A Phase II, Open-label, Multi-center, Basket Study of the ATR Kinase Inhibitor ART0380 Administered Orally as Monotherapy to Patients With Biologically Selected Advanced or Metastatic Solid Tumors (ARTIST)

This interventional study will evaluate the efficacy and safety of ART0380 as monotherapy in patients whose tumors have a biology to predict for sensitivity to inhibition of Ataxia-Telangiectasia Mutated and Rad3-related protein kinase (ATR).

开始日期2023-09-06

申办/合作机构

Artios Pharma Ltd.

NCT04657068

/ Recruiting临床1/2期

A Phase I/IIa, Open-label, Multi-center Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of the ATR Kinase Inhibitor ART0380 Administered Orally as Monotherapy and in Combination to Patients With Advanced or Metastatic Solid Tumors

This clinical trial is evaluating a drug called ART0380 in participants with advanced or metastatic solid tumors. The main goals of this study are to:
* Find the recommended dose of ART0380 that can be given safely to participants alone and in combination with gemcitabine or irinotecan
* Learn more about the side effects of ART0380 alone and in combination with gemcitabine or irinotecan
* Learn more about the effectiveness of ART0380 alone and in combination with gemcitabine or irinotecan

开始日期2021-01-27

申办/合作机构

Artios Pharma Ltd.

100 项与 Alnodesertib 相关的临床结果

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100 项与 Alnodesertib 相关的转化医学

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100 项与 Alnodesertib 相关的专利（医药）

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项与 Alnodesertib 相关的文献（医药）

2026-03-19·Future Medicinal Chemistry

Recent advances in small molecule ATR kinase inhibitors as anticancer agents

Review

作者: Singh, Gurpreet ; Gautam, Vinod ; Hsu, Sung-Po ; Sharma, Ram ; Dhingra, Ashwani Kumar ; Nepali, Kunal

Ataxia telangiectasia and Rad3-related (ATR) kinase is a crucial regulator of the DNA damage response, supporting replication fork stability, enforcing cell-cycle checkpoints, and coordinating repair mechanisms. Tumor cells, which often experience oncogene-induced replication stress, rely more heavily on ATR signaling, presenting a potential therapeutic target for anticancer drug discovery and development. Over the last decade, intensive medicinal chemistry efforts have generated a broad pipeline of ATR inhibitors, including ceralasertib, elimusertib, camonsertib, berzosertib, ART0380, and gartisertib, many of which are in Phase I/II clinical trials. These compounds effectively disrupt checkpoints, induce replication catastrophe, and work synergistically with PARP inhibitors, topoisomerase poisons, platinum-based chemotherapies, radiotherapy, and immunotherapy. Although promising, challenges such as hematologic toxicities and resistance mechanisms persist. Future research aims to improve patient selection through biomarkers like replication-stress signatures, RAD51 foci tests, and liquid biopsy DNA damage markers; develop advanced modalities including brain-penetrant scaffolds, PROTAC degraders, and dual ATR/PARP or ATR/HDAC inhibitors; and optimize intermittent dosing to expand therapeutic windows. Incorporating these strategies into adaptive platform trials with pharmacodynamic markers and patient-centered outcomes will speed up translation. Overall, ATR inhibitors highlight progress in DNA damage response therapies, from understanding mechanisms to biomarker-driven clinical use, with the potential to revolutionize treatment across various cancers.

2025-05-07·Journal of the American Chemical Society

Ruthenium-Catalyzed Enantioselective Alkylation of Sulfenamides: A General Approach for the Synthesis of Drug Relevant S-Methyl and S-Cyclopropyl Sulfoximines

Article

作者: Boyer, Zachary W. ; Ellman, Jonathan A. ; Kwon, Na Yeon

Sulfoximines are increasingly utilized in pharmaceuticals and agrochemicals with all sulfoximine clinical candidates incorporating either an S-methyl or an S-cyclopropyl substituent. Here, we report on a general and efficient sequence for the asymmetric synthesis of both of these sulfoximine substitution patterns. The asymmetric synthesis of sulfilimine intermediates by the first Ru-catalyzed enantioselective alkylation of sulfenamides enables the first examples of enantioselective S-alkylation with monosubstituted diazo compounds. The reaction proceeds at ≤1 mol % Ru-catalyst loading, and for tert-butyl diazoacetate, high yields and ≥98:2 er are achieved for an exceedingly broad range of sulfenamides, including with S-(hetero)aryl, -alkenyl, -methyl, -benzyl, -branched alkyl, and -tert-butyl substituents and for sterically and electronically diverse N-acyl groups. Sulfenamides derived from densely functionalized advanced drug intermediates also alkylated with 99:1 er. After oxidation of an N-pivaloyl S-tert-butyl acetate substituted sulfilimine to the corresponding sulfoximine, treatment with trifluoracetic acid in an aprotic solvent resulted in decarboxylation to the S-methyl N-pivaloyl sulfoximine, while aqueous HCl resulted in both decarboxylation and cleavage of the N-acyl group to give the S-methyl NH sulfoximine. Alternatively, sulfoximine alkylation with dibromoethane followed by acid-mediated decarboxylation provided the S-cyclopropyl sulfoximine. The efficient asymmetric synthesis of the preclinical candidate LTGO-33 and the formal asymmetric synthesis of the phase II clinical candidate ART0380 demonstrate the utility of the disclosed approach.

2024-12-26·JOURNAL OF MEDICINAL CHEMISTRY

Discovery of ART0380, a Potent and Selective ATR Kinase Inhibitor Undergoing Phase 2 Clinical Studies for the Treatment of Advanced or Metastatic Solid Cancers

Article

作者: Ding, Yanbing ; Vijayan, R. S. K. ; Cross, Jason B. ; Smith, Graeme C. M. ; Lapointe, David ; Shepard, Hannah E. ; Jiang, Yongying ; Carroll, Christopher L. ; Do, Mary K. Geck ; Lively, Sarah ; Heald, Robert A. ; Johnson, Michael G. ; Liu, Chiu-Yi ; Kang, Zhijun ; Giuliani, Virginia ; Pang, Jihai ; Di Francesco, M. Emilia ; Heffernan, Timothy ; Wu, Qi ; Fang, Cheng ; Jones, Philip ; Williams, Christopher C. ; Suarez, Catalina ; Li, Meng ; Ma, XiaoYan ; Bardenhagen, Jennifer P. ; Yau, Anne Ju ; Yap, Timothy A. ; Lv, Xiaobing ; Robinson, Helen M. R.

One of the hallmarks of cancer is high levels of DNA replication stress and defects in the DNA damage response (DDR) pathways, which are critical for maintaining genomic integrity. Ataxia telangiectasia and Rad3-related protein (ATR) is a key regulator of the DDR machinery and an attractive therapeutic target, with multiple ATR inhibitors holding significant promise in ongoing clinical studies. Herein, we describe the discovery and characterization of ART0380 (6), a potent and selective ATR inhibitor with a compelling in vitro and in vivo pharmacological profile currently undergoing Phase 2 clinical studies in patients with advanced or metastatic solid tumors as monotherapy and in combination with DNA-damaging agents (NCT04657068 and NCT05798611). ART0380 (6) has a favorable human PK profile suitable for both intermittent and continuous once-daily (QD) dosing, characterized by a dose-proportional increase in exposure and low variability.

项与 Alnodesertib 相关的新闻（医药）

2026-05-26

·BioSpace

Artios Announces First Patient Dosed in Randomized Phase 2 POLKA Study Evaluating DNA Polymerase Theta Inhibitor ART6043 in gBRCA-mutated HER2-Negative Breast Cancer

Key milestone positions ART6043 as the most advanced Pol-theta inhibitor in clinical development; the potentially first-in-class program is supported by U.S. FDA Fast Track designation CAMBRIDGE, United Kingdom and NEW YORK, May 26, 2026 – Artios Pharma Limited (“Artios” or “the Company”), a clinical-stage biopharmaceutical company pioneering the development of new classes of DNA Damage Response (DDR) medicines to deliver meaningful survival benefits for patients with cancer, today announced the dosing of the first patient in a randomized Phase 2 clinical trial ( NCT05898399 ). The global study is evaluating Artios’ potential first-in-class DNA Polymerase Theta (Polθ) inhibitor, ART6043, in combination with the PARP inhibitor olaparib, in adult patients with germline BRCA-mutated (gBRCAm) HER2-negative breast cancer who are eligible to receive a PARP inhibitor. The Phase 2 POLKA trial is supported by Phase 1/2a clinical data for ART6043, which show an attractive tolerability profile, expected PK/PD activity, and promising clinical signals. The POLKA trial is designed to investigate the safety and tolerability of ART6043 plus olaparib and to evaluate the preliminary efficacy of the combination compared to olaparib alone. Artios was granted a Fast Track designation by the U.S. Food and Drug Administration (FDA) in February 2026 for the combination treatment regimen in this patient population. The supporting Phase 1/2a data were presented at the 2025 European Society of Medical Oncology (ESMO) Congress. “Dosing the first patient in the Phase 2 POLKA study marks a significant step in realizing the potential of ART6043 and advancing a new class of targeted therapies for patients with gBRCAm HER2-negative breast cancer,” said Ian Smith, Chief Medical Officer of Artios . “Patients continue to face limited effective treatment options, underscoring the need for new therapies beyond current standards of care. With Fast Track designation and this study now underway, we are focused on establishing ART6043 as a potential first‑in‑class therapy that can deliver more meaningful benefits for patients.” “While PARP inhibitors have become a cornerstone of treatment for HER2-negative breast cancer, there remains a significant need for more effective combination strategies to overcome resistance,” added Graeme Smith, Chief Scientific Officer of Artios . “By targeting the complementary DNA repair pathway mediated by Polθ, ART6043 is rationally designed to enhance the cancer cell killing activity of PARP inhibition and to potentially prevent the emergence of resistance to PARP inhibition. We look forward to evaluating this in the Phase 2 POLKA study.” The global, multicentre, Phase 2 trial is enrolling 80 patients randomized 1:1 with gBRCAm HER2-negative, locally advanced or metastatic breast cancer who received up to three prior lines of chemotherapy and no or ≤ 1 month of prior treatment with a PARP inhibitor. Eligible patients will be assigned to receive ART6043 plus olaparib or olaparib alone to assess comparative efficacy as measured by the primary endpoint, progression-free survival. Secondary endpoints include overall response rate, overall survival, and a comparison of the rate of BRCA mutation reversion. About ART6043 ART6043 is a potential first-in-class, selective, orally bioavailable, small‑molecule inhibitor of the polymerase domain of DNA polymerase theta (Polθ), a DNA repair enzyme that is preferentially expressed in cancer cells but is virtually absent in most healthy tissues. By inhibiting Polθ, ART6043 targets microhomology-mediated end joining (MMEJ) to exploit tumor dependence on error-prone DNA repair, with broad rationale for use as a combination partner with PARP inhibition and other DNA‑damaging modalities. Artios’ differentiated approach is to evaluate ART6043 with olaparib in molecularly defined solid tumors such as gBRCAm cancers. The Phase1/2a study of ART6043 highlighted an attractive tolerability pro combination with the leading PARP inhibitor olaparib, expected PK/PD activity, and promising clinical signals. About Artios Pharma Ltd. Artios’ mission is to develop new classes of medicines that harness DNA Damage Response (DDR) pathways, targeting DNA replication stress and synthetic lethality, to deliver meaningful survival benefits for patients with cancer. Its three potentially first-in-class programs, each with a novel mechanism of action, include ATR inhibitor alnodesertib, the DNA polymerase theta (Polθ) inhibitor ART6043, and a preclinical portfolio of DDRi-ADC candidates with novel payloads. Together, these programs are designed to eliminate cancer cells’ survival mechanisms, driving cancer cell death and improving clinical outcomes. Visit our website at to learn more about Artios. For more information, please contact: Trophic Communications Jacob Verghese or Verena Schossmann Tel: +49 151 219 412 77 Email: artios@trophic.eu

临床2期快速通道

2026-05-16

·精准药物

药化人必读的JMC深度综述：什么是成功的药物优化？

点击蓝字 ↑ 关注PharmaView 近日，在药物化学权威期刊Journal of Medicinal Chemistry上发表了一篇题为"成功优化中发生了什么？——2018−2024年文献调研"的观点论文，资深药物化学家Paul D. Leeson对2018至2024年间478对起始化合物-候选药物优化组合进行了迄今最大规模的公开文献调研，系统剖析了成功优化的分子轨迹与策略演变。该研究覆盖487个优化配对，涵盖激酶、GPCR、蛋白酶等主要靶标类别，以及肿瘤、CNS、感染等多元疾病领域。分析表明，口服候选药物中86.3%符合Lipinski五规则（Ro5），优化过程中分子量平均增加81 Da，但脂溶性（logP）基本维持不变——这一"分子生长"与"脂溶性控制"的平衡已成为当代药物优化的核心范式。研究深入揭示了优化背后的结构驱动力：sp³杂化碳原子、氢键受体、杂芳环及天然产物片段的引入显著增加，而碳芳环数量趋于减少；候选药物平均保留起始化合物70%的最大公共子结构，体现了"保守修饰"与"理性跃迁"并存的优化哲学。尤为值得关注的是，作者对"先导化合物样"（lead-like）概念的当代适用性进行了重新审视——鉴于分子膨胀趋势，仅23%的筛选命中符合传统的MW<<350且clogP<<3标准，远低于1995年前的58%。研究同时追踪了超越Ro5（bRo5）空间的新兴候选药物，包括PROTAC、分子胶和大环肽等"新模态"分子的理化性质特征，为日益拓展的口服可药性边界提供了数据支撑。此外，作者结合KRAS抑制剂、EGFR第三代药物、口服GLP-1激动剂等大量经典案例，生动诠释了从高通量筛选到片段筛选、从已知化合物到天然产物等多样化起点的优化路径差异。该文不仅是对近七年成功优化实践的系统性"解剖"，更为药物化学家设计筛选库、制定优化策略及评估候选质量提供了循证指南，对AI/ML时代下"数字药物化学家"如何融合计算预测与人类直觉亦具有重要启示意义。 Introduction 先导化合物发现与优化是药物化学的核心。早期研究表明优化过程中分子量和脂溶性均增加，由此提出"先导化合物样"假说：理想筛选库应含低分子量（MW<<350）和低脂溶性（logP<<3）的分子，以便为后续多参数优化保留"分子生长"空间；类似原则也是片段药物发现（FBDD）成功的基石。近期研究证实优化中分子量增加而脂溶性不变，且起始化合物与候选药物的分子量均高于历史数据。配体效率指标（尤其是LLE）在优化中通常增加。大规模回顾性研究发现候选药物系列脂溶性更低、sp³碳比例更高，且25%的候选药物在合成不足60个化合物后即出现。为获得当代优化趋势，本研究自2018年起系统收集487对起始化合物−候选药物配对，分析疾病领域、靶标类别、化学起点、给药途径和作用模式的影响。同期Brown和Rácz等团队也开展了类似研究，显示大多数临床候选药物来源于已知化合物，筛选来源的候选药物分子量平均增加约80 Da，而脂溶性和氢键供体数量基本不变。本数据集为迄今公开来源最大规模，且在起始化合物来源判定和分子性质分析范围上更为全面，涵盖原子类型变化、环系、天然产物片段及共享子结构等。 Results ①数据收集本研究手动收集2018−2024年间通向候选药物的"成功"优化配对，未采用关键词检索。因部分文献未明确区分hit-to-lead阶段，主要分析限定为"起始到终点"的完整配对。纳入标准包括明确进入临床或高级临床前阶段且优化路径清晰的化合物，498个候选药物中JMC贡献68%，专利优先日期集中于2011−2016年，平均文献发表滞后7.0年。487个配对具有可识别化学起点，其中469个报告了体外活性，2015年后候选药物平均分子量从466升至506。起始化合物按既有优化程度分为六类：现有药物（12%）、已知化合物（27%）、药效团假说（7%）、定向筛选（12%）、片段筛选（5%）和多样性筛选（37%），DNA编码库筛选仅占0.8%。与Brown分类的关键差异在于本研究进一步细分已知化合物并追溯其原始筛选来源，使多样性筛选占比升至37%。数据收集存在手工筛选无法穷尽、部分候选药物被终止开发未明确标识、分类主观性等局限。理化性质通过SWISS ADME、DataWarrior和ADMETLab3计算，经比较确定XLogP3最优；体外活性转换为p(activity)，以XLogP3计算LLE；选用MCE-18评估分子复杂度，同时分析天然产物片段、伪天然产物及环系变化，并确定每对的最大公共子结构（MCS）。 ②总体性质变化趋势 Table 1汇总了487对起始化合物−候选药物配对的关键性质数据。与早期研究一致，候选药物在分子量（MW，平均+81 Da）、重原子数（HA，+5.7）、总表面积（TSA，+53 Å²）、摩尔折射率（MR，+18.9）、氢键受体（HBA，+2.0）、拓扑极性表面积（TPSA，+17.6 Å²）、可旋转键（+1.1）、氟原子数（+0.6）和活性（p(activity)，+1.5）上普遍增加；而脂溶性（cLogP、XLogP3、logD）、氢键供体（HBD）、OH+NH计数、氯原子和硫原子数平均变化极小或无变化。Figure 3显示，起始化合物的MW高度依赖其来源（多样性筛选起始MW最低，药物最高），但优化后候选药物的MW趋于一致（中位数445−482 Da），其中多样性筛选的MW增幅最大（中位数+76），药物最小（+27），片段筛选是唯一脂溶性显著增加的类别（XLogP3平均+1.4）。Figure 4进一步展示，按靶标类别、疾病领域、作用机制和给药途径分类时，靶标类别对性质差异的影响最为显著且贯穿优化始终：CNS候选药物MW最低，呼吸疾病（含吸入给药）候选MW最高；激动剂XLogP3高于拮抗剂/抑制剂；口服候选MW低于胃肠外和外用制剂；3D t-SNE图显示，来源于筛选策略的起始化合物与候选药物在化学空间中密度差异较文献来源更为明显。 ③效力与配体效率演变在全数据集中，活性平均增加1.5个数量级，伴随MW等体积参数增加和脂溶性基本不变。Figure 5按起始来源和靶标类别展示效力优化轨迹：按起始来源，MW−p(activity)向量方向近乎一致，片段、多样性筛选等低MW起点的活性增幅最大；按靶标类别，轨迹呈平行但分离状态，提示靶标类别决定了不同的平均性质起点和终点。由于HA数与p(activity)同步增加，传统配体效率（LE）在优化中基本不变（平均变化为0），但尺寸独立配体效率（SILE）在所有类别中均增加；脂溶性配体效率（LLE）因活性增加而脂溶性不变，在全集中平均增加1.6，其中多样性筛选组的LLE提升同时受益于活性增加（p(activity)+1.9）和脂溶性降低（XLogP3−0.5）。 ④复杂度与结构特征变化 HA增加几乎完全由六种原子类型贡献，依次为：Csp³（+2.77）> 芳环氮（ArN，+0.77）> 氧（+0.63）≈ Csp²+Csp¹（+0.62）≈ 氟（+0.60）> 非芳环氮（+0.24）。Figure 6和Figure 7的归一化分析显示，每100个HA中Csp³原子净增4.6个，而Csp²+Csp¹净减7.0个；氢键受体显著增加，氢键供体变化微弱；碳芳环减少，杂芳环和脂环增加。Figure 8表明，片段起始的杂芳环密度在优化中几乎不变，而激酶起始的杂芳环密度最高但在优化中减少，这与ATP结合位点需要富氮杂环的先例有关；所有靶标类别的碳芳环均减少。Figure 9将性质变化归一化后分为四象限：合成可及性、可旋转键、TPSA等增加与HA增加成正比；碳芳环、HBD和Csp²+Csp¹增加不足；氟原子、立体中心、脂环和杂芳环增加超过HA比例但增加配对不足50%；仅MCE-18复杂度、Csp³计数、HBA和天然产物片段同时满足"增加超过HA比例"且"超过50%配对增加"。Figure 10以立体中心、杂脂环和碳脂环的组合变化作为脂族复杂度代理指标，27种可能组合中出现24种，仅8%的配对至少一项减少而其余不变，56%的配对至少一项增加而其余不变。 ⑤片段优化与复杂/非复杂分类 Table 3显示，本研究23个片段候选药物的芳环数均值（3.48）高于其他464个候选药物（2.96），Fsp³更低，Ar−Csp³差值更高；与54个文献报道的FBDD临床化合物比较，芳环含量一致，但198个文献片段先导化合物因多为未推进至临床的"不成功"分子而芳环含量更高。Figure 11进一步展示，文献片段先导的杂芳环密度高于本研究片段候选，而临床阶段FBDD化合物与本研究轨迹一致。Figure 12将MCE-18与MW关联分析，发现61个候选药物（9.2%）和150个起始化合物处于"非复杂"区域（MCE-18<<45，主要为芳环连接无环非手性基团的"旧式"分子），其中46个候选来自同样非复杂的起始点，其余15个来自更复杂的起点；另有104个非复杂起始化合物在优化中增加了MCE-18复杂度。 ⑥环系、天然产物片段与结构保留 Figure 13显示，46个常见环系（在候选中出现≥5次）占所有环系的77.1%，其中吡啶、环丙烷、吡唑、吡咯烷、吗啉、嘧啶和吡喃等在优化中较起始化合物明显增加，氧杂环丁烷未在起始中出现但存在于11个候选中，这些环系均为已知天然产物片段。Figure 14表明，所有起始来源和靶标类别的天然产物（NP）片段计数在优化中均显著增加，药物和已知化合物的增幅最小（约0.5−0.6），激酶候选的NP片段数最高（平均3.3）。候选药物为伪天然产物（PNP）的几率是起始化合物的2.3倍，66%的候选为PNP，而起始为46%。Figure 15分析最大公共子结构（MCS），全数据集平均保留起始化合物70%的重原子框架（中位数70.6%），显著高于100组随机配对的34.4%；按起始来源，多样性筛选的MCS最低（64%），药物最高（78%）；9.4%的配对保留了100%的起始化合物骨架。 ⑦成药性规则与先导化合物样性质 Figure 16统计445个口服候选药物的Ro5合规性：86.3%符合Ro5（违反0或1条），13.7%违反>1条；违规主要由MW>500（30.6%）和cLogP>5（14.0%）驱动，OH+NH>5的违规仅4例（0.9%）。90百分位数据显示，传统cutoff（MW 500、cLogP 5）对当前候选偏低，而OH+NH cutoff（5）过高。Figure 17对比显示，本研究中仅23%的筛选命中（多样性、定向和片段筛选）符合1999年提出的先导化合物样标准（MW<<350且cLogP<<3），远低于1995年前历史数据的57.8%；40.5%的筛选命中已具有MW>350且cLogP>3的"类药"特征。Table 4按起始化合物MW四分位分组总结口服优化结果：最低四分位（MW<<330）显示经典的先导化合物行为，MW增幅（+88）、MCE-18增幅（+42）、活性增幅（+2.2）和HBA增幅（+2.6）均为最大，最终候选MW最低（402）且XLogP3最低（2.5）；而高四分位（MW>530）候选MW达558，但各四分位的立体中心和环计数变化相似，HBD、Fsp³和杂芳环数对起始MW依赖较小。 ⑧热点靶标的"跟风效应"与系列药物衍生 KRAS G12C抑制剂是典型"跟风"案例：2013年发现的片段 tethering 命中化合物11经优化得到ARS-1620（12），该分子启发了后续一系列候选药物，包括首个获批的sotorasib（17）、adagrasib（19）以及MK-1084（16）、glecirasib（18）、AZD4625（13）、AZD4747（14）、MRTX1133（20）、INCB159020（15）和JDQ443（21）等，体现了基于结构的设计和杂芳环骨架跃迁策略。ATR激酶抑制剂（Figure 19）展示了单一聚焦筛选命中化合物22（含吗啉-嘧啶核心）如何衍生出ceralasertib（24，III期）、ART0380（25）、AD1058（26）、elimusertib（27）、camonsertib（28）和YY2201（29）等多个临床候选。第三代EGFR抑制剂（Figure 20）则围绕奥希替尼（30）展开：为克服N-去甲基代谢途径，分别开发了氘代药物dosimertinib（33）、咪唑并吡啶类似物YK-029A（32）和mobocertinib（31）；此外还有sunvozertinib（34）、limertinib（35）、lazertinib（37）等已获批或临床阶段药物，多数保留母核结构且MW均有增加。 ⑨单一HTS命中产生多个候选药物三个案例展示了同一高通量筛选命中如何导向多个临床候选。PI3Kα亚型选择性抑制剂inavolisib（45）及taselisib（43）、GDC-0326（44）均源自三环HTS命中42，优化中通过环扩张和杂芳环替换增加LLE。Orexin-2受体激动剂oveporexton（49）及danavorexton（47）、firazorexton（48）源自HTS命中46，保留了核心二氨基乙基单元，通过引入偕二氟和叔醇克服代谢毒性。口服GLP-1受体激动剂danuglipron（51）源自HTS命中50，其苯并咪唑骨架在优化中高度保留（MCS=91%），关键步骤为引入羧基模拟肽底物酸性；该系列后续还开发了lotiglipron（52）、DD202-114（53）、DA-302168S（54）和naperiglipron（55），但部分因肝毒性终止。 ⑩高MW筛选命中的截短策略与低活性高MW命中的推进对于高MW筛选命中，截短是常见策略。FGFR抑制剂ASP5878（59）的优化（Figure 22a）从HTS命中56（MW=582）出发，经选择性先导57（MW=760）和溶解性先导58（MW=583），最终通过去除溶剂暴露的碱性哌嗪并降低hERG和清除率，使MW和XLogP3总体降低175 Da和2.8单位，MCS仅22%。sGC激活剂runcaciguat（63）的优化（Figure 22b）从HTS命中60（MW=558）经历酸先导61和4-Cl截短先导62（MW=400），最终MW降至488，同时碳芳环减少2个。Table 5汇总了10个高MW（>470）且低活性（p(activity)<<6.0）命中的优化案例：其中paltusotine（65）、AZD9898（67）和LEOPPPIm（69）通过截短实现MW降低和LE/LLE显著提升；其余案例如ensitrelvir（71）、ABBV/GLPG-3221（73）和CK-136（75）等则适度增加MW（+32至+54），通过氟代或结构替换改善代谢稳定性和渗透性。基于药效团假说的理性设计当HTS失败时，基于结构的药效团设计可成功获得起始化合物。Bayer的FXIa抑制剂asundexian（88，Figure 23a）利用BMS专利化合物84和85的信息，通过双羰基靶向FXIa氧阴离子空穴设计得到命中86，经占据P1'口袋优化为候选。BMS的FXIa抑制剂milvexian（95，Figure 23b）则源自聚焦筛选命中89，历时约10年，经SBDD驱动优化，最终通过大环结构94平衡效力与PK，MW从403增至626但脂溶性增幅有限。在MC2拮抗剂atumelnant（98，Figure 24a）的发现中，从选择性MC4拮抗剂96出发，去除外围取代基并断裂亚甲基连接子得到命中97，后续优化保留哌嗪核心，以三氟甲基环丁烷作为生物电子等排体替换苯环。M4正构调节剂emraclidine（102，Figure 24b）则从已知M4 PAMs 99和100出发，通过降低HBD数以促进CNS渗透，得到片段样命中101（MW=230），后续引入氮杂环丁烷-吡啶基团增加效力，最终MW=390且HBD=0，脑/血浆游离比为0.5。核心骨架保留与低复杂度优化路径 Table 6列举了8个仅需微小结构改动（起始化合物MCS=100%）即获得候选药物的案例，包括sigma-2调节剂（104仅需1个亚甲基添加）、CDK9拮抗剂（106需2个亚甲基和构型翻转）、Wee1抑制剂（116）等；多数活性提升有限，但部分通过引入极性原子（醚氧、腈基）实现活性增加2.0−2.5个数量级。Table 7展示了4个"非复杂"起始化合物优化为"非复杂"候选药物（MCE-18<<45）的案例：vimseltinib（120）保留聚焦筛选命中119的双吡啶醚核心并去除苄基以降低MW和脂溶性；AG-946（122）利用蛋白假C2对称性，具有数据集中最高的杂芳环密度；lirafugratinib（124）保留片段命中123的全部原子；CVN293（126）则仅需单氟化和吡啶→哒嗪替换以降低代谢清除率。从低复杂度到bRo5空间及芳环趋势例证 Table 8展示4个"非复杂"命中经增加脂族复杂度进入bRo5空间（MW>500且O+N>10）的案例：fenebrutinib（128）在BTK聚焦筛选命中127两端各添加2个脂环，显著增加LLE和激酶选择性；BIIB091（130）源自HTS命中129，同样利用"H3"位点；WRN抑制剂HR0761（132）从ATP结合测定命中131经SBDD优化，MW增加309至702 Da，末端含脱氢吡喃和非经典两性离子5-羟基嘧啶；CFTR调节剂GLPG2737（134）从HTS命中133出发，去除1个碳芳环并增加3个脂环。Table 9则例证了优化中碳芳环减少、杂芳环增加的整体趋势：LPA1拮抗剂admilparant（136）将BMS 986020（135）的3个苯环全部替换，MW降低37 Da，XLogP3降低3.2，溶解度和暴露量显著改善；MC4R拮抗剂PF 07258669（139）通过螺环化策略锁定构象，苯环减少2个、杂芳环增加2个，消除hERG和P450风险；ROMK抑制剂BMS-986308（141）用三唑和吡啶替换2个苯环，XLogP3降低2.4；DGAT2抑制剂ervogastat（143）以双吡啶氧基替换苯氧基哌啶，MW降低69 Da，消除反应性代谢风险。新模态、特殊起点与给药途径的优化实例 Figure 26展示了PROTAC候选药物的发现：IRAK-4降解剂KT-474将预优化的Cereblon配体与已知IRAK-4抑制剂经linker连接，优化后MW=866且具分子内氢键；BTK降解剂NX-2127和bexobrutideg源自同一lead，通过修饰配体和linker改善暴露极性分布与CNS渗透性。Figure 27−28呈现了天然产物来源的bRo5候选药物：桦木酸衍生的HIV成熟抑制剂系列（GSK3532795、GSK3640254、VH-937）及抗真菌药ibrexafungerp均为口服两性离子；从sanglifehrin A的Cyclophilin A结合域出发，经tethering与大环化策略开发的KRAS分子胶系列（daraxonrasib、elironrasib、zoldonrasib、RMC-5127）MW超过1000，但通过分子内氢键降低溶剂暴露极性以实现口服生物利用度。Figure 29列举了表型筛选来源的候选药物：两个抗利什曼原虫化合物（GSK3186899和GSK3494245）分别从HTS命中经骨架跃迁优化，后分别证实作用于CDK12和蛋白酶体；HSF1通路调节剂CCT361814源自卵巢癌细胞表型筛选，靶标未知但生物标志物调节与通路抑制一致。Table 10汇总了吸入候选药物的设计策略：CHF-6523从idelalisib添加极性基团降低渗透性以延长肺部滞留，AZD8154采用低溶解度策略，AZD4604添加碱性哌嗪增加肺滞留，ENaC抑制剂BI 1265162和ETD001则通过引入极性基团降低渗透性实现长效。Table 11展示了以批准药物为起点的优化：TM38837从rimonabant引入酸性四唑降低logD和CNS渗透实现外周CB1选择性；rilzabrutinib保留ibrutinib全部重原子框架作为可逆共价BTK抑制剂；LNP1892从cinacalcet降低脂溶性和可旋转键数，成为两性离子且跨物种生物利用度高；TUL01101从filgotinib以脂环替换苯环增加脂族复杂度，MW仅增加3 Da而JAK1选择性显著改善。 Conclusions 本分析涵盖2018−2024年文献，实际反映2011−2019年创新；86%口服候选符合Ro5，口服PROTAC、分子胶及AI/ML应用在当前数据集中反映尚有限。优化中起始化合物的低性质值趋于增加而高值趋于降低，整体收敛至候选"规范"；平均分子量增加81 Da与活性提升相关，但靶标类别差异贯穿始终。由于重原子数与活性同步增加，传统配体效率基本不变，而尺寸独立配体效率和脂溶性配体效率平均增加。分子量增长主要由Csp³、芳环氮、氧和氟等原子贡献，伴随杂芳环与脂环增加、碳芳环减少及立体中心增多；仅MCE-18复杂度、Csp³计数、氢键受体和天然产物片段的增加同时超过重原子增长所能解释的程度。优化平均保留起始化合物70%的最大公共子结构。鉴于分子膨胀，仅23%筛选命中符合传统先导样标准，但核心原则未变：理想起始化合物应具备在增加分子量和复杂度的同时提升效力的潜力。值得注意的是，25%的候选药物在合成不足60个化合物后即出现，明确候选目标特征并尽早体内筛选有助于加速识别。当前AI/ML主导策略的案例尚少，尽管计算工具发展迅速，但人类判断仍至关重要；发现时间线可缩短，但临床开发的疗效与安全性瓶颈并未因此解决。展望未来，传统Ro5合规空间仍将是主要来源，支持在筛选库和优化中增加三维脂族环、伪天然产物片段及杂芳环替代苯环；在超越Ro5空间，PROTAC和分子胶等候选预计将增长，溶剂暴露极性与分子内氢键等"变色龙"性质将成为与脂溶性同等关键的设计参数。无论技术如何演进，药物化学家的逻辑思维、创造力与坚持不懈仍是成功优化不可或缺的根本要素。文献详细全面信息请跳转原文阅读： https://doi.org/10.1021/acs.jmedchem.5c03171 说明欢迎合理转载，请写明来源于【PharmaView】，公众号以个人学习和分享最新科研成果为目的，本文内容为阅读文献提炼总结的内容，因学识有限，难免有所疏漏和谬误，恳请批评指正。标记【原创】指原创编译，是出于便于传播目的，著作权归出版社与作者所有。分享让更多人看看

2026-05-12

·BioSpace

Artios Announces Clinical Trial Collaboration with GSK to Evaluate Alnodesertib in Combination with Risvutatug Rezetecan, a B7-H3-Targeted ADC in Gastrointestinal Tumors

CAMBRIDGE, United Kingdom and NEW YORK, May 12, 2026 – Artios Pharma Limited (“Artios”), a clinical-stage biopharmaceutical company pioneering the development of new classes of DNA Damage Response (DDR) medicines to deliver meaningful survival benefits for patients with cancer, today announced a clinical trial collaboration and supply agreement with GSK to evaluate alnodesertib, Artios’ ATR inhibitor, in combination with risvutatug rezetecan (also referred to as Ris-Rez), GSK’s novel investigational B7-H3-targeting topoisomerase-1 (Topo-1) antibody-drug conjugate (ADC), in patients with gastrointestinal tumors. “We’re excited to collaborate with GSK to investigate the potential of this combination strategy to provide meaningful benefit to patients with GI tumors,” said Mike Andriole, Chief Executive Officer of Artios . “As we advance the development of alnodesertib in multiple solid tumors, this collaboration enables Artios to broaden our combinatorial strategy and unlock the full potential of exploiting replication stress biology in cancer.” Under the terms of the agreement, GSK will sponsor and conduct the Phase 1 study and provide its B7-H3 Topo-1 ADC, while Artios will supply alnodesertib. Each party will maintain rights to its respective products, and the agreement is mutually non-exclusive. The clinical study is expected to open by the end of the year. About risvutatug rezetecan Ris-Rez is a novel investigational B7-H3-targeted antibody-drug conjugate composed of a fully human anti-B7-H3 monoclonal antibody covalently linked to a topoisomerase inhibitor payload. GSK acquired exclusive worldwide rights (excluding China’s mainland, Hong Kong, Macau, and Taiwan) from Hansoh Pharma to progress clinical development and commercialisation of Ris-Rez. GSK’s global phase III trial (NCT07099898) for Ris-Rez in relapsed extensive stage small-cell lung cancer (ES-SCLC) began in August 2025. Regulatory designations received for Ris-Rez to date include orphan drug designations from the US Food and Drug Administration (FDA) and Japan’s Ministry of Health, Labor and Welfare in SCLC and the European Medicines Agency (EMA) in a category of cancer that includes SCLC, called pulmonary neuroendocrine carcinoma; Priority Medicines (PRIME) Designation from the EMA for relapsed or refractory ES-SCLC; and Breakthrough Therapy Designations for relapsed or refractory ES-SCLC and relapsed or refractory osteosarcoma from the US FDA. About alnodesertib Alnodesertib, formerly known as ART0380, is a potential first-in-class, orally administered, selective small molecule inhibitor of ataxia-telangiectasia and Rad3-related protein (ATR). Artios is developing alnodesertib in patients whose tumor harbours high degrees of replication stress using ATM status as a key biomarker. When used in combination with low-dose chemotherapy to further amplify replication stress, alnodesertib demonstrated unprecedented response rates across eight different solid tumors in ATM-deficient patients. Alnodesertib has received U.S. Fast Track designation in combination with a low dose of chemotherapeutic agent irinotecan, for the treatment of adult patients with ATM-negative metastatic colorectal cancer (mCRC) in the third-line setting. About GSK GSK is a global biopharma company with a purpose to unite science, technology, and talent to get ahead of disease together. Find out more at About Artios Pharma Ltd. Artios’ mission is to develop new classes of medicines that harness DNA Damage Response (DDR) pathways, targeting DNA replication stress and synthetic lethality, to deliver meaningful survival benefits for patients with cancer. Its three potentially first-in-class programs, each with a novel mechanism of action, include ATR inhibitor alnodesertib, the DNA polymerase theta (Polθ) inhibitor ART6043, and a preclinical portfolio of DDRi-ADC candidates with novel payloads. Together, these programs are designed to eliminate cancer cells’ survival mechanisms, driving cancer cell death and improving clinical outcomes. Visit our website at to learn more about Artios. For more information, please contact: Trophic Communications Jacob Verghese or Verena Schossmann Tel: +49 151 7441 6179 Email: artios@trophic.eu Attachment PDF Version

100 项与 Alnodesertib 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
转移性实体瘤	临床2期	美国	Artios Pharma Ltd.	2023-09-06
转移性实体瘤	临床2期	法国	Artios Pharma Ltd.	2023-09-06
转移性实体瘤	临床2期	西班牙	Artios Pharma Ltd.	2023-09-06
腺泡细胞癌	临床2期	美国	Artios Pharma Ltd.	2021-01-27
腺泡细胞癌	临床2期	法国	Artios Pharma Ltd.	2021-01-27
腺泡细胞癌	临床2期	西班牙	Artios Pharma Ltd.	2021-01-27
腺泡细胞癌	临床2期	英国	Artios Pharma Ltd.	2021-01-27
晚期癌症	临床2期	美国	Artios Pharma Ltd.	2021-01-27
晚期癌症	临床2期	法国	Artios Pharma Ltd.	2021-01-27
晚期癌症	临床2期	西班牙	Artios Pharma Ltd.	2021-01-27

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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


NCT04657068 (STELLA, ASCO2026)	临床1期	胰腺导管腺癌 ATM-negative	100	Alnodesertib 200mg + Irinotecan 60mg/m2	選糧膚網衊廠願壓獵壓(簾遞範壓鏇襯餘製獵繭) = 蓋鬱窪簾鏇鏇醖醖遞遞願艱觸鹹構齋製淵壓觸 (製廠獵願鹽構鬱膚範襯 ) 更多	积极	2026-05-29
NCT04657068 (GEICO 114-O, ESGO2026)	临床2期	铂耐药性卵巢癌	64	Alnodesertib + Gemcitabine	構鏇範觸簾鹹範夢鬱願(鬱齋襯鹹壓廠窪觸獵製): HR = 0.71 (90.0% CI, 0.46 ~ 1.1), P-Value = 0.09 更多	积极	2026-02-28
				Gemcitabine
NCT04657068 (AACR2025) 人工标引	临床1/2期	实体瘤	87	ART0380 + irinotecan	壓觸鏇鏇憲膚夢糧艱觸(憲壓繭蓋鬱壓簾鹹淵廠) = The most common treatment related adverse events were neutropenia (53%), anemia (41%), fatigue (33%) and diarrhea (31%). Grade≥3 related diarrhea, nausea and vomiting each occurred in 1 pt. 築餘廠膚壓膚壓積鏇蓋 (顧積積襯築願構壓憲築 )	积极	2025-04-29
				ART0380 + irinotecan (ATM negative)
NCT04657068 (ESMO2023) 人工标引	临床1期	晚期恶性实体瘤	49	ART0380 intermittent doses between 100mg and 1200mg	簾壓糧衊繭餘選築夢淵(鏇製蓋糧鏇淵廠選繭選) = 36% of pts experienced the only Grade 3 treatment-related adverse event of anemia 餘範壓衊願網膚顧憲簾 (製積鹹鑰構積鬱願鹹繭 ) 更多	积极	2023-10-23
				ART0380 QD doses of 200mg and 400mg