FDA认定：突破性疗法认定（BTD）作用机制 Tri-complex分子胶：诱导KRAS G12D与Cyclophilin A（CypA）形成三元复合物，锁定KRAS于非活性GDP结合状态，阻断与下游效应蛋白（RAF、PI3K）的相互作用。注意这是功能抑制而非蛋白降解。临床意义首个临床阶段的KRAS G12D选择性抑制剂，攻克40年"不可成药"靶点。KRAS G12D占所有KRAS突变的约40%，是胰腺癌患者的潜在突破性疗法。最新数据单药ORR（客观缓解率）显示活性，联合化疗协同效应明显，安全性可控，主要不良反应可管理。2. Mezigdomide (CC-92480) - Bristol Myers Squibb 基本信息适应症：复发/难治性多发性骨髓瘤（R/R MM）临床阶段：Phase III 预期获批：2026-2027年作用机制 CRBN调节剂：结合cereblon E3连接酶，诱导降解Ikaros（IKZF1）和Aiolos（IKZF3）转录因子，比来那度胺降解活性更强（约10倍），同时具有免疫调节作用。临床优势对来那度胺难治患者仍有效，可与其他疗法（蛋白酶体抑制剂、抗CD38单抗）联用，口服给药，患者依从性好。3. Iberdomide (CC-220) - Bristol Myers Squibb 基本信息适应症：多发性骨髓瘤、系统性红斑狼疮（SLE）临床阶段：Phase III（MM）、Phase II（SLE）作用机制新一代CRBN调节剂，更强的Ikaros/Aiolos降解活性，独特的免疫调节特性。临床特点克服IMiD耐药，在自身免疫病领域显示潜力，扩展适应症策略。4. Golcadomide (CC-99282) - Bristol Myers Squibb 基本信息适应症：非霍奇金淋巴瘤（NHL）临床阶段：Phase III 作用机制 CRBN调节剂，选择性降解Aiolos（IKZF3），对B细胞恶性肿瘤特异性更高。临床定位针对B细胞淋巴瘤优化，与抗CD20单抗联用，潜在的弥漫大B细胞淋巴瘤（DLBCL）一线疗法。5. BG-3839 (cDAC) - BeiGene 基本信息适应症：血液系统恶性肿瘤临床阶段：Phase III 中国创新：首个进入Phase III的国产TPD药物作用机制嵌合降解激活化合物（cDAC）平台，新型分子胶机制（具体靶点未完全公开），可能涉及新型E3连接酶。战略意义代表中国在TPD领域的突破，展示中国工程化能力，有望成为首个中国原创的分子胶药物。三、分子胶成药性的辩证分析优势（Advantages）1. 靶向"不可成药"蛋白质突破传统限制无需活性位点：不依赖靶蛋白的酶活性或结合口袋。扩展成药空间：可靶向转录因子、支架蛋白、结构蛋白。成功案例 Ikaros/Aiolos（无酶活性的转录因子） GSPT1（翻译终止因子） KRAS G12D（缺乏深口袋的GTPase）统计数据传统"可成药"靶点约3,000个（占人类蛋白质组的约15%），分子胶潜在靶点理论上可扩展至整个蛋白质组（约20,000个）。2. 催化性降解机制事件驱动 vs 占位驱动传统抑制剂需要持续占据靶点（occupancy-driven），分子胶降解剂一次结合可催化多轮降解（event-driven）。药效学优势低剂量高效：亚纳摩尔浓度即可有效。持久效应：即使药物清除，降解效应持续至蛋白重新合成。降低毒性：更低的系统暴露量。定量比较传统抑制剂：1个药物分子抑制1个靶蛋白，需要高浓度维持。分子胶：1个药物分子降解多个靶蛋白，催化循环。3. 优越的药物化学性质分子量对比类型典型分子量口服生物利用度细胞膜通透性传统小分子 300-500 Da 高优秀分子胶 350-550 Da 中-高良好 PROTAC 700-1200 Da 低-中较差抗体 150,000 Da 无（注射）无 "类药五规则"符合度分子量通常小于600 Da（优于PROTAC），LogP适中（2-5），氢键供体/受体在可控范围，大多数可实现口服给药。实例来那度胺：分子量259 Da，口服生物利用度约82%。RMC-6236：分子量约500 Da，口服给药。4. 克服耐药机制多重耐药突破靶点突变耐药：降解整个蛋白，不依赖特定结合位点。过表达耐药：催化降解可应对高表达。旁路激活耐药：消除蛋白功能而非仅抑制活性。临床证据 Iberdomide对来那度胺耐药的MM患者仍有效，机制是更强的降解活性克服CRBN表达下调。5. 合成与制造优势化学合成单一小分子：无需复杂的连接子设计（vs PROTAC）。合成路线短：通常5-10步。成本效益：规模化生产成本低。中国优势强大的化学合成能力，完善的原料药（API）产业链，快速的工艺优化能力。劣势与挑战（Disadvantages & Challenges）1. 发现困难：从偶然到理性历史依赖偶然沙利度胺完全意外发现，机制阐明用了50年。大多数分子胶通过表型筛选偶然发现。理性设计困难：需要同时满足与E3连接酶和靶蛋白的结合。筛选挑战传统小分子筛选：药物加靶蛋白产生结合，检测简单。分子胶筛选：药物加E3连接酶加靶蛋白形成三元复合物，然后泛素化、降解、检测，过程复杂。技术瓶颈无独立亲和力：分子胶对E3或靶蛋白单独结合力弱。三元复合物预测：需要高精度结构建模。假阴性率高：传统筛选方法易遗漏。改善途径 AI辅助设计：AlphaFold预测三元复合物结构。高通量蛋白质组学：无偏筛选降解底物。DEL技术：DNA编码化合物库筛选。自动化合成：机器人平台快速迭代。2. 脱靶效应（Off-target Effects）非特异性降解风险 E3连接酶底物广泛：CRBN有多个天然底物。意外降解：可能降解非预期蛋白。沙利度胺致畸机制降解SALL4（肢体发育关键转录因子），导致严重出生缺陷，警示脱靶效应可能致命。其他脱靶案例 IMiDs降解CK1α（casein kinase 1α）可能与某些副作用相关。降解ZFP91（锌指蛋白）功能影响未知。降低策略结构优化：提高三元复合物选择性。蛋白质组学监测：全面评估降解谱。患者分层：避免特定人群（孕妇、儿童）。3. E3连接酶的限制可用E3连接酶有限人类E3连接酶约600个，已用于药物开发的不到10个，包括CRBN（最常用）、VHL（von Hippel-Lindau）、IAP（inhibitor of apoptosis）、MDM2、DCAF15、DCAF16等。 CRBN依赖的风险过度集中：超过80%的分子胶靶向CRBN。组织特异性：CRBN在不同组织表达差异。耐药风险：CRBN突变或表达下调。临床耐药证据 MM患者长期使用IMiDs后出现CRBN突变，CRBN表达下调导致耐药。扩展策略开发新型E3连接酶招募剂，组织特异性E3连接酶利用，双E3连接酶策略。4. 从抑制剂到降解剂的转化挑战结构要求根本不同抑制剂设计目标是高亲和力结合靶蛋白活性位点，要求占据口袋、阻断功能，结构填充结合腔。分子胶设计目标是诱导靶蛋白-E3连接酶相互作用，要求形成生产性三元复合物，结构桥接两个蛋白表面。转化失败案例许多高效抑制剂无法转化为降解剂，结合模式不利于三元复合物形成，空间位阻阻碍E3连接酶接近。成功要素合适的结合位置：靶蛋白表面可接近。正确的取向：泛素化位点（赖氨酸）靠近E3连接酶。适当的柔性：允许三元复合物形成。定量数据抑制剂转化为降解剂的成功率低于10%，需要大量结构优化和迭代。5. 药物性质的权衡 "类药五规则"挑战分子量虽比PROTAC小，但仍可能超过500 Da。疏水性需要结合两个蛋白表面，LogP可能偏高。溶解度疏水性增加导致水溶性下降。口服吸收问题某些分子胶口服生物利用度低于30%，需要制剂技术改善。代谢稳定性平衡活性与代谢稳定性，避免快速清除或过度蓄积。实例对比化合物分子量 LogP 口服BA 挑战来那度胺 259 0.5 82% 致畸性泊马度胺 273 0.4 73% 骨髓抑制 RMC-6236 约500 约3 中等需优化6. 可逆性与可控性不可逆降解一旦蛋白降解，需要重新合成才能恢复。半衰期长的蛋白（如转录因子）恢复慢。难以快速逆转副作用。剂量调整困难催化机制导致剂量-效应关系非线性，难以精确控制降解程度。对比PROTAC PROTAC也面临类似问题，但分子胶因催化效率更高，可控性更差。7. 生物标志物与患者分层疗效预测困难 E3连接酶表达：需要检测CRBN等表达水平。靶蛋白表达：基线表达影响降解效果。泛素-蛋白酶体系统：功能状态影响降解效率。伴随诊断需求需要开发检测E3连接酶表达的诊断工具，识别可能耐药的患者群体。临床复杂性增加临床试验设计复杂度，提高患者筛选成本。四、成药性综合评价适合分子胶的最佳场景场景理由实例 "不可成药"靶点无活性位点，传统方法无效 Ikaros、KRAS G12D 转录因子缺乏小分子结合口袋 Aiolos、SALL4 慢性疾病需要持久药效，催化机制有利多发性骨髓瘤耐药肿瘤降解绕过突变耐药来那度胺耐药MM 低剂量需求催化机制降低系统暴露神经系统疾病不太适合的场景场景理由替代方案需要快速可逆降解不可逆，恢复慢传统抑制剂 E3缺失肿瘤 CRBN突变/缺失导致无效 PROTAC（多E3）极度脱靶敏感如孕妇、儿童其他疗法组织特异性高 E3表达限制组织分布抗体药物未来发展方向 AI驱动的理性设计 AlphaFold预测三元复合物，机器学习优化分子结构，虚拟筛选加速发现。新型E3连接酶开发扩展至CRBN以外，组织特异性E3利用，双E3策略。精准医疗整合生物标志物开发，伴随诊断，患者分层策略。联合疗法与免疫疗法联用，与靶向药物协同，克服耐药。新适应症拓展神经退行性疾病，自身免疫病，病毒感染。总结分子胶的发展是从悲剧到突破的传奇故事。1957-2010年偶然发现，机制未知。2010年CRBN发现，机制阐明。2015年后理性设计时代开启。2020年代临床应用爆发。成药性评价方面，优势显著：靶向"不可成药"蛋白、催化机制、优越药物性质。挑战存在：发现困难、脱靶风险、E3限制。中国机遇包括强大的化学合成与工程化能力，丰富的临床试验资源，AI与自动化技术加持，BeiGene等公司已取得突破。

100 项与 KRAS G12D/G12V抑制剂(百济神州) 相关的药物交易

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