Phase I Study to Evaluate the Mass Balance, PK, Metabolism and Excretion of Berzosertib (Intravenous) Containing Microtracer [14C]Berzosertib in Participants With Advanced Solid Tumors (DDRiver Solid Tumors 208)

The study will be conducted in two periods, Period 1 (mass balance) and Period 2 (extension). The purpose of Period 1 of this study is to provide a quantitative characterization of the mass balance, rates and routes of elimination, and metabolic pathways after a single intravenous administration of [14C]berzosertib. The purpose of Period 2 is to assess safety and efficacy of berzosertib in combination with topotecan.

开始日期2022-02-15

申办/合作机构

Merck Healthcare KGaA

NCT04807816 / Recruiting临床2期IIT

Targeting ATR in Soft-tissue Sarcomas: a Randomized Phase II Study. TARSARC Study

Multicenter, prospective, open-labeled, 2-arm, non-comparative randomized phase II trial to assess the antitumor activity of berzosertib in association with gemcitabine

开始日期2022-02-09

申办/合作机构

Institut Bergonié

[+1]

NCT04826341 / Recruiting临床1/2期IIT

A Phase I/II Study of Sacituzumab Govitecan Plus Berzosertib in Small Cell Lung Cancer, Extra-Pulmonary Small Cell Neuroendocrine Cancer and Homologous Recombination-Deficient Cancers Resistant to PARP Inhibitors

Background:
Small cell lung cancer and PARP inhibitor resistant tumors are aggressive cancers. Current treatments for people with these tumors yield little benefit. Researchers want to see if a combination of drugs can help.
Objective:
To find a safe combination of sacituzumab govitecan and berzosertib and to see if this will cause small cell lung cancer and PARP inhibitor resistant tumors to shrink.
Eligibility:
People ages 18 and older with a solid tumor, small cell lung cancer, or a homologous recombination-deficient cancer that is resistant to PARP inhibitors
Design:
Participants will be screened with:
Standard clinical exams and tests
EKG to test the heart
Medical documentation to confirm cancer diagnosis
Participants will get sacituzumab govitecan by vein on days 1 and 8 of each 21-day cycle. They will get berzosertib by vein on days 2 and 9. Treatment will continue as long as they can tolerate the drugs and their tumors are either stable or getting better.
Before treatment and at least once per cycle, participants will have a physical exam and blood tests. Before treatment and every 2 or 3 cycles, they will have a CT scan. They will have a contrast agent injected into a vein for the scan.
Participants will give blood and hair samples and tumor biopsies for research. Biopsies will be taken with a small needle under imaging guidance.
After they stop treatment, participants will have a visit 1 month later. They will then be contacted by phone or email every 3 months for the rest of their lives.

开始日期2021-09-20

申办/合作机构

National Cancer Institute

100 项与 Berzosertib 相关的临床结果

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100 项与 Berzosertib 相关的专利（医药）

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项与 Berzosertib 相关的文献（医药）

2023-12-01·Journal of enzyme inhibition and medicinal chemistry

Inhibitors of phosphoinositide 3-kinase (PI3K) and phosphoinositide 3-kinase-related protein kinase family (PIKK).

Review

作者: Xueqin Huang ; Li You ; Eugenie Nepovimova ; Miroslav Psotka ; David Malinak ; Marian Valko ; Ladislav Sivak ; Jan Korabecny ; Zbynek Heger ; Vojtech Adam ; Qinghua Wu ; Kamil Kuca

Phosphoinositide 3-kinases (PI3K) and phosphoinositide 3-kinase-related protein kinases (PIKK) are two structurally related families of kinases that play vital roles in cell growth and DNA damage repair. Dysfunction of PIKK members and aberrant stimulation of the PI3K/AKT/mTOR signalling pathway are linked to a plethora of diseases including cancer. In recent decades, numerous inhibitors related to the PI3K/AKT/mTOR signalling have made great strides in cancer treatment, like copanlisib and sirolimus. Notably, most of the PIKK inhibitors (such as VX-970 and M3814) related to DNA damage response have also shown good efficacy in clinical trials. However, these drugs still require a suitable combination therapy to overcome drug resistance or improve antitumor activity. Based on the aforementioned facts, we summarised the efficacy of PIKK, PI3K, and AKT inhibitors in the therapy of human malignancies and the resistance mechanisms of targeted therapy, in order to provide deeper insights into cancer treatment.

2023-11-07·Investigational new drugs

The ATR inhibitor berzosertib acts as a radio- and chemosensitizer in head and neck squamous cell carcinoma cell lines.

Article

作者: Julia Schnoell ; Carmen Sparr ; Sega Al-Gboore ; Markus Haas ; Faris F Brkic ; Lorenz Kadletz-Wanke ; Gregor Heiduschka ; Bernhard J Jank

Alterations in the DNA damage response play a crucial role in radio- and chemoresistance of neoplastic cells. Activation of the Ataxia telangiectasia and Rad3-related (ATR) pathway is an important DNA damage response mechanism in head and neck squamous cell carcinoma (HNSCC). Berzosertib, a selective ATR inhibitor, shows promising radio- and chemosensitizing effects in preclinical studies and is well tolerated in clinical studies. The aim of this study was to elucidate the effect of berzosertib treatment in combination with radiation and cisplatin in HNSCC. The HNSCC cell lines Cal-27 and FaDu were treated with berzosertib alone and in combination with radiation or cisplatin. Cell viability and clonogenic survival were evaluated. The effect of combination treatment was evaluated with the SynergyFinder or combination index. Apoptosis was assessed via measurement of caspase 3/7 activation and migration was evaluated using a wound healing assay. Berzosertib treatment decreased cell viability in a dose-dependent manner and increased apoptosis. The IC₅₀ of berzosertib treatment after 72 h was 0.25-0.29 µM. Combination with irradiation treatment led to a synergistic increase in radiosensitivity and a synergistic or additive decrease in colony formation. The combination of berzosertib and cisplatin decreased cell viability in a synergistic manner. Additionally, berzosertib inhibited migration at high doses. Berzosertib displays a cytotoxic effect in HNSCC at clinically relevant doses. Further evaluation of combination treatment with irradiation and cisplatin is strongly recommended in HNSCC patients as it may hold the potential to overcome treatment resistance, reduce treatment doses and thus mitigate adverse events.

2023-10-12·JAMA oncology

Berzosertib Plus Topotecan vs Topotecan Alone in Patients With Relapsed Small Cell Lung Cancer: A Randomized Clinical Trial.

Article

作者: Nobuyuki Takahashi ; Zhonglin Hao ; Liza C Villaruz ; Jun Zhang ; Jimmy Ruiz ; W Jeffrey Petty ; Hirva Mamdani ; Jonathan W Riess ; Jorge Nieva ; Jose M Pachecho ; Alexander D Fuld ; Elaine Shum ; Aman Chauhan ; Samantha Nichols ; Hirity Shimellis ; Jessie McGlone ; Linda Sciuto ; Danielle Pinkiert ; Chante Graham ; Meenakshi Shelat ; Robbie Kattappuram ; Melissa Abel ; Brett Schroeder ; Deep Upadhyay ; Manan Krishnamurthy ; Ajit Kumar Sharma ; Rajesh Kumar ; Justin Malin ; Christopher W Schultz ; Shubhank Goyal ; Christophe E Redon ; Yves Pommier ; Mirit I Aladjem ; Steven D Gore ; Seth M Steinberg ; Rasa Vilimas ; Parth Desai ; Anish Thomas

Importance:

Patients with relapsed small cell lung cancer (SCLC), a high replication stress tumor, have poor prognoses and few therapeutic options. A phase 2 study showed antitumor activity with the addition of the ataxia telangiectasia and Rad3-related kinase inhibitor berzosertib to topotecan.

Objective:

To investigate whether the addition of berzosertib to topotecan improves clinical outcomes for patients with relapsed SCLC.

Design, Setting, and Participants:

Between December 1, 2019, and December 31, 2022, this open-label phase 2 randomized clinical trial recruited 60 patients with SCLC and relapse after 1 or more prior therapies from 16 US cancer centers. Patients previously treated with topotecan were not eligible.

Interventions:

Eligible patients were randomly assigned to receive topotecan alone (group 1), 1.25 mg/m2 intravenously on days 1 through 5, or with berzosertib (group 2), 210 mg/m2 intravenously on days 2 and 5, in 21-day cycles. Randomization was stratified by tumor sensitivity to first-line platinum-based chemotherapy.

Main Outcomes and Measures:

The primary end point was progression-free survival (PFS) in the intention-to-treat population. Secondary end points included overall survival (OS) in the overall population and among patients with platinum-sensitive or platinum-resistant tumors. The PFS and OS for each treatment group were estimated using the Kaplan-Meier method. The log-rank test was used to compare PFS and OS between the 2 groups, and Cox proportional hazards models were used to estimate the treatment hazard ratios (HRs) and the corresponding 2-sided 95% CI.

Results:

Of 60 patients (median [range] age, 59 [34-79] years; 33 [55%] male) included in this study, 20 were randomly assigned to receive topotecan alone and 40 to receive a combination of topotecan with berzosertib. After a median (IQR) follow-up of 21.3 (18.1-28.3) months, there was no difference in PFS between the 2 groups (median, 3.0 [95% CI, 1.2-5.1] months for group 1 vs 3.9 [95% CI, 2.8-4.6] months for group 2; HR, 0.80 [95% CI, 0.46-1.41]; P = .44). Overall survival was significantly longer with the combination therapy (5.4 [95% CI, 3.2-6.8] months vs 8.9 [95% CI, 4.8-11.4] months; HR, 0.53 [95% CI, 0.29-0.96], P = .03). Adverse event profiles were similar between the 2 groups (eg, grade 3 or 4 thrombocytopenia, 11 of 20 [55%] vs 20 of 40 [50%], and any grade nausea, 9 of 20 [45%] vs 14 of 40 [35%]).

Conclusions and Relevance:

In this randomized clinical trial, treatment with berzosertib plus topotecan did not improve PFS compared with topotecan therapy alone among patients with relapsed SCLC. However, the combination treatment significantly improved OS.

Trial Registration:

ClinicalTrials.gov Identifier: NCT03896503.

项与 Berzosertib 相关的新闻（医药）

2023-11-09

·PRNewswire

China Leads in ATR Protein Inhibitors Clinical Trials, Accounting for Over 60% of Ongoing Research Efforts

DUBLIN, Nov. 9, 2023 /PRNewswire/ -- The "Global ATR Protein Inhibitors Clinical Trials & Market Opportunity Insight 2024" report has been added to ResearchAndMarkets.com's offering. A promising frontier in cancer pharmaceutical research, the inhibition of Ataxia telangiectasia and Rad3 related kinase (ATR kinase) is poised to revolutionize cancer treatment and extend its reach to neurodegenerative and infectious diseases. This exciting development is highlighted in the recently released "Global ATR Protein Inhibitors Clinical Trials & Market Opportunity Insight 2024" report, providing a comprehensive overview of this transformative field. Key Report Highlights: Clinical Trials: Over 15 ATR protein inhibitors are currently in clinical trials, demonstrating the significant investment and research efforts in this area. China Dominance: China leads ATR protein inhibitors clinical trials, accounting for over 60% of ongoing trials. Clinical Phase: ATR protein inhibitors are advancing rapidly, with several candidates reaching Phase III clinical trials. Pipeline Analysis: The report offers insights into the global ATR protein inhibitors clinical pipeline, categorized by company, indication, and phase. Development Trends: ATR inhibitors are expanding their scope to include neurodegenerative diseases and viral infections, opening new avenues for treatment. Competitive Landscape: The competitive landscape section provides insights into key players and their contributions to ATR inhibition research. ATR kinase, a serine/threonine-protein kinase, plays a pivotal role in maintaining genomic integrity and responding to DNA damage. Dysregulation of ATR has been linked to various diseases, particularly cancer. Inhibiting ATR presents a novel opportunity to exploit cancer cell vulnerabilities and enhance the effectiveness of existing therapies. The primary focus of ATR inhibition is in oncology, where ATR inhibitors have shown promise in augmenting the efficacy of DNA-damaging cancer treatments such as chemotherapy and radiation. These inhibitors hold great potential for combination therapies in various cancer types, including ovarian cancer, bile duct carcinoma, breast carcinoma, small cell cancer, high-grade neuroendocrine cancers, and hematological malignancies. Key candidates under investigation include ATG-018, Elimusertib (BAY 1895344), Camonsertib (RP-3500), and Ceralasertib (AZD6738), developed by Antengene, Bayer, Repare Therapeutics, and AstraZeneca, respectively. Recent research has expanded the scope of ATR inhibitors to neurodegenerative diseases, where ATR kinase's role in maintaining neuronal genomic activity presents a potential target for conditions like Parkinson's and Alzheimer's disease. Additionally, ATR inhibition has shown promise in combating microbial infections, particularly those caused by viruses like HIV-1 and COVID-19, opening avenues for novel therapeutics. The pharmaceutical industry has made significant investments in ATR inhibition, with numerous clinical trials underway to evaluate candidate efficacy. VE-821, developed by Vertex Pharmaceuticals, paved the way for the development of VE-822, now licensed to Merck as Berzosertib. These inhibitors, including M1774, have demonstrated promising results in early-phase clinical trials by enhancing cancer cell sensitivity to DNA-damaging chemotherapies, potentially reducing side effects. ATR inhibitors offer several advantages over traditional cancer therapies. They sensitize cancer cells to conventional treatments, potentially reducing dosages and side effects. ATR inhibition can also overcome resistance mechanisms that cancer cells develop against treatment, improving patient outcomes. Furthermore, ATR inhibitors enable a personalized approach to cancer treatment by targeting specific genetic vulnerabilities in patients. While challenges remain, such as refining patient selection criteria and understanding potential side effects, ATR inhibitors hold immense promise. As they continue to show potential, their integration into combination therapies is expected to reshape cancer treatment regimens. Advances in molecular profiling and genetic testing may further enable targeted ATR inhibition. The ongoing clinical and market trends for ATR inhibitors present a compelling narrative in the pharmaceutical domain. This innovative approach to targeting DNA damage response pathways has the potential to revolutionize cancer treatment and extend its reach to neurodegenerative and infectious diseases. With ongoing research revealing more about ATR kinase and its implications in different indications, the full potential of ATR inhibition is yet to be realized, promising a new wave of development in the global pharmaceutical market. Key Topics Covered: 1. Introduction to ATR Inhibition 1.1 Overview of ATR Protein & ATR Inhibition 1.2 History & Evolution of ATR Inhibitors 2. ATR Inhibitors: Research & Clinical Trials Overview by Indication 2.1 Solid Cancers 2.2 Hematological Cancers 3. Global ATR Inhibitors Market Outlook 3.1 Current Market Trends & Developments 3.2 Future Growth Avenues 4. ATR Inhibitors Development Trends by Region 4.1 US 4.2 EU 4.3 UK 4.4 Canada 4.5 China 4.6 Japan 4.7 Australia 5. Global ATR Protein Inhibitors Clinical Trials Overview 5.1 By Country 5.2 Indication 5.3 Phase 5.4 Therapy Class 6. Global ATR Protein Inhibitors Clinical Pipeline By Company, Indication & Phase 6.1 Research 6.2 Preclinical 6.3 Phase-I 6.4 Phase-I/II 6.5 Phase-II 6.6 Phase-III 7. Global ATR Inhibitors Market Drivers & Challenges 7.1 Drivers & Opportunities 7.2 Challenges & Restraints 8. Competitive Landscape 8.1 Antengene Corporation 8.2 Aprea 8.3 AstraZeneca 8.4 Bayer 8.5 Beijing Tide Pharmaceutical 8.6 Biocity Biopharmaceutics 8.7 Chipscreen Biosciences 8.8 IMPACT Therapeutics 8.9 Laevoroc Neuro-Oncology 8.10 Repare Therapeutics 8.11 Shanghai De Novo Pharmatech 8.12 Shanghai Junshi Biosciences 8.13 ShangPharma 8.14 Vertex Pharmaceuticals For more information about this report visit About ResearchAndMarkets.com ResearchAndMarkets.com is the world's leading source for international market research reports and market data. We provide you with the latest data on international and regional markets, key industries, the top companies, new products and the latest trends. Media Contact: Research and Markets Laura Wood, Senior Manager [email protected] For E.S.T Office Hours Call +1-917-300-0470 For U.S./CAN Toll Free Call +1-800-526-8630 For GMT Office Hours Call +353-1-416-8900 U.S. Fax: 646-607-1904 Fax (outside U.S.): +353-1-481-1716 Logo: SOURCE Research and Markets

临床3期临床1期

2023-02-16

·药渡Daily

“合成致死”新兴靶点研发进展汇总

1922年，哥伦比亚大学摩尔根实验室的遗传学家Calvin Bridges，在黑腹果蝇身上发现一种有趣的现象：当某两个特定的基因同时突变失活时，会导致果蝇的死亡；而这两个基因单独任何一个突变失活，都不会给果蝇带来致命的伤害。1946年，Theodosius Dobzhansky给这种现象取了个名字—— “合成致死”效应。所谓“合成致死”，就是对于细胞中的两个基因，其中任何一个单独突变或者不发挥作用时，都不会导致细胞死亡；而两者同时突变或者不能表达时，就会导致细胞死亡，利用该原理可实现选择性杀伤肿瘤细胞而不对正常体细胞产生影响。基于合成致死原理的肿瘤治疗尽管如今“合成致死”的概念已蓬勃发展，成为新兴热门赛道。但是其发展经历了漫长的过程。2014年，全球首款“合成致死”理念相关药物PARP（多聚ADP核糖聚合酶）抑制剂Olaparib，获FDA批准用于治疗卵巢癌。自此，“合成致死”由概念变成现实。如今，国内外大量资源投入到“合成致死”研究中，除了PARP外，PRMT5、WEE1、ATR、ATM等靶点的研究也逐渐展露头角，它们的研究进展到哪一步了呢？PRMT5抑制剂PRMT（蛋白质精氨酸甲基转移酶）能够使多种蛋白甲基化，并在基因表达、剪接和DNA损伤修复等生物学过程中发挥重要作用。在哺乳动物中，共有9种PRMTs, 分为I、II、III三种类型。其中I型包括PRMT1、2、3、4、6、8，主要催化生成单甲基精氨酸（MMA）和不对称二甲基精氨酸（ADMA）；Ⅱ型包括PRMT5、9，主要催化生成MMA和对称二甲基精氨酸（SDMA）；III型包括PRMT7，主要催化生成MMA。其中PRMT5是关注度最高的一种亚型。PRMT5通过对称二甲基化，翻译后修饰组蛋白和其他蛋白质；这种由PRMT5催化的蛋白质底物甲基化在调节关键细胞进程中起着重要作用，如DNA修复、细胞周期进展、转录调控和RNA剪接等。PRMT5被认为是一种潜在的致癌基因。PRMT5作用机制2016年，发表在《Science》的文章首次报道了抑制PRMT5在MTAP（甲硫腺苷磷酸化酶）缺失肿瘤中的“合成致死”效应，文章指出与PRMT5构成合成致死的基因是MTAP，这是一种抑癌基因，常在肿瘤中发生缺失。因此，PRMT5/MTAP抑制剂被认为是潜在的抗肿瘤药物。目前，大约有十几款PRMT5抑制剂已进入临床阶段。全球部分在研PRMT5抑制剂来源：公开资料其中，Epizyme和GSK共同研发的GSK3326595是目前进展最快的PRMT5选择性小分子抑制剂。它带有一个四氢异喹啉片段（THIQ），THIQ环与PRMT5特有的残基Phe327形成潜在的π-π堆积作用，可有效抑制肿瘤体积。另外，GSK3326595具有良好的脑通透性和抗肿瘤效果。WEE1抑制剂Wee1激酶最早发现于裂殖酵母中，是丝氨酸/苏氨酸蛋白激酶家族的重要成员之一。它是一种高度保守的细胞周期调节蛋白，主要由3个结构域组成，即N-端结构域、中心激酶结构域和1个短的C-端结构域。N-端结构域是Wee1激酶的激活结构域，也是抑制周期蛋白依赖性激酶1-周期蛋白B（CDK1-CyclinB）复合物去磷酸化的潜在位点，这些泛素化识别位点可以严格控制Wee1的细胞内半衰期；C-端结构域主要包含催化段和活化段。Wee1激酶作用机制来源：PROGRESS IN PHARMACEUTICAL SCIENCES 2022,46 (1): 71-80Wee1激酶可通过磷酸化CDK的Thr14和Tyr15位点来抑制CDK激酶的活性，进而抑制细胞进入有丝分裂。与Wee1 形成合成致死效应的搭档是TP53。该基因翻译的P53蛋白是细胞生长、增殖和损伤修复的重要调节因子。正常情况下，当细胞的DNA受损时，P53蛋白会阻止细胞增殖而停止于G1/S期，直到损伤修复好后才能进入G2期，如不能修复则促进细胞凋亡。因此，TP53属于抑癌基因，在多种恶性肿瘤中会发生TP53突变。由于TP53突变在多种癌症中普遍存在，因此Wee1抑制剂具有巨大的市场潜力，目前在研的Wee1药物有十余种。全球部分在研Wee1抑制剂来源：高特佳投资、公开资料在全球Wee1抑制剂研发进展中，Zentalis的ZN-c3进展最快。ZN-c3由Zentails公司开发，是一款治疗晚期实体瘤的Wee1口服抑制剂。它能使癌细胞在不修复DNA损伤的情况下进行有丝分裂，导致有丝分裂提前进行，造成癌细胞凋亡。ZN-c3作用机制ZN-c3已在单药和联合用药中展现出广泛疗效。与单药治疗相比，Wee1和PARP抑制剂联合用药具有更强的抗肿瘤能力。Wee1抑制剂加吉西他滨治疗铂类难治性复发性卵巢癌、单药治疗复发性或持续性子宫浆液性癌均取得较好的抗肿瘤效果。在国内Wee1抑制剂研发上，布局的企业仍只是少数，仅有英派药业、智康弘仁、首药控股等。ATR抑制剂ATR全称共济失调毛细血管扩张突变基因Rad3相关激酶，是一种在DNA损伤后能够激活细胞应答，进而阻滞细胞周期进程并稳定复制叉及修复DNA，从而回避细胞凋亡的重要激酶。当细胞内DNA复制压力、DNA损伤产生时，ATR被募集至DNA损伤部位，多种蛋白参与调控ATR的激活。当ATR激活后，可通过多种信号调控细胞生物过程，包括细胞周期阻滞、抑制复制起点、启动复制叉以及修复DNA双链断裂等。ATR作用机制由于肿瘤细胞的多种DNA修复通路存在缺陷，因此相对于正常细胞，肿瘤细胞更依赖ATR修复通路并对ATR抑制剂更加敏感。因此ATR抑制剂凭借选择性影响肿瘤细胞、而对正常细胞影响较小的优势，有望成为肿瘤治疗的优异潜在药物。ATR抑制剂赛道吸引了一批跨国药企入局，目前全球已有多款ATR抑制剂处于临床阶段。全球部分在研ATR抑制剂来源：公开资料Berzosertib是全球首款进入临床试验的ATR 激酶抑制剂。此前，由美国国家癌症研究所（NCI）开展的一项II期概念验证性研究的结果证实，Berzosertib联合拓扑替康（一种化疗药物）治疗复发性小细胞肺癌（SCLC）患者疗效显著，客观缓解率（ORR）达36%（n=9/25），试验达到主要疗效终点。而且在铂耐药患者中，大部分患者表现出持久的缓解（通常情况下铂耐药患者会在复发的数周内死亡）。目前国内布局ATR抑制剂的企业仍较少，进入临床阶段的仅有英派药业和智康弘义。ATM抑制剂ATM是PIKK家族的成员，主要参与对DNA双链断裂（DSB）的反应。ATM 有五个主要的自磷酸化位点：Ser367，Ser1893，Ser1981、Ser2996 和 Thr1885。正常状态下，ATM以二聚体的状态存在，当ATM 受到 DNA 损伤的刺激，其二聚体形式就会解离并转化为单体，导致上述残基（自磷酸化位点）的磷酸化。ATM的下游通路来源：Progress towards a clinically-successful ATR inhibitor for cancer therapyATM磷酸化后，会相继调控其他激酶活性，如细胞周期检测点激酶2（CHK2）；另P53曾经被用作ATM活化的标记物，其作用机制也被广泛研究。目前ATM抑制剂均处于临床早期阶段，仅有4款处于临床I期，分别是：阿斯利康的AZD-1390、默克的M-4076、XRadTherapeutics的XRD-0394，威尚生物的WSD0628。全球部分在研ATM抑制剂来源：公开资料今年1月18日，威尚生物宣布其创新药物WSD0628获FDA批准在美国开展临床试验。WSD0628是一款能穿透血脑屏障的ATM靶向抑制剂，拟开发联合放疗作为放疗增敏剂用于脑胶质母细胞瘤、间变型胶质瘤以及其他肿瘤的神经中枢转移。“合成致死”疗法为原本只能针对1个靶点的小分子靶向治疗打开了无限想象空间。这既有潜力针对部分传统上不可成药的常见致癌基因；又能克服由常规靶向疗法耐药突变的一些情况；此外，还可通过联合用药，造成主动合成致死的情况。可以说，合成致死作为肿瘤治疗的新兴领域，前途无限。当前，合成致死领域商业化成功运作的只有PARP抑制剂，也是竞争激烈的赛道。与其在PARP抑制剂这片红海中内卷，不如转而尝试以上刚刚崭露头角的靶点，寻找适合自己的差异化破局之道。参考来源Yuanxiang Wang et al; Protein Arginine Methyltransferase 5 (PRMT5) as an Anticancer Target and ItsInhibitor Discovery; J. Med. Chem. 2018, 61, 9429−9441；Yudao shen et al; Discovery of First-in-Class Protein Arginine Methyltransferase 5 (PRMT5) Degraders; J. Med. Chem. 2020, 63, 9977−9989；Genetic control of cell size at cell division in yeast[J]. Nature, 1975, 256(5518): 547-551；Nijman S M, Friend S H. Potential of the Synthetic Lethality Principle[J]. Science, 2013, 342(6160): 809-811. DOI：10.1126/science.1244669；《“合成致死”赛道风再起，ATR抑制剂会是下一片蓝海？》，免疫时间，2022-06-06。END👇关注药渡数据媒体矩阵

临床2期临床1期引进/卖出抗体药物偶联物临床申请

2023-01-16

·CPHI制药在线

新药 | ATR抑制剂：或合成致死新星，泰德制药TCC1727申报临床，罗氏超13亿美元引进

关注并星标CPHI制药在线1月11日，北京泰德制药股份有限公司1类新药「TCC1727片」的临床试验申请获CDE受理。据公开资料，TCC1727是选择性ATR激酶抑制剂，靶向作用于DNA损伤修复（DDR）通路重要激酶ATR 。 TCC1727作用机理为合成致死，通过抑制ATR功能，干扰DNA损伤修复，使癌细胞DNA损伤后得不到修复而死亡，同时ATR还参与调节肿瘤微环境，现有数据显示其对多个瘤种具有显著的抗肿瘤活性。 TCC1727 拟开发用于治疗非小细胞肺癌、小细胞肺癌、卵巢癌、三阴乳腺癌等多个癌种，重点针对 PD-(L)1 疗法、铂类化疗及 PARP 抑制剂治疗进展或耐药的癌症患者群体。 ATR，即共济失调毛细血管扩张和 Rad-3-相关蛋白，是一类蛋白丝氨酸/苏氨酸家族激酶，是DNA损伤修复通路的核心成员。而且，ATR 激酶是临床多种抗肿瘤疗法耐药的关键因子，包括铂类、吉西他滨及 PARP 抑制剂等重磅品种。合成致死是抗肿瘤药物开发热门领域，PARP是目前研发最快，且最成功的合成致死靶点。ATR被业界认为是继PARP后最有希望的合成致死靶点之一。 ATR和ATM是DNA损伤反应信号网络中的两种重要蛋白，被DNA损伤激活。ATR抑制剂通过阻断ATR介导的信号通路，可以扰乱DNA损伤修复。研究显示，在ATM缺失的肿瘤细胞中，ATR抑制剂可以产生合成致死效应，在导致ATM缺失肿瘤细胞死亡的同时，并不影响正常细胞。目前，全球已出现多款在研ATR抑制剂（详见下表），这些药物被开发作为单药疗法或联合其他药物用于治疗多种肿瘤，其中已有多款取得积极结果。值得一提的是，我国药企如英派药业、智康弘义也积极布局ATR抑制剂市场。 ♦ Camonsertib是一种选择性ATR口服小分子抑制剂，用于治疗具有特定合成致死基因组改变的肿瘤，包括 ATM（共济失调-毛细血管扩张突变）基因。2022 AACR大会上公布的1/2期临床试验结果显示：Camonsertib在晚期卵巢癌（n=20）队列中表现出可喜的活性。这些患者中90%曾经接受过PARP抑制剂治疗后出现耐药性，85%对含铂化疗耐药。Camonsertib在这一患者群体中的总缓解率达到25%，包括1名完全缓解和3名部分缓解。中位无进展生存期为35周。 ♦ Berzosertib是一种首创、强效、选择性ATR抑制剂，原名为VX-970，2017年默克从Vertex制药公司获得许可。由美国国家癌症研究所(NCI)开展并发表于国际医学期刊《癌症细胞》(Cancer Cell)的一项2期概念验证研究(NCT02487095)的结果证实：berzosertib联合化疗拓扑替康(TOP1抑制剂)治疗复发性小细胞肺癌(SCLC)患者疗效显著，客观缓解率(ORR)达36%(n=9/25)，达到了主要疗效终点。特别是，在病情缓解的铂耐药患者中，大部分患者表现出持久缓解。 ♦ M1774 是德国默克子公司EMDSerono 研究所研发的一种ATR激酶抑制剂，目前正处于单药或联合PARP抑制剂尼拉帕立治疗转移性或局部晚期不可切除实体瘤正的1期临床试验中。 ♦ Ceralasertib是阿斯利康开发的一款ATR抑制剂。2021 ASCO大会上公布的2期临床研究结果显示：ceralasertib联合度伐利尤单抗表现出有前景的抗肿瘤活性，尤其是在标准治疗（包括抗PD-1单抗治疗）失败的黑色素瘤患者中。不过，2022 ESMO乳腺癌大会上公布的奥拉帕利联合ceralasertib或WEE1抑制剂adavosertib二/三线治疗转移性三阴性乳腺癌（mTNBC）中的2期临床研究（VIOLETTE）结果显示：无论是否存在同源重组修复(HRR)基因突变和BRCA突变，与奥拉帕利单药治疗相比，奥拉帕利+ceralasertib未能改善mTNBC患者的无进展生存期（PFS）。 ♦ ART-0380 是由Artios Pharma 公司从美国MD Anderson 癌症中心和中国Shang PharmaInnovation获得许可开发的一种新的口服ATR抑制剂，2021年1月在美国启动单药或联合吉西他滨治疗晚期或转移性实体瘤的1/2a期临床研究。 ♦ elimusertib是拜耳开发的一款高度选择性强力ATR抑制剂。AACR大会上公布的1b期扩展临床研究显示：在143名携带不同DDR缺陷的晚期实体瘤患者中，elimusertib让约35%的患者疾病得到控制至少16周。在卵巢癌患者中，27.8%的患者临床获益时间超过6个月，其中包括对含铂化疗耐药并且接受过PARP抑制剂治疗的患者。在ATM表达缺失的患者中，部分缓解率为8.9%，55.9%的患者疾病稳定。 ♦ IMP9064是英派药业自主研发的一款ATR抑制剂。临床前数据显示，IMP9064对ATR具有高抑制活性，相比于其他激酶也展示了高选择性。同时，IMP9064在ATM缺陷型细胞系和移植瘤模型中都显示了良好的抗肿瘤活性和体内活性，具有获得更宽的治疗窗口、以及单药长期用药和联合用药的潜力。 ♦ SC0245是国内首个获批临床的ATR抑制剂，目前正在开展一项开放、单臂的1a/1b期研究。据悉，SC0245在临床前研究中展现出良好的安全性，在体内体外药效均优于同靶点产品AZD6738。 ♦ ATG-018是一款由德琪医药研发团队自主开发的作用于ATR激酶的口服、强效、选择性小分子抑制剂。2022 AACR大会上公布的临床前研究结果显示：ATG-018在多个具有同源重组缺乏的实体瘤/血液肿瘤的体内模型和体外试验中显示了单药疗效。而且，研究还发现了多个与ATG-018敏感性相关的基因表达变化，这些差异基因具有成为预测性生物标志物的潜力。整体来看，ATR抑制剂的研发还处于早期阶段，但其市场潜力已被越来越多的企业看重。值得一提的是，去年6月，罗氏与Repare Therapeutics就Camonsertib达成全球许可和合作协议，交易金额超13亿美元。期待未来ATR抑制剂可以早日问世，造福广大肿瘤患者。扫描下方二维码，发送“新年快乐”，领取新年好礼来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~

AACR会议临床结果临床2期临床申请

100 项与 Berzosertib 相关的药物交易

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KEGG	Wiki	ATC	Drug Bank
D11148	-	-	DB11794

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卵巢癌	临床2期	比利时更多	-
实体瘤	临床2期	英国更多	Merck KGaA 更多
小细胞肺癌	临床2期	西班牙更多	EMD Serono Research & Development Institute, Inc. 更多
腹膜癌	临床2期	英国更多	-
输卵管癌	临床2期	-	Vertex Pharmaceuticals, Inc. 更多

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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


NCT02567409 (CTgov)	临床2期	肾盂输尿管移行细胞癌转移 \| 转移性尿路上皮癌	87	Berzosertib+Gemcitabine Hydrochloride+Cisplatin (Arm A (Berzosertib, Gemcitabine Hydrochloride, Cisplatin))	鏇窪蓋窪網構觸鹹簾蓋(構積鹹窪艱積觸製夢憲) = 醖鏇鹹觸製製襯觸艱窪齋積蓋蓋憲觸簾繭壓製 (繭衊選築壓獵憲範願鑰, 築壓夢構蓋獵鹹壓襯範 ~ 遞網鑰鬱獵鑰壓積遞簾) 更多	-	2023-10-17
NCT02567409 (CTgov)	临床2期	肾盂输尿管移行细胞癌转移 \| 转移性尿路上皮癌	87	Gemcitabine Hydrochloride+Cisplatin (Arm B (Gemcitabine Hydrochloride, Cisplatin))	鏇窪蓋窪網構觸鹹簾蓋(構積鹹窪艱積觸製夢憲) = 鬱鬱鹽醖積積壓鹽繭製齋積蓋蓋憲觸簾繭壓製 (繭衊選築壓獵憲範願鑰, 獵網鏇鑰蓋築製壓構鑰 ~ 範築鏇糧製憲顧範鹹繭) 更多	-	2023-10-17
NCT03718091 (CTgov)	临床2期	实体瘤 \| 平滑肌肉瘤 \| 骨肉瘤	30	M6620 (Cohort T1: ATRX-mutant Leiomyosarcoma)	範製鬱艱鹽鏇窪餘網廠(範製壓積艱遞齋繭窪願) = 壓衊顧衊壓築獵醖壓築醖繭夢鬱夢憲糧齋繭鑰 (鬱獵繭廠遞遞繭糧壓衊, 願顧積鏇窪願壓窪積鏇 ~ 鏇顧鹽獵遞窪蓋襯廠憲) 更多	-	2023-07-07
NCT03718091 (CTgov)	临床2期	实体瘤 \| 平滑肌肉瘤 \| 骨肉瘤	30	M6620 (Cohort T2: Truncating ATM Mutation)	範製鬱艱鹽鏇窪餘網廠(範製壓積艱遞齋繭窪願) = 廠選積衊遞範鬱觸蓋窪醖繭夢鬱夢憲糧齋繭鑰 (鬱獵繭廠遞遞繭糧壓衊, 觸糧淵鹽顧憲網顧遞鹽 ~ 鬱蓋窪糧鹹餘獵窪鏇鹹) 更多	-	2023-07-07
NCT03641313 (ASCO2023) 人工标引	临床2期	胃食管交界处癌 TP53 Mutation	17	Irinotecan Hydrochloride+Berzosertib	鹹範襯獵餘製廠糧製顧(鬱構鹽襯憲淵齋簾窪構) = 顧壓鬱窪願壓築願顧製顧構簾遞艱構鏇積餘鬱 (積鏇獵壓製憲餘襯艱憲 ) 更多	不佳	2023-05-26
NCT02589522 (CTgov)	临床1期	转移性肺非小细胞癌 \| 小细胞肺癌 \| 肺神经内分泌肿瘤 ... 更多	15	berzosertib (Group 1 - Dose Level 1)	醖糧壓壓遞築鹽廠襯選(製網顧膚淵襯齋繭遞範) = 繭鏇簾鑰繭鬱積糧範鑰範願願構壓淵壓願繭膚 (簾鹽餘膚糧憲糧淵衊憲, 壓餘構鑰鏇襯獵構遞廠 ~ 齋鹹觸蓋顧範鹽膚構餘) 更多	-	2023-05-19
NCT02589522 (CTgov)	临床1期	转移性肺非小细胞癌 \| 小细胞肺癌 \| 肺神经内分泌肿瘤 ... 更多	15	berzosertib (Group 1 - Dose Level 2)	醖糧壓壓遞築鹽廠襯選(製網顧膚淵襯齋繭遞範) = 壓簾鏇衊網顧淵鬱蓋簾範願願構壓淵壓願繭膚 (簾鹽餘膚糧憲糧淵衊憲, 齋糧簾廠衊廠簾觸鹽衊 ~ 廠夢築繭積簾選衊鬱淵) 更多	-	2023-05-19
NCT04826341 (AACR2023) 人工标引	临床1期	实体瘤 ATM Mutation \| BRCA1 Mutation	-	sacituzumab govitecan+berzosertib	遞範鬱鏇積襯衊壓餘製(願襯繭遞構艱窪鬱壓淵) = 遞鏇網範繭遞觸鏇範蓋積網壓廠憲壓蓋壓膚衊 (窪積醖鹹遞鬱衊鹽鑰顧 ) 更多	积极	2023-04-14
NCT04768296 (DDRiver SCLC 250, ESMO2022) 人工标引	临床2期	小细胞肺癌复发 \| 小细胞癌	6	Berzosertib 105 mg/m2+Topotecan 1.25 mg/m2 (solid tumours)	餘艱遞壓選遞艱醖齋淵(淵衊鑰願鬱鹹顧糧顧積) = 餘鹽憲淵窪積獵獵廠淵糧繭膚艱鹽醖蓋膚簾簾 (構繭簾範願衊鬱鏇壓繭 ) 更多	积极	2022-09-10
NCT04768296 (DDRiver SCLC 250, ESMO2022) 人工标引	临床2期	小细胞肺癌复发 \| 小细胞癌	6	Berzosertib 210 mg/m2+Topotecan 1.25 mg/m2 ( pt-resistant SCLC)	餘艱遞壓選遞艱醖齋淵(淵衊鑰願鬱鹹顧糧顧積) = 淵憲壓獵構選醖夢艱齋糧繭膚艱鹽醖蓋膚簾簾 (構繭簾範願衊鬱鏇壓繭 ) 更多	积极	2022-09-10
NCT03641547 \| EUCTR2015-003965-27-GB (CHARIOT, ESMO2022) 人工标引	临床1期	肿瘤	18	cisplatin+capecitabine+Berzosertib	膚積觸鏇鏇醖鑰鑰繭蓋(選網膚獵廠糧壓獵獵夢) = Berzosertib 140mg/m2 once weekly 遞獵鹹鏇淵鏇遞壓餘鬱 (餘鬱積衊簾鹽壓壓選鹹 ) 更多	积极	2022-09-10
NCT02567422 (ESMO2022) 人工标引	临床1期	局部晚期头颈部鳞状细胞癌	39	cisplatin+M6620+XRT	艱淵壓衊積鑰繭積構夢(蓋鏇醖製衊齋顧憲構範) = 襯夢艱遞窪鬱鬱鹽餘遞鏇齋觸襯構築齋夢製鏇 (選鹹餘窪築鏇築鏇製築 ) 更多	积极	2022-09-10
NCT02595931 (ASCO2022) 人工标引	临床1期	HR阳性/HER2低表达实体瘤	51	Irinotecan+Berzosertib	齋築鏇願廠遞夢簾鹽醖(觸糧襯願膚糧齋壓醖築) = Berzosertib 270 mg/m2 - irinotecan 180 mg/m2 was declared the RP2D. 獵憲壓餘齋鏇膚鹹鹽願 (壓鏇範衊築鏇廠簾餘憲 ) 更多	积极	2022-06-02
NCT02487095 (ASCO2022) AI 标引	临床2期	小细胞癌	62	Berzosertib and Topotecan	襯鏇繭願鹽選鏇積簾簾(積築築鏇醖觸襯觸鏇夢) = 獵鹽憲積淵淵鑰顧齋願築餘糧積鏇鹽淵鏇膚衊 (顧網範蓋選觸鑰窪夢鹽 )	积极	2022-06-02