This study is being done to answer the following question: Can testing breast cancer for DNA abnormalities or "biomarkers" help predict which patients are most likely to be helped by certain treatments? The pre-study screening is being done to test a sample of blood (or tumour tissue) for biomarkers to see if patients can participate in the study

开始日期2023-06-13

申办/合作机构

Canadian Cancer Trials Group

NCT05251714

/ Active, not recruiting临床1/2期

A Dose-confirming Study of CFI-402257 as a Single Agent in Advanced Solid Tumors and in Combination With Fulvestrant in Patients With ER+/HER2- Advanced Breast Cancer After Disease Progression on Prior CDK4/6 and Endocrine Therapy

The purpose of this study is to test the safety of an investigational drug called CFI-402257 alone in advanced solid tumors and in combination with Fulvestrant in advanced breast cancer patients.

开始日期2022-05-27

申办/合作机构

Treadwell Therapeutics, Inc.

NCT03568422

/ Active, not recruiting临床1/2期IIT

A Phase Ib and Open Label Phase II Study of CFI-402257 in Combination With Weekly Paclitaxel in Patients With Advanced/Metastatic HER2-Negative Breast Cancer

The standard or usual treatment for this disease is to undergo chemotherapy to slow the spread of disease and relieve some symptoms of cancer. One of the standard types of chemotherapy is a drug called paclitaxel (Taxol) given in a low dose every week for three out of four weeks.
CFI-402257 is a new type of drug for breast cancer. Laboratory tests show that it may help slow the growth of breast cancer. This drug has been shown to shrink tumours in animals. CFI-402257 has been studied in a few people and appears well tolerated with little side effects. CFI-402257 seems promising but it is not clear if it can offer better results when given with paclitaxel compared to paclitaxel alone.

开始日期2019-02-05

申办/合作机构

Canadian Cancer Trials Group

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100 项与 CFI-402257 相关的转化医学

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100 项与 CFI-402257 相关的专利（医药）

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项与 CFI-402257 相关的文献（医药）

2026-10-01·COMPUTATIONAL BIOLOGY AND CHEMISTRY

Computational exploration of quercetin derivatives from Azadirachta indica leaf as threonine tyrosine kinase inhibitors for potential lung and pancreatic cancer treatment

Article

作者: Sarker, Susen ; Al Imran, A Q M ; Priya, Samsun Nahar ; Hossain, Md Rezoan ; Al Ashik, Sheikh Abdullah

Lung and pancreatic adenocarcinomas account for substantial cancer-related mortality worldwide, with current therapeutic efficacy severely limited by the development of high drug resistance. Threonine tyrosine kinase (TTK) has emerged as both a therapeutic target and a critical prognostic marker in these malignancies, with elevated expression correlating strongly with poor clinical outcomes. Therefore, this study aimed to investigate natural quercetin derivatives from Azadirachta indica leaf as novel TTK inhibitors through comprehensive computational approaches. From initial TTK expression and survival analyses to subsequent Molecular docking, machine learning models predicted bioactivity estimation, quantum chemical calculations, molecular dynamics (MD) simulations, post-dynamics MM-PBSA calculations, and in silico toxicity profiling were performed to identify TTK inhibitors. TTK overexpression significantly correlated with diminished survival in both cancer types (hazard ratios: 1.5-2.0). Quercetin-3-rhamnoside, quercetin-3-glucoside, quercetin-3-O-galactoside, and quercetin-3-rutinoside demonstrated superior binding affinities (-9.5 to -11.089 kcal/mol) compared to control drug Luvixasertib (-8.869 kcal/mol), with enhanced electronic properties (electrophilicity index: 3.53-4.67 compared to control 2.70). Furthermore, Machine learning predictions demonstrated promising bioactivity (pIC₅₀: 6.915-7.835), while 200 ns MD simulations confirmed structural stability with optimal RMSD (1.419-2.035 Å). Subsequently, MM-PBSA calculations revealed markedly favorable binding free energies for quercetin-3-rhamnoside and quercetin-3-glucoside (-33.104 and -32.676 kcal/mol) compared to control (-28.430 kcal/mol). Additionally, toxicity profiling revealed favorable safety profiles with no hepatotoxic, carcinogenic, or mutagenic potential for most derivatives. Therefore, Quercetin derivatives from A. indica leaf represent promising lead compounds for targeted TTK inhibitors in lung and pancreatic adenocarcinomas, highlighting their potential for further experimental validation against TTK.

2026-08-01·INTERNATIONAL IMMUNOPHARMACOLOGY

cGAS-STING Signalling in the tumour microenvironment: Implications for immune surveillance and therapeutic strategies

Review

作者: Rahiman, Siti Sarah Fazalul ; Murugaiyah, Vikneswaran ; Al-Ramamneh, Rahmeh Saad ; Attiq, Ali ; Mohamed, Rafeezul ; Afzal, Sheryar ; Ahmad, Waqas ; Al-Adayleh, Teeb Yasir Mahmoud

The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway links cytosolic DNA sensing to type I interferon production and inflammatory signalling, making it central to innate immunity. In addition to defending against pathogens, it shapes the tumour microenvironment by regulating immune surveillance, antitumour activity, and tumour progression. Short-term cGAS-STING activation enhances dendritic cell maturation, antigen presentation, macrophage polarisation, and cytotoxic lymphocyte recruitment. However, prolonged activation shifts the TME into an immunosuppressive state by inducing NF-κB-mediated inflammation, expanding regulatory T cells, increasing myeloid-derived suppressor cell accumulation, and elevating immune checkpoint expression. Crosstalk among the STAT3, TGF-β, and autophagy pathways further impacts angiogenesis, fibrosis, and metastasis. Additionally, metabolic stress, mitochondrial DNA (mtDNA) release, and epigenetic silencing of pathway components under hypoxic or chromosomally unstable conditions modify STING responsiveness, ultimately affecting therapeutic outcomes. Pharmacological activation using cyclic dinucleotides (CDN) STING agonists (ADU-S100 and MK-1454) and non-CDN STING agonists (diABZI and MSA-2), as well as MPS1 inhibitors (CFI-402257, BAY-1217389, and CC-671), has effectively triggered strong type I interferon responses and caused tumour regression in preclinical and clinical trials. When combined with radiotherapy, PARP inhibitors, or immune checkpoint blockers, these agents exhibit enhanced synergy but are constrained by tumour heterogeneity and context-dependent toxicity. Here, we reviewed the complexity of the cGAS-STING and its potential as a double-edged sword in cancer treatment, underscoring the need for strict strategies to harness this pathway while enhancing antitumour immunity and mitigating pro-tumorigenic effects.

2025-08-01·NEOPLASIA

Targeting monopolar spindle kinase I (Mps1 or TTK) induces radiosensitization in syngeneic models of triple negative breast cancer (TNBC) and potentiates type I interferon (T1IFN) signaling

Article

作者: Wilson, Cydnee M ; Rae, James M ; Jungles, Kassidy M ; Liu, Meilan ; Speers, Corey W ; Wilder-Romans, Kari ; Pierce, Lori J ; Jungles, Kalli R ; Bishop, Caroline R

Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype that disproportionately impacts Black women and has limited effective therapeutic options. Consequently, there is an urgent need to develop novel approaches for the treatment of TNBC. Previously, we identified monopolar spindle kinase I (Mps1 or TTK), which is upregulated in TNBC patients after radiotherapy, as a potential therapeutic target. We found that TTK inhibition sensitizes human TNBC to radiotherapy (RT) both in vitro and in vivo; however, these studies were performed in immunodeficient models. Here, we extended those studies into syngeneic murine models of TNBC using two TTK inhibitors: empesertib and the novel TTK inhibitor CFI-402257 (also known as luvixasertib) that was recently granted FDA fast track approval in breast cancer. These studies demonstrate that TTK inhibition radiosensitizes syngeneic murine models of TNBC and increases the production of micronuclei and aneuploidy. Mechanistic studies demonstrate that TTK inhibition and RT alter the tumor immune microenvironment of TNBC by modifying the production of antitumoral type I interferon (T1IFN). In vivo, TTK inhibition sensitizes syngeneic models of TNBC to RT. Furthermore, combining TTK inhibition and RT also potentiates T1IFN signaling, suggesting that combination treatment may induce antitumoral immunity in immunocompetent models. Taken together, these studies demonstrate that TTK inhibition enhances radiosensitivity and TTK inhibition with RT modulates the immune landscape of TNBC. Collectively, this combination may represent a novel therapeutic strategy to improve outcomes for patients with TNBC by both direct tumor cytotoxicity and by promoting an immune-responsive environment.

项与 CFI-402257 相关的新闻（医药）

2026-07-04

·灵枢探药

DDR1靶点药物研发报告

编制日期：2026年7月3日数据来源：PubMed、ClinicalTrials.gov、ASCO 2026、Nature (2021)、Drug Discovery Today (2024)、智慧芽新药情报库、医药魔方NextPharma、Human Protein Atlas分析范围：靶点生物学、疾病关联、信号通路、药物研发管线（含最新临床数据）、成药性评估、竞争格局、投资视角目录靶点基本信息蛋白结构与功能信号通路与核心机制疾病关联全景DDR1的免疫排斥机制——转化医学里程碑药物研发管线——全景图谱关键临床数据详解成药性综合评估竞争格局分析关键研究里程碑时间线投资视角评估核心结论与建议1. 靶点基本信息属性内容基因官方名DDR1全称Discoidin Domain Receptor Tyrosine Kinase 1别名CD167a、MCK10、NEP、PTK3、RTK6、TRKE、EDDR1蛋白家族受体酪氨酸激酶（RTK）——盘状结构域受体亚家族同家族成员DDR2染色体位点6p21.33蛋白结构胞外域（DS + DS-like结构域）→ 跨膜域 → 胞内激酶域配体天然配体为胶原蛋白（主要为I-III型纤维状胶原）活化方式胶原结合触发缓慢且持续的自磷酸化（不同于大多数RTK的快速激活）亚型5种：DDR1a/b/c（全长活性受体）、DDR1d/e（缺乏激酶活性）组织表达上皮细胞广泛表达，尤其在上皮来源组织（肺、肾、乳腺、结肠、脑） ⚠️ 注意区分：DDR1 ≠ DRR1/FAM107A。DDR1是胶原激活的RTK，而DRR1是肌动蛋白结合蛋白，两者无任何关联。2. 蛋白结构与功能2.1 结构特征 DDR1 蛋白结构域架构 N-端 C-端 ┌──────────┬──────────┬──────┬──────────────┬──────────┐ │ DS域 │DS-like域 │ EJXM │ 跨膜域 │ 激酶域 │ │(胶原结合)│ │ TM │ │ + C-tail │ └──────────┴──────────┴──────┴──────────────┴──────────┘ 胞外域 (~400 aa) 胞内域 (~480 aa)结构域功能关键特征DS域（Discoidin）胶原蛋白结合与凝血因子V/VIII同源；胶原结合不依赖金属离子DS-like域辅助胶原识别与DS域协同形成胶原结合界面EJXM（胞外近膜区）受体二聚化含亮氨酸拉链样基序，调控配体非依赖性二聚化跨膜域膜锚定对自二聚化至关重要激酶域信号转导典型RTK激酶折叠；胶原激活后缓慢自磷酸化IJXM（胞内近膜区）激酶活性调控调控下游信号通路选择性2.2 五大核心生物学功能胶原感应与信号转导唯一以胶原为配体的RTK家族成员激活后磷酸化，启动下游Src、Notch、IKK、JAK2/STAT3、PYK2等通路细胞外基质（ECM）重塑调控胶原纤维排列对齐调节MMP表达，影响ECM降解与沉积细胞黏附与迁移调控通过PYK2-RAP1通路促进上皮-间质转化（EMT）调控灶性黏附动态变化免疫排斥——核心转化发现（§5详述）2021年Nature里程碑：DDR1通过强制胶原纤维排列形成物理屏障不依赖激酶活性：仅胞外域即可实现免疫排斥阻断DDR1→破坏胶原排列→T细胞浸润恢复组织纤维化驱动肾纤维化：DDR1缺失小鼠高血压肾病组织学损伤显著减轻肺纤维化：DDR1-KO小鼠肺胶原沉积减少肝纤维化：DDR1过表达促进肝星状细胞活化3. 信号通路与核心机制3.1 DDR1信号网络全景 DDR1 信号通路网络胶原(I/II/III型) │ ▼ ┌─────────────────────────────────────────┐ │ DDR1 受体 │ │ ┌──────────────────────────────────┐ │ │ │ ECD:胶原结合 → 受体二聚化 │ │ │ │ ↓ │ │ │ │ ICD:自磷酸化 → 激酶激活 │ │ │ └──────────────────────────────────┘ │ └─────────────────────────────────────────┘ │ │ │ 激酶依赖性 │ 激酶非依赖性 │ (经典通路) │ (非经典通路) ▼ ▼ ┌──────────┐ ┌──────────────┐ │ Src │ │ ECM重塑 │ │ Notch │ │ 胶原排列对齐 │ │ IKK │ │ (不依赖磷酸化) │ │ STAT3 │ └──────────────┘ │ PYK2 │ │ └──────────┘ ▼ │ ┌──────────────┐ ▼ │ T细胞排斥 │ ┌──────────┐ │ 免疫逃逸 │ │ 细胞增殖 │ │ 肿瘤生长 │ │ EMT │ └──────────────┘ │ 存活 │ │ 侵袭 │ └──────────┘3.2 关键信号轴信号轴通路细节生物学效应与DDR1靶向治疗的关系DDR1-胶原-EMTDDR1→PYK2→RAP1→EMT促进肿瘤侵袭转移激酶抑制剂可靶向DDR1-Src/STAT3DDR1→JAK2→STAT3促进增殖、存活、分化激酶抑制剂可靶向DDR1-胶原排列-T细胞排斥DDR1-ECD结合胶原→强制纤维排列→物理屏障免疫逃逸（核心）仅抗体可靶向（需要ECD中和）DDR1-TGF-β/整合素协同DDR1+整合素→协同胶原信号→N-cadherin上调增强纤维化可能需要联合策略DDR1-NF-κBDDR1→IKK→NF-κB炎症/促存活信号激酶抑制剂可靶向3.3 DDR1与整合素的协同效应（重要警示） DDR1与整合素（特别是αv亚基丰富的整合素）在胶原介导的信号中存在协同作用。阻断整合素-TGF-β1与DDR1的协同信号可能影响单一DDR1靶向策略的疗效，提示联合靶向DDR1 + 整合素或DDR1 + TGF-β可能具有协同增效潜力。4. 疾病关联全景4.1 肿瘤领域癌种DDR1表达变化致病机制临床相关性参考文献三阴性乳腺癌(TNBC)↑ 上调DDR1→胶原排列→T细胞排斥高表达=不良预后+免疫治疗抵抗Nature, 2021 (Chen/Joyce)非小细胞肺癌(NSCLC)↑ 上调DDR1→免疫排斥高表达=不良预后+PD-L1阴性伴免疫排斥ASCO 2026 (PRTH-101)胸腺上皮癌(TEC)↑ 上调DDR1→免疫排斥免疫治疗效果有限ASCO 2026 (PRTH-101)乳腺癌浸润性导管癌↑ 上调DDR1+DDR2升高与TNM分期和淋巴结转移显著相关—卵巢癌↑ 上调———食管癌↑ 上调———胰腺癌(PDAC)↑ 上调胶原驱动的免疫抵抗—MDPI IJMS, 2025脑癌/胶质瘤↑ 上调———结直肠癌(CRC)异常表达———4.2 纤维化疾病疾病DDR1角色关键证据治疗策略肾纤维化正向驱动因子DDR1-KO小鼠高血压肾病纤维化显著减轻；DDR1通过BCR/STAT3促进肾脏炎症和纤维化DDR1抑制剂可减轻纤维化肺纤维化(IPF)正向驱动因子DDR1在IPF中表达升高；DDR1-KO小鼠肺胶原沉积减少DDR1抑制剂可能延缓疾病进展肝纤维化正向驱动因子DDR1过表达促进肝星状细胞活化和胶原产生—Alport综合征正向驱动因子DNA编码文库来源DDR1抑制剂可防止小鼠模型纤维化和肾功能丧失DDR1抑制剂显示临床前疗效4.3 神经系统疾病疾病DDR1角色关键发现阿尔茨海默病(AD)潜在驱动因子尼洛替尼（含DDR1抑制活性）可改变CSF miRNAs、减少炎症和血管纤维化帕金森病DDR1抑制→神经保护DDR1抑制可减轻神经病理和炎症自闭症DDR1基因变异关联—精神分裂症(SCZ)DDR1基因变异关联—双相情感障碍(BPD)DDR1基因变异关联—4.4 其他疾病疾病DDR1角色动脉粥样硬化DDR1抑制显示潜在治疗效果干眼综合征AVI-4015（DDR1抑制剂）特异性开发适应症多发性硬化症DDR1与疾病进展相关骨关节炎DDR1与疾病进展相关5. DDR1的免疫排斥机制——转化医学里程碑 2021年Nature论文（Sun et al., 2021）是DDR1靶点走向转化医学的分水岭，它揭示了DDR1通过一种不依赖激酶活性的全新机制推动肿瘤免疫排斥，彻底改变了DDR1药物开发的策略重心——从激酶抑制转向胞外域阻断。5.1 核心发现 DDR1驱动的免疫排斥机制肿瘤细胞表面 DDR1-ECD │ │ 结合胶原蛋白 ▼ 胶原纤维强制排列对齐（通过DDR1-ECD，不依赖激酶域！） │ │ SHG显微镜可定量检测纤维排列对齐度 ▼ 形成物理屏障 → 阻碍CD8⁺ T细胞瘤内浸润 │ ▼ T细胞被排斥在肿瘤边缘 → 免疫逃逸 │ ▼ 肿瘤无限制生长 → 免疫治疗（抗PD-1/PD-L1）无效5.2 关键实验证据实验发现细节意义激酶域非必需删除激酶域(ΔKD)的DDR1仍能完全挽救Ddr1-KO肿瘤生长颠覆了"靶向激酶即可"的战略ECD即可驱动仅表达胞外域(ECD)即可实现免疫排斥ECD是充分必要条件可溶性Fc-ECD足够膜不拴 tethered的游离DDR1-ECD即可挽救肿瘤生长提示ECD-collagen互作是核心胶原结合位点必需W54A突变（胶原结合位点突变）无法挽救验证了ECD-胶原结合是关键CD8⁺ T细胞依赖清除CD8⁺ T细胞后Ddr1-KO优势消失证实免疫系统依赖性免疫记忆建立Ddr1-KO肿瘤消退小鼠→再挑战无肿瘤生长持久免疫记忆形成5.3 对抗体开发的启示这一发现直接解释了为何单纯的DDR1激酶抑制剂（小分子）可能不足以解决免疫排斥问题——因为DDR1的免疫排斥功能通过ECD-胶原相互作用实现，不依赖激酶活性。因此，靶向DDR1-ECD的单克隆抗体（如PRTH-101）成为逆转免疫排斥的首选策略。5.4 人类TNBC验证数据库/队列发现TCGA TNBC (n=162)DDR1 mRNA ↔ GZMB/IFNG/PRF1 显著负相关CPTAC 蛋白组DDR1蛋白 ↔ 细胞溶解通路负相关TNBC 患者队列 (n=12)CD8⁺ T细胞% ↔ DDR1⁺ 肿瘤细胞% 负相关Kaplan-Meier PlotterDDR1高表达 ↔ 较短OS6. 药物研发管线——全景图谱6.1 管线总览截至2026年7月，全球共有至少6家机构积极推进DDR1靶向药物开发，涵盖抗体、多靶点小分子、选择性抑制剂和降解剂四种模式。药物/候选物开发机构模式类型靶点选择性最高阶段核心适应症最新动态PRTH-101Incendia Therapeutics (原Parthenon)人源化IgG1单抗DDR1高选择性（胞外域结合）Phase 1TEC、NSCLCASCO 2026公布阳性I期数据AVI-4015Avixgen（韩国）小分子抑制剂多靶点（主DDR1）Phase 2干眼综合征韩国I期完成ICP-033诺诚健华(InnoCare)小分子抑制剂（口服）多靶点（DDR1/2/VEGFR2/3/PDGFRα/β）Phase 1晚期实体瘤NCT05367232进行中LLC-355英矽智能→中科院上海有机所PROTAC降解剂DDR1选择性降解临床前肿瘤AI驱动发现（GENTRL）Redx DDRRedx Pharma（英国）小分子抑制剂DDR选择性临床前纤维化口服、选择性DDR抑制剂尼洛替尼(Nilotinib)诺华（已上市）多靶点TKI（BCR-ABL为主）非选择性（含DDR1/2）已上市CMLDDR1不作为主要靶点6.2 按治疗模式分类模式类型代表药物优势劣势抗体（ECD结合）PRTH-101✅可阻断DDR1-胶原免疫排斥功能✅高选择性✅Fc效应功能❌静脉给药❌生产成本高多靶点小分子ICP-033、AVI-4015✅口服便利✅多通路同时靶向✅成本低❌选择性不足❌可能仅抑制激酶依赖功能❌脱靶毒性选择性小分子Redx DDR✅口服✅可能更好的安全窗❌仅抑制激酶依赖功能❌可能无法解决免疫排斥PROTAC/降解剂LLC-355✅彻底消除蛋白功能✅可能克服激酶非依赖性信号❌口服生物利用度挑战❌E3连接酶组织特异性❌临床前阶段已上市TKI再利用尼洛替尼、达沙替尼✅安全性数据成熟✅口服✅可直接进入II期❌DDR1非主要靶点❌脱靶效应严重7. 关键临床数据详解7.1 PRTH-101 — ASCO 2026 I期数据（最新）⭐项目详情试验编号NCT05753722试验设计开放标签、剂量递增+扩展、单药+联合Pembrolizumab剂量范围8–1600 mg，Q3W，IVRP2D1200 mg Q3W入组人数72例（截至ASCO 2026）DLT无剂量限制性毒性既往治疗多数患者多线治疗失败，包括免疫治疗疗效数据——按癌种癌种最佳缓解细节TEC2例PR1例PR(RECIST)—1200 mg+联合Pembrolizumab（PD-L1阴性）1例PR(mRECIST)—1600 mg单药TEC SD率72%全部TEC患者TEC mPFS5.7个月（全部）8个月（接受>1周期）—NSCLC1例PRPD-L1阴性肿瘤，1200 mg 单药（Pembrolizumab首剂不耐受后）NSCLC SD1例SD >15个月PD-L1阳性肿瘤，24→80 mg 单药DDR1生物标志物分析发现意义所有检测肿瘤均表达DDR1DDR1在TEC和NSCLC中广泛表达DDR1高表达(≥25百分位)患者PFS显著更长首个临床证据验证DDR1作为预测性生物标志物MRI显示肿瘤空洞化和血管减少与DDR1阻断后ECM/血管重塑一致 🔬 关键解读：PRTH-101在多重治疗失败（含免疫治疗）的晚期TEC和NSCLC患者中展示了明确的单药活性和联合活性信号，特别是在PD-L1阴性肿瘤中——这是免疫治疗几乎无效的人群。DDR1表达水平与PFS的正相关性为DDR1作为伴随诊断标志物提供了有力证据。7.2 ICP-033 — Phase 1项目详情试验编号NCT05367232开发机构诺诚健华(InnoCare Pharma)药物类型口服小分子多靶点抑制剂靶点DDR1/2 + VEGFR2/3 + PDGFRα/β适应症晚期实体瘤试验设计剂量探索、安全性与PK、初步抗肿瘤活性当前状态I期进行中（2024年2月更新） 📝 注：ICP-033为多靶点抑制剂，靶向谱广，可能通过同时阻断血管生成（VEGFR/PDGFR）和DDR1通路发挥抗肿瘤作用。目前临床数据尚未公开披露。7.3 AVI-4015 — Phase 1/2项目详情开发机构Avixgen（韩国）当前阶段Phase 2（全球最高）适应症干眼综合征给药方式眼用制剂（局部给药）特点不仅减轻角膜炎症，还治疗炎症引起的角膜损伤韩国I期已完成（首尔大学盆唐医院、首尔大学医院） 📝 注：AVI-4015是目前DDR1管线中研发阶段最高的药物（Phase 2），但适应症为干眼综合征（而非肿瘤），采用局部给药，规避了系统性DDR1靶向的安全性顾虑。7.4 尼洛替尼的DDR1相关性（历史数据）发现来源尼洛替尼、伊马替尼、达沙替尼均可抑制DDR1/2Day et al., Eur J Pharmacol, 2008尼洛替尼抑制DDR1→改变CSF miRNAs→减少AD炎症和血管纤维化多项AD临床探索性研究尼洛替尼对DDR1的IC₅₀约为40 nM— ⚠️ 注意：上述TKI并非选择性DDR1抑制剂，其临床疗效不能直接归因于DDR1抑制。但因安全性数据充分，可作为DDR1抑制剂概念验证（POC）的参考基准。8. 成药性综合评估8.1 成药性维度评分评估维度评分(1-5)评语靶点验证★★★★★基因敲除、抗体逆转、Nature机制阐明——多层次验证结构成药性★★★★☆RTK家族，激酶域有成熟靶向范式（ATP竞争性抑制）选择性挑战★★☆☆☆DDR1 vs DDR2及与其他RTK的选择性是主要瓶颈生物标志物★★★★★DDR1 IHC表达与疗效正相关（PRTH-101 ASCO 2026证实）未满足临床需求★★★★★PD-L1阴性NSCLC/TEC高度未满足；IPF/肾纤维化无治愈方案临床POC★★★★☆PRTH-101已展示I期POC信号（PR+SD+mPFS 5.7-8月）适应症清晰度★★★★☆TEC/NSCLC（肿瘤免疫）+ 纤维化（抗纤维化）双路径竞争壁垒★★★★☆ECD抗体策略（免疫排斥）vs 小分子抑制剂（激酶活性）差异化明确安全性信号★★★★☆PRTH-101 72例无DLT；AVI-4015眼用安全；激酶抑制剂需注意脱靶工业界关注度★★★☆☆多家公司布局但均为中小型biotech，大型药企参与有限综合成药性评级：A-（临床POC初现阶段）DDR1是当前RTK靶点中验证最充分、但选择性挑战最突出的靶点之一。PRTH-101的ASCO 2026数据提供了关键临床POC信号。首推PRTH-101的抗体策略（解决激酶非依赖性免疫排斥），其次关注纤维化领域的小分子抑制剂。8.2 靶向DDR1的三大战略选择战略药物形式解决的问题无法解决的问题代表ECD阻断单克隆抗体胶原排列→免疫排斥（激酶非依赖性）激酶依赖的增殖/EMT信号PRTH-101激酶抑制小分子TKI增殖/EMT/STAT3信号（激酶依赖性）胶原排列→免疫排斥Redx, ICP-033蛋白降解PROTAC彻底移除DDR1所有功能口服PK、组织选择性LLC-355 🎯 最佳策略可能是"ECD抗体 + 小分子抑制剂"联合，同时阻断胶原排列（免疫排斥）和激酶信号（增殖/侵袭）。9. 竞争格局分析9.1 竞争格局总览 DDR1靶向药物竞争态势（按阶段排列） Phase 2 ▓▓▓▓▓▓▓▓▓▓▓▓▓▓▓▓ AVI-4015 (Avixgen, 干眼综合征) Phase 1 ▓▓▓▓▓▓▓▓▓▓▓▓▓▓▓▓ PRTH-101 (Incendia, TEC/NSCLC) ⭐最佳数据 ▓▓▓▓▓▓▓▓▓▓▓▓▓▓▓▓ ICP-033 (诺诚健华, 实体瘤) 临床前 ▓▓▓▓▓▓▓▓▓▓▓▓▓▓▓▓ LLC-355 (中科院上海有机所, 肿瘤) ▓▓▓▓▓▓▓▓▓▓▓▓▓▓▓▓ Redx DDR (Redx Pharma, 纤维化) 已上市 ▓▓▓▓▓▓▓▓▓▓▓▓▓▓▓▓ 尼洛替尼/达沙替尼 (诺华/BMS, 非选择性)9.2 主要竞争者深度对比维度PRTH-101ICP-033AVI-4015LLC-355Redx DDR公司Incendia Therapeutics诺诚健华Avixgen中科院上海有机所Redx Pharma国家美国中国韩国中国英国药物类型IgG1单抗多靶点小分子小分子PROTAC小分子靶点选择性高(DDR1)低(6靶点)中(主DDR1)高(DDR1)中(DDR)给药途径IV口服局部(眼)—口服免疫排斥阻断✅ 可❌ 理论不可❌ 理论不可✅ 可❌ 理论不可临床数据成熟度⭐⭐⭐⭐⭐⭐⭐——差异化优势仅有的ECD靶向策略中国biotech低价优势非肿瘤赛道AI+PROTAC双概念纤维化专注关键风险单药疗效待扩大样本验证选择性不足、数据未公开市场较小PROTAC口服PK挑战仅抑制激酶依赖性功能9.3 竞争壁垒评估壁垒类型高度评语专利壁垒中等ECD抗体专利由Incendia布局，但小分子抑制剂领域竞争空间仍大技术壁垒高ECD抗体开发技术门槛高；高选择性DDR1小分子vs DDR2区分难度大数据壁垒中等PRTH-101拥有最多的临床数据，但后续竞争者可通过差异化适应症追赶适应症壁垒低TEC/NSCLC/纤维化等多个适应症均可切入，市场空间充裕10. 关键研究里程碑时间线 2000前 │ DDR1首次被克隆和鉴定为胶原激活的RTK │2008 │ Day et al.: 伊马替尼/尼洛替尼/达沙替尼可抑制DDR1/2 │ ——首次发现已上市药物具有DDR1抑制活性 │2011- │ 系列研究验证DDR1在肾/肺/肝纤维化中的关键驱动作用2015 │ │2019 │ Richter et al. (ACS Chem Biol): DNA编码文库发现DDR1抑制剂 │ ——可防止Alport综合征小鼠模型纤维化和肾功能丧失 │2020 │ 英矽智能GENTRL平台：AI仅用21天发现DDR1激酶抑制剂 │ ——AI药物发现领域的标志性案例 │2021.11 │ **Nature 里程碑**: Sun, Chen, Joyce et al. │ DDR1-ECD→胶原排列→免疫排斥（激酶非依赖性） │ ——彻底改变DDR1药物开发策略重心 │2022 │ Frontiers Oncol: DDR1在肿瘤休眠、免疫排斥 │ 和基质胶原沉积驱动的治疗耐药中的新功能综述 │2023 │ PRTH-101 I期FIH试验启动(NCT05753722) │ ICP-033 I期启动(NCT05367232) │2024.05 │ Drug Discovery Today综述: DDR1靶向治疗的 │ 当前局限与未来潜力（中国药科大学） │2025 │ MDPI IJMS: DDR1驱动胶原重塑与免疫排斥——泛癌分析 │2026.05 │ **ASCO 2026**: PRTH-101 I期阳性数据 │ ——TEC mPFS 5.7-8月、NSCLC PR+长期SD │ ——首个临床验证DDR1表达作为预测性生物标志物 │ ——PD-L1阴性肿瘤中展示活性11. 投资视角评估11.1 靶点成熟度评估（基于医药投资框架）评估维度评级说明生物学验证⭐⭐⭐⭐⭐Nature级机制阐明+基因敲除+抗体逆转+人类TNBC验证临床POC⭐⭐⭐⭐PRTH-101 I期展示明确信号（DLT=0、PR、mPFS 5.7-8月）未满足临床需求⭐⭐⭐⭐⭐PD-L1阴性NSCLC（免疫治疗抵抗）、IPF（无治愈）竞争强度⭐⭐ (低)仅3家进入临床，无大型药企入局技术可行性⭐⭐⭐⭐RTK家族靶向范式成熟、抗体开发路径清晰市场潜力⭐⭐⭐⭐NSCLC全球市场>300亿美元、TEC孤儿药潜力、纤维化市场>百亿美元专利可建性⭐⭐⭐⭐ECD抗体策略专利空间充裕临床开发确定性⭐⭐⭐需II期随机数据验证；生物标志物策略降低风险退出门槛⭐⭐尚无大型药企M&A先例11.2 关键催化事件与时间线 2026 Q3-Q4 │ PRTH-101 I期完整数据发表、II期启动 │ 催化剂：若能获FDA突破性疗法认定(BTD) │2027 │ PRTH-101 + Pembrolizumab 联合扩展队列数据 │ 催化剂：NSCLC PD-L1阴性人群的ORR/PFS │ ICP-033 I期数据可能披露 │2028 │ PRTH-101 潜在关键性II期启动 │ 催化剂：若II期ORR>20%且PFS>6月，估值飞跃 │ M&A/合作事件：大型药企开始关注DDR1 │2029-2030 │ PRTH-101 可能提交BLA（视加速审批路径） │ Redx DDR、LLC-355可能进入I期11.3 风险提示风险类型具体风险严重程度缓解因子科学风险DDR1激酶非依赖性功能使小分子抑制剂可能疗效不足🟡 中PRTH-101（抗体）已验证ECD阻断路径临床风险I期小样本数据可能无法在II期大规模验证中复制🟡 中生物标志物（DDR1 IHC）分层策略降低风险选择性风险多靶点抑制剂（ICP-033）脱靶毒性🟡 中PRTH-101为高选择性抗体竞争风险PD-1/PD-L1联合策略赛道拥挤🟢 低DDR1靶向独特——针对PD-L1阴性/免疫排斥人群市场风险TEC为罕见肿瘤，市场天花板低🟡 中NSCLC扩展+纤维化适应症提供上行空间M&A风险大型药企对DDR1关注度有限🟡 中PRTH-101阳性数据可能触发M&A兴趣生物标志物风险DDR1 IHC检测需标准化和监管批准🟢 低伴随诊断开发路径成熟11.4 估值参考框架对标资产阶段适应症交易/估值参考意义PRTH-101Phase 1TEC/NSCLC私募可比：I期免疫肿瘤biotech估值 $200-500MICP-033Phase 1实体瘤诺诚健华公开多靶点→较低溢价AVI-4015Phase 2干眼韩国非肿瘤→不同估值逻辑若PRTH-101在TEC或NSCLC中推进至关键性II期且数据积极，参照同类免疫肿瘤biotech资产，潜在估值区间可望达到$500M–1.5B（视适应症大小和数据强度）。纤维化适应症（IPF/肾纤维化）的成功可进一步大幅扩展估值天花板。12. 核心结论与建议12.1 DDR1靶点核心画像 DDR1是继PD-1/PD-L1之后，最有潜力解决"免疫排斥型"肿瘤的靶点之一。其独特的胶原感应器功能和激酶非依赖性免疫排斥机制，使其在现有免疫肿瘤靶点中具有明确的差异化定位。2021年Nature机制阐明+2026年ASCO I期阳性数据，构成了从基础生物学到临床POC的完整证据链。12.2 投资/研发建议——分层优先级优先级策略理由🥇 优先级1密切跟踪PRTH-101的II期开发ECD抗体策略唯一解决免疫排斥；ASCO 2026数据强劲；PD-L1阴性人群差异化定位清晰；DDR1生物标志物已初步验证🥈 优先级2关注DDR1小分子抑制剂在纤维化中的机会Redx DDR（IPF/肾纤维化）若获POC，市场空间极大；AVI-4015（干眼症）验证了非肿瘤赛道的可行性🥉 优先级3评估PROTAC降解剂策略LLC-355为AI+PROTAC双重概念；中科院背景；但技术成熟度和临床转化仍需验证远期选项布局DDR1+整合素/TGF-β联合策略DDR1-整合素协同作用提示联合靶向可能增效；但需更多机制研究支持12.3 DDR1 vs 其他免疫肿瘤靶点的差异化定位靶点机制适用人群与DDR1差异PD-1/PD-L1解除T细胞抑制信号PD-L1阳性肿瘤DDR1解决PD-L1阴性/免疫排斥型CTLA-4增强T细胞priming与PD-1联合DDR1解决的是物理屏障而非检查点TGF-β调控免疫抑制微环境多种肿瘤DDR1更特异性作用于胶原-免疫轴DDR1打破胶原物理屏障→T细胞浸润DDR1过表达+免疫排斥型唯一靶向ECM-免疫物理屏障的靶点12.4 关键监测节点时间事件重要性2026年下半年PRTH-101 II期启动（预计TEC或NSCLC）🔴 最高2027年PRTH-101联合Pembrolizumab扩展队列数据🔴 最高2027年ICP-033 I期数据可能披露🟡 中等2027-2028年PRTH-101 II期中期数据🔴 最高2028年Redx DDR可能进入I期🟡 中等持续大型药企对DDR1领域的M&A动向🟡 中等附录A：DDR1 vs DRR1 快速区分属性DDR1DRR1 (FAM107A)全称Discoidin Domain Receptor 1Down-Regulated in Renal Cell Carcinoma 1蛋白类型受体酪氨酸激酶(RTK)肌动蛋白结合蛋白配体胶原蛋白F-actin亚细胞定位细胞膜应力纤维/核斑点/细胞质药物管线3个临床阶段 + 多个临床前零临床项目成药性A-（临床POC初步验证）C+（早期探索）核心机制胶原感应→免疫排斥/纤维化肌动蛋白调控→NF-κB/EMT代表药物PRTH-101 (Phase 1)CFI-402257 (间接靶向TTK)附录B：数据来源明细来源URL/ID数据用途Nature (2021)s41586-021-04057-2DDR1-免疫排斥核心机制Drug Discovery Today (2024)S1359644624001004DDR1靶向治疗综述ASCO 2026JCO.2026.44.16_suppl.e20510PRTH-101 I期临床数据ClinicalTrials.govNCT05753722PRTH-101试验详情ClinicalTrials.govNCT05367232ICP-033试验详情智慧芽新药情报库DDR1LLC-355研发详情医药魔方NextPharmaICP-033ICP-033靶点与阶段Avixgen官网avixgen.comAVI-4015管线信息Redx Pharmaredxpharma.comDDR抑制剂管线MDPI IJMS (2025)26/16/7731DDR1泛癌免疫排斥分析免责声明：本报告基于公开学术文献和数据库信息

2024-02-20

·BioSpace

Treadwell Announces Ocifisertib, a First-in-Class PLK4 Inhibitor, has Received Orphan Designation from U.S. FDA for the Treatment of Acute Myeloid Leukemia

With a Focus on Potential Pivotal Studies in 2025, Treadwell has Strengthened its Leadership Team by Appointing Brenda Marczi, PharmD, MBA as SVP and Head of Regulatory Affairs TORONTO & SAN FRANCISCO--(BUSINESS WIRE)-- Treadwell Therapeutics, a privately held clinical-stage biotechnology company pioneering and advancing novel first-in-class medicines for unmet needs in cancer, today announced the U.S. Food and Drug Administration (FDA) has granted orphan drug designation to ocifisertib (CFI-400945), a first-in-class, investigational PLK4 inhibitor for the treatment of acute myeloid leukemia (AML). Ocifisertib is currently being evaluated in a Phase 1b/2 study in adults with relapsed/refractory AML following standard of care therapy. Orphan drug designation is granted by the FDA to drugs intended for treatment, prevention or diagnosis of a rare disease or condition that affects fewer than 200,000 people in the U.S. at the time of designation. Under the FDA’s Orphan Drug Act, orphan drug status provides incentives, grants, tax credits and waiver of certain administrative fees as well as seven years of market exclusivity following marketing authorization. Treadwell also announced today the appointment of Brenda Marczi, as SVP and Head of Regulatory Affairs. Brenda comes to Treadwell with over 30 years of regulatory experience in the pharmaceutical and biotechnology industries. She most recently served as Senior Vice President, Regulatory Affairs at Tracon Pharmaceuticals, Inc., where she oversaw their regulatory function and led all of their strategies and filing activities in the US and UK. Brenda holds a Master of Science in Pharmaceutical Sciences from Rutgers University, a PharmD from the University of Maryland, and an MBA from Wharton, University of Pennsylvania. “The FDA’s decision to grant orphan drug designation, along with the previous FDA Fast Track designation for ocifisertib underscores Treadwell’s dedication to addressing this patient population with few treatment options. Patients with relapsed and/or refractory AML, in particular TP53 mutated disease suffer poor overall survival and represents a high unmet clinical need,” said Roger Sidhu, M.D., Acting CEO of Treadwell. “We look forward to advancing ocifisertib in partnership with investigators, regulators, patients and their families for those with limited treatment options in tough to treat AML. In addition, we are thrilled to have Brenda join us to lead Regulatory Affairs at Treadwell. She is a seasoned strategic leader with a broad experience in leading regulatory strategy from early development through approval. Her leadership will be invaluable to Treadwell as we advance ocifisertib into potentially pivotal studies in 2025.” About Treadwell Therapeutics Treadwell Therapeutics is a clinical-stage oncology company developing novel medicines to address unmet needs in patients with cancer. The Company's robust, internally developed clinical pipeline includes ocifisertib (PLK4 inhibitor), CFI-402257 (TTK/Mps1 inhibitor) and CFI-402411 (HPK1 inhibitor). Treadwell also has a broad pre-clinical pipeline with multiple biologic and next generation TCR based autologous cell therapy programs. For more information, please visit .

孤儿药快速通道

2023-12-15

·BioSpace

Treadwell Therapeutics Announces a Presentation at the 2023 ASH Annual Meeting and Advisory Board Meeting

TORONTO and SAN MATEO, Calif., Dec. 15, 2023 (GLOBE NEWSWIRE) -- Treadwell Therapeutics, a clinical-stage biotechnology company developing novel first-in-class medicines for unmet needs in cancer, today announced a presentation for the Company's lead program, CFI-400945, a first-in-class inhibitor of Polo-like Kinase 4 (PLK4) being advanced in relapsed/refractory AML, at the 65th American Society of Hematology (ASH) Annual Meeting and Exposition being held from December 9-12, 2023. Treadwell also conducted a clinical advisory board meeting on December 10th at ASH with experienced experts in the treatment of AML and in clinical trials of novel agents, which included current investigators and thought leaders new to the program. "CFI-400945 is demonstrating complete remissions as a single agent and in combination with azacitadine in relapsed, adverse risk AML, including those with TP53 mutant disease. As we optimize dose and schedule, we are encouraged by the data with this oral dosing regimen," said Principal Investigator and Advisory Board Co-Chair Dr. Gautam Borthakur, MD, Professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center. “The advisory board confirmed the enthusiasm about the data to date in the relapsed AML setting, in particular with TP53 mutant disease and look forward to working with Treadwell to advance and shape this program.” "CFI-400945, our lead program and first-in-class PLK4 inhibitor, represents an opportunity to address a substantial unmet in relapsed/refractory AML, including TP53 mutant AML," said Roger Sidhu, MD, Acting CEO at Treadwell Therapeutics. “We look forward to advancing the program into key dose expansion studies in monotherapy and in combination in 2024 with a view to initiating pivotal studies in 2025.” 2023 ASH Poster Presentations and Details: Title: Preliminary Results from a Phase 1b/2 Open-Label, Multicenter, Dose Optimization Clinical Study of the Safety, Tolerability, and Pharmacokinetic (PK) and Pharmacodynamic (PD) Profiles of CFI-400945 As a Single Agent or in Combination with Azacitidine in Patients (Pts) with Acute Myeloid Leukemia, Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia (TWT-202) Session Name: 616. Acute Myeloid Leukemias: Investigational Therapies, Excluding Transplantation and Cellular Immunotherapies: Poster III Publication Number: 4294 Session Date: Monday, December 11, 2023 Presentation Time: 6:00 PM - 8:00 PM Location: San Diego Convention Center, Halls G-H CFI-400945 has been generally well tolerated in this difficult to treat patient population, including patients whose disease has progressed on or following venetoclax based therapies. Three of 6 evaluable patients with AML achieved a response (MLFS=2, CRi=1 with MRD+) at the 96mg dose. After this data cut, one additional MLFS response (end of cycle 1) and two additional CRs (end of cycle 2) were seen in two patients treated with 80 mg + azacitidine combination cohort and became transplant eligible (PI communication). PK characteristics support daily dosing of CFI-400945 and PD studies are ongoing. Dose expansions are planned and enrollment continues. About Treadwell Therapeutics Treadwell Therapeutics is a clinical-stage oncology company developing novel medicines to address unmet needs in patients with cancer. The Company's robust, internally developed clinical pipeline includes CFI-400945 (PLK4 inhibitor), CFI-402257 (TTK/Mps1 inhibitor) and CFI-402411 (HPK1 inhibitor). Treadwell also has a broad pre-clinical pipeline with multiple biologic and next generation TCR based autologous cell therapy programs. For more information, please visit Contact ir@treadwelltx.com

临床结果ASH会议细胞疗法免疫疗法AACR会议

100 项与 CFI-402257 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
晚期恶性实体瘤	临床2期	美国	Treadwell Therapeutics, Inc.	2022-05-27
ER阳性/HER2阴性乳腺癌	临床2期	美国	Treadwell Therapeutics, Inc.	2022-05-27
乳腺癌	临床2期	-	University Health Network	-
急性髓性白血病	药物发现	加拿大	Treadwell Therapeutics Canada, Inc.	2024-12-07
急性髓性白血病	药物发现	中国香港	香港大学	2024-12-07

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临床结果

适应症

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT03568422 (CTgov)	临床1/2期	HER2 阴性乳腺癌	37	Paclitaxel+CFI-402257	壓壓網齋願觸構鑰醖壓 = 遞壓構鹽醖夢廠衊遞簾艱製鑰齋壓築襯築鏇壓 (蓋築艱顧遞鬱襯鑰憲鑰, 鹽顧壓鑰鹽選遞遞夢簾 ~ 醖醖顧膚廠淵鹽艱積繭)	-	2024-06-26
SABCS2023	临床1期	HER2 阴性乳腺癌 HER2-negative	37	CFI-402257	廠遞鏇鹹膚膚積觸築憲(淵窪網築壓廠淵膚憲繭) = Frequent AEs (>5%; all dose levels) considered at least possibly related to treatment were: alopecia (11%) 繭顧鬱顧膚壓鹽糧艱艱 (築繭積積憲夢鏇壓醖壓 ) 更多	积极	2023-03-01
				Paclitaxel
SABCS2023	临床1期	HER2 阴性乳腺癌 ER+ \| TNBC \| RB1 loss	87	CFI-402257 monotherapy	衊壓鑰觸製築構願窪鑰(遞壓襯壓簾齋糧構廠壓) = 蓋襯壓餘鹽遞製構簾範糧願遞壓衊艱廠選獵鑰 (窪築餘鹽糧窪膚積獵範 ) 更多	积极	2023-03-01
				CFI-402257 in combination with Fulvestrant	願襯淵夢齋夢獵淵簾網(獵積顧鑰艱壓繭齋夢獵) = 鬱襯壓製繭艱網艱憲憲鏇夢蓋觸蓋構膚鏇鹹襯 (鹽鹽遞願選壓鹹遞壓範 )
NCT05251714 (TWT-203, ASCO2022)	临床1/2期	HR阳性/HER2低表达实体瘤 \| ER阳性/HER2阴性乳腺癌	-	CFI-402257 monotherapy	艱網遞餘網壓網齋鏇範(鹽衊餘艱積願鹹夢壓窪) = Safety endpoints include incidence of treatment emergent adverse events 膚艱獵襯遞憲觸糧顧積 (構網觸蓋鑰窪窪構築憲 )	-	2022-06-02
P1-18-17 (SABCS2022)	临床1期	晚期乳腺癌 ER+ \| HER2- \| TNBC ... 更多	66	CFI-402257 5mg	鏇糧鬱壓顧艱顧膚選壓(觸醖鬱窪鏇製繭遞蓋衊) = 夢壓鹹齋夢範襯築鑰醖醖顧艱繭膚構築憲艱憲 (遞鑰膚襯範鑰夢廠願願 ) 更多	积极	2022-02-15
				CFI-402257 168mg	選簾簾鏇膚鹹獵廠簾鏇(艱觸鏇遞夢簾鏇夢壓選) = 醖積鏇鬱範鹹簾醖願醖夢範鑰鏇鏇窪蓋艱鏇夢 (遞選餘膚壓構壓觸鏇鑰 ) 更多