This research study is being done to investigate how Azenosertib affects tumor cells of persistent or recurrent uterine serous carcinoma.
The name of the study drug involved in this study is:
-Azenosertib (a type of Wee1 inhibitor)

开始日期2024-09-01

申办/合作机构

Zentalis Pharmaceuticals, Inc.

[+1]

NCT06364410 / Not yet recruiting临床1期IIT

Phase 1 Study of Trastuzumab Deruxtecan (DS-8201a) in Combination With Azenosertib (ZN-c3) in HER2-Expressing/Amplified Cyclin E-Amplified Gastric/Gastroesophageal Junction Cancer and Other Solid Tumors With HER2 Expression

This phase I trial tests the safety, side effects, and best dose of azenosertib in combination with trastuzumab deruxtecan in treating patients with HER2-positive and cyclin E amplified gastric or gastroesophageal junction cancer and other HER2-positive solid tumors that have spread to nearby tissue or lymph nodes (locally advanced), that have spread from where it first started (primary site) to other places in the body (metastatic), or that cannot be removed by surgery (unresectable). Azenosertib is in a class of medications called kinase inhibitors. It inhibits a protein called Wee1. Inhibition of the Wee1 protein can make tumor cells more vulnerable to chemotherapy drugs, leading to tumor cell death. Trastuzumab deruxtecan is in a class of medications called antibody-drug conjugates. It is composed of a monoclonal antibody, called trastuzumab, linked to a chemotherapy drug, called deruxtecan. Trastuzumab attaches to HER2 positive cancer cells in a targeted way and delivers deruxtecan to kill them. Giving azenosertib in combination with trastuzumab deruxtecan may be safe, tolerable, and/or more effective in treating patients with locally advanced, metastatic, or unresectable HER2-positive gastric, gastroesophageal junction, or other solid tumors, compared to just trastuzumab deruxtecan alone.

开始日期2024-08-30

申办/合作机构

National Cancer Institute

NCT06351332 / Recruiting临床1/2期IIT

A Phase I/II Single-arm Trial of Azenosertib (ZN-c3) Combined With Carboplatin and Pembrolizumab in Patients With Metastatic Triple-negative Breast Cancer (ZAP-IT)

This research is being done to evaluate the safety and effectiveness of a drug currently known as Azenosertib (ZN-C3) in combination with the drugs carboplatin and pembrolizumab in metastatic triple-negative breast cancer.
The names of the study drugs involved in this study are:
Azenosertib (a type of WEE1 inhibitor)
Carboplatin (a type of platinum compound)
Pembrolizumab (a type of monoclonal antibody)

开始日期2024-05-01

申办/合作机构

Dana-Farber Cancer Institute, Inc.

[+2]

100 项与 Azenosertib 相关的临床结果

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100 项与 Azenosertib 相关的转化医学

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100 项与 Azenosertib 相关的专利（医药）

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项与 Azenosertib 相关的文献（医药）

2022-12-02·Expert opinion on therapeutic patents

Inhibitors of cell cycle checkpoint target Wee1 kinase – a patent review (2003–2022)

Review

作者: Jiang, Yiqing ; Zhu, Yong ; Zhuang, Lili ; Chen, Yadong ; Yan, Jingxue ; Wang, Yong ; Tu, Zhenlin ; Dong, Chao

INTRODUCTION:

DNA damage repair in most malignancies with mutation of p53 is more dependent on the G2/M checkpoint. Wee1 kinase is a key regulator of the G2/M checkpoint. If Wee1 is inhibited, it results in cells with unrepaired DNA damage entering mitosis prematurely, leading to mitotic catastrophe and subsequent cell death via the apoptotic program. Therefore, inhibition of Wee1 kinase which overexpressed in several cancer cell lines has emerged as a promising therapy for cancer treatment.

AREAS COVERED:

This review summarizes for the first time the structures of small-molecule inhibitors of Wee1 reported in patents published from 2003 to 2022 and the recent clinical developments. It also provides perspectives on the challenges and the future directions. We used different methods to search different databases (PubMed, Reaxys, clinicaltrials.gov)for the literature we needed.

EXPERT OPINION:

Although the small-molecule inhibitors of Wee1, Adavosertib, and ZN-C3 have entered the clinical phase II, the clinical toxicity exhibited by Adavosertib remains the subject of greater concern. The use of Wee1 inhibitors as monotherapy or in combination therapy remains the main trend in Wee1 inhibitors at present.

2021-09-09·Journal of medicinal chemistry1区 · 医学

Discovery of ZN-c3, a Highly Potent and Selective Wee1 Inhibitor Undergoing Evaluation in Clinical Trials for the Treatment of Cancer

1区 · 医学

Article

作者: Paliwal, Sunil ; Abraham, Sunny ; Hopkins, Chad D. ; Bunker, Kevin D. ; Liu, Hui ; Huang, Peter Q. ; Hegde, Sayee G. ; Samatar, Ahmed A. ; Li, Jiali ; Unni, Aditya K. ; Boren, Brant C.

Wee1 inhibition has received great attention in the past decade as a promising therapy for cancer treatment. Therefore, a potent and selective Wee1 inhibitor is highly desirable. Our efforts to make safer and more efficacious Wee1 inhibitors led to the discovery of compound 16, a highly selective Wee1 inhibitor with balanced potency, ADME, and pharmacokinetic properties. The chiral ethyl moiety of compound 16 provided an unexpected improvement of Wee1 potency. Compound 16, known as ZN-c3, showed excellent in vivo efficacy and is currently being evaluated in phase 2 clinical trials.

104

项与 Azenosertib 相关的新闻（医药）

2024-07-01

·GlobeNewswire-Health Care

Zentalis Pharmaceuticals Announces Inducement Grants Under Nasdaq Listing Rule 5635(c)(4)

SAN DIEGO, July 01, 2024 (GLOBE NEWSWIRE) -- Zentalis® Pharmaceuticals, Inc. (Nasdaq: ZNTL), a clinical-stage biopharmaceutical company discovering and developing clinically differentiated small molecule therapeutics targeting fundamental biological pathways of cancers, today announced that on July 1, 2024, the Compensation Committee of Zentalis’ Board of Directors granted non-qualified stock options to purchase an aggregate of 40,875 shares of the Company’s common stock to five newly hired employees. The stock options were granted under the Zentalis Pharmaceuticals, Inc. 2022 Employment Inducement Incentive Award Plan (2022 Inducement Plan) as an inducement material to each such individual’s entering into employment with Zentalis in accordance with Nasdaq Listing Rule 5635(c)(4). The 2022 Inducement Plan is used exclusively for the grant of equity awards to individuals who were not previously employees of Zentalis, or following a bona fide period of non-employment, as an inducement material to each such individual’s entering into employment with Zentalis, pursuant to Nasdaq Listing Rule 5635(c)(4). The stock options have an exercise price of $4.19 per share, which is equal to the closing price of Zentalis’ common stock on The Nasdaq Global Market on the date of grant. The stock options have a 10-year term and will vest over four years, with 25% of the options vesting on the first anniversary of the vesting commencement date and the remaining 75% of the options vesting in equal monthly installments over the three years thereafter. Vesting of the stock options is subject to the employee’s continued service to Zentalis on each vesting date. About Zentalis Pharmaceuticals Zentalis® Pharmaceuticals, Inc. is a clinical-stage biopharmaceutical company discovering and developing clinically differentiated small molecule therapeutics targeting fundamental biological pathways of cancers. The Company’s lead product candidate, azenosertib (ZN-c3), is a potentially first-in-class and best-in-class WEE1 inhibitor for advanced solid tumors and hematologic malignancies. Azenosertib is being evaluated as a monotherapy and in combination across multiple clinical trials and has broad franchise potential. In clinical trials, azenosertib has been well tolerated and has demonstrated anti-tumor activity as a single agent across multiple tumor types and in combination with several chemotherapy backbones. As part of its azenosertib clinical development program, the Company is exploring enrichment strategies targeting tumors of high genomic instability, such as Cyclin E1 positive tumors, homologous recombination deficient tumors and tumors with oncogenic driver mutations. The Company is also leveraging its extensive experience and capabilities across cancer biology and medicinal chemistry to advance its research on protein degraders. Zentalis has operations in San Diego. For more information, please visit www.zentalis.com. Follow Zentalis on Twitter at @ZentalisP and on LinkedIn at www.linkedin.com/company/zentalis-pharmaceuticals. ZENTALIS® and its associated logo are trademarks of Zentalis and/or its affiliates. All website addresses and other links in this press release are for information only and are not intended to be an active link or to incorporate any website or other information into this press release. Contacts: Elizabeth HickinVice President, Investor Relationsehickin@zentalis.com

2024-07-01

·BioSpace

Zentalis Pharmaceuticals Announces Inducement Grants Under Nasdaq Listing Rule 5635(c)(4) - July 01, 2024

SAN DIEGO, July 01, 2024 (GLOBE NEWSWIRE) -- Zentalis® Pharmaceuticals, Inc. (Nasdaq: ZNTL), a clinical-stage biopharmaceutical company discovering and developing clinically differentiated small molecule therapeutics targeting fundamental biological pathways of cancers, today announced that on July 1, 2024, the Compensation Committee of Zentalis’ Board of Directors granted non-qualified stock options to purchase an aggregate of 40,875 shares of the Company’s common stock to five newly hired employees. The stock options were granted under the Zentalis Pharmaceuticals, Inc. 2022 Employment Inducement Incentive Award Plan (2022 Inducement Plan) as an inducement material to each such individual’s entering into employment with Zentalis in accordance with Nasdaq Listing Rule 5635(c)(4). The 2022 Inducement Plan is used exclusively for the grant of equity awards to individuals who were not previously employees of Zentalis, or following a bona fide period of non-employment, as an inducement material to each such individual’s entering into employment with Zentalis, pursuant to Nasdaq Listing Rule 5635(c)(4). The stock options have an exercise price of $4.19 per share, which is equal to the closing price of Zentalis’ common stock on The Nasdaq Global Market on the date of grant. The stock options have a 10-year term and will vest over four years, with 25% of the options vesting on the first anniversary of the vesting commencement date and the remaining 75% of the options vesting in equal monthly installments over the three years thereafter. Vesting of the stock options is subject to the employee’s continued service to Zentalis on each vesting date. About Zentalis Pharmaceuticals Zentalis® Pharmaceuticals, Inc. is a clinical-stage biopharmaceutical company discovering and developing clinically differentiated small molecule therapeutics targeting fundamental biological pathways of cancers. The Company’s lead product candidate, azenosertib (ZN-c3), is a potentially first-in-class and best-in-class WEE1 inhibitor for advanced solid tumors and hematologic malignancies. Azenosertib is being evaluated as a monotherapy and in combination across multiple clinical trials and has broad franchise potential. In clinical trials, azenosertib has been well tolerated and has demonstrated anti-tumor activity as a single agent across multiple tumor types and in combination with several chemotherapy backbones. As part of its azenosertib clinical development program, the Company is exploring enrichment strategies targeting tumors of high genomic instability, such as Cyclin E1 positive tumors, homologous recombination deficient tumors and tumors with oncogenic driver mutations. The Company is also leveraging its extensive experience and capabilities across cancer biology and medicinal chemistry to advance its research on protein degraders. Zentalis has operations in San Diego. For more information, please visit . Follow Zentalis on Twitter at @ZentalisP and on LinkedIn at . ZENTALIS® and its associated logo are trademarks of Zentalis and/or its affiliates. All website addresses and other links in this press release are for information only and are not intended to be an active link or to incorporate any website or other information into this press release. Contacts: Elizabeth Hickin Vice President, Investor Relations ehickin@zentalis.com

2024-06-20

·同写意

合成致死，难觅风口？一家药企的十年坚持与落寞

同写意20周年大会：中国医药创新未来之路！“意”同创新，穿越周期，赢取未来。7月中旬，苏州金鸡湖畔，让我们与“新药写意人”一起为中国医药创新“同写意”！在今年的ASCO年会上，Zentalis Pharmaceuticals首席执行官Kimberly Blackwell表示，近一两年将得出关于azenosertib单一疗法的活性、安全性及有效性相关数据。但仅过了半个月，这款跑在前面的WEE1抑制剂就被判“死缓”。 6月18日，Zentalis宣布，FDA已暂停azenosertib的3项临床研究，分别是：单药治疗实体瘤的I期剂量递增研究（ZN-c3-001），治疗铂耐药卵巢癌的II期ZN-c3-005（DENALI）研究以及治疗子宫浆液性癌的II期ZN-c3-004（TETON）研究。之所以如此，是因为在DENALI研究中出现两例因疑似败血症而死亡的病例。这对于向市场兜售“合成致死”概念的Zentalis，无疑是又一重打击。 Zentalis成立于2014年，专注于发现和开发针对癌症基本生物学途径的小分子疗法，更具体一点，专注于WEE1抑制剂azenosertib的开发。但这款热门领域中的新兴靶点，并没有给Zentalis带来惊喜，惊吓倒是一个接一个。尽管Zentalis尚未有放弃的打算，但随着此次临床暂停，一系列规划都需要重新调整。问题是，这家Biotech能有多长的窗口期？ 1 “水逆”之年 2022年，WEE1抑制剂集体遭受重创。 8月，第一款进入临床阶段的WEE1抑制剂adavosertib被停止开发。这款产品由阿斯利康在2013年自默沙东引进，曾在欧盟获批孤儿药资格，用于治疗卵巢癌。在临床前研究中，adavosertib增强了化学疗法和放射疗法的抗肿瘤作用。II期临床试验也表明，adavosertib单药治疗对于携带CCNE1基因扩增的难治性实体瘤（特别是上皮性卵巢癌）效果显著，且毒性可控。发表于Clinical Cancer Research的一项临床试验结果也证实，adavosertib联合化疗药治疗原发铂耐药的卵巢癌、输卵管癌、腹膜癌的效果显著，疾病控制率最高可达100%。无论是单药还是联合治疗，adavosertib都有不错的效果。但阿斯利康还是放弃了这款开发近10年的资产，原因是高毒副作用。据悉，adavosertib单药或联合用药均出现频率较高的不良事件，主要为腹泻、呕吐等胃肠道相关及贫血等血液问题。不仅阿斯利康，同样拥有WEE1抑制剂的Nuvation Bio也在同年宣布，其在研究中的WEE1抑制剂NUV-569不再作为重点项目，目前的公司管线中并未展示出这款产品。 Nuvation Bio公司管线，图源：官网对于本次主角Zentalis来说，2022年更是难熬，开年即遭遇股价大跳水，一年跌超75%，到现在都没爬起来。在当年的AACR年会上，已将azenosertib推至Ib期的Zentalis，报告了治疗晚期卵巢癌初期试验数据：在43名可以评估疗效的患者中，组合疗法达到30.2%的客观缓解率（ORR）和86.0%的疾病控制率（DCR）。但对比来看，30%的ORR不及阿斯利康的PARP抑制剂Lynparza表现（ORR 42.6%），且与被阿斯利康放弃的adavosertib相差无几。再者，单看azenosertib亚组，其与PLD连用的ORR仅为12.5%。组合疗法的进展消息见报，Zentalis股价应声跌去30%。 2022年AACR上公布的临床数据虽然数据看起来并没有更有效，但Jefferies的分析师Akash Tewari指出，azenosertib耐受性可能更好。十几天后，辉瑞与Zentalis达成了2500万美元的股权合作，共同推进azenosertib的临床开发。Blackwell也在后来募集了2亿美元，支持公司开发这款WEE1抑制剂用于子宫浆液性癌和实体瘤的治疗。 2 单药完败 Zentali围绕azenosertib开展了十多项临床研究，目前来看，所有处在临床阶段的单药疗法都已被暂停。但Zentalis表示仍将继续推进azenosertib的研究。Kimberly Blackwell指出，在迄今的试验中，已有超过500例患者接受了azenosertib单药治疗，仅DENALI试验就在队列Ib中纳入了超过100例患者。Zentalis将在今年晚些时候分享总体疗效和安全性数据。单药虽然已被搁置，但Zentalis还有很多联合疗法。去年的ASCO会议上，Zentalis分享了azenosertib联合紫杉醇化疗治疗卵巢癌的Ib期研究数据，该研究显示总缓解率为50%，与吉西他滨的联合疗法中，ORR为38.5%。总体而言，目前数据显示，间隔式给药与化疗联合的数据优于SOC联用的方案（紫杉醇+卡铂或PLD+卡铂）。 Zentalis当时表示，这些数据足以开展azenosertib与卡铂或者紫杉醇联用的Cyclin E1+的铂敏感卵巢癌的III期临床研究。最初的计划是在2024年第一季度启动后期试验，但已被推迟到2025年。此外，新闻稿称，Zentalis将于2024年下半年报告I期实体瘤试验，以及azenosertib与GSK的niraparib联合治疗卵巢癌的I/II期试验的最终结果。 Zentalis和GSK的合作始于2021年4月，联合评估azenosertib与PARP抑制剂niraparib在晚期上皮性卵巢癌患者中的治疗功效。 Adavosertib在研管线，图源：Zentalis官网本月初，Zentalis带着azenosertib联合吉西他滨化疗治疗复发性或难治性骨肉瘤的I期试验数据亮相ASCO。该公司指出，在最大耐受剂量下，最常见的3级或以上不良事件是血小板减少和淋巴细胞减少，没有4级血小板减少事件或发热性中性粒细胞减少病例。 3 一个篮子 PARP抑制剂带火了“合成致死”，这是两个非致死基因同时被抑制会导致细胞死亡的现象。在这中间，还有一个重要的概念——DNA损伤修复。细胞不断受到外源性和内源性应激物的干扰，导致可能出现的DNA损伤，从而触发DNA损伤反应，进而激活多种DNA修复通路。抑制肿瘤细胞中的DNA修复机制，也被认为是治疗癌症最有希望的方法之一，DNA损伤修复涉及多种细胞信号通路。在这个领域，PARP抑制剂研究火热。阿斯利康的Lynparza凭借其在该领域的稳固地位，可能会保持竞争优势，但辉瑞的talzenna和强生/GSK的niraparib也在奋起直追，未来可能会与Lynparza形成三足鼎立的态势。与MNC已经较为成熟的产品竞争显然不太明智，另起炉灶挣得FIC才是Biotech的出路。 Zentalis选择的WEE1是DNA损伤修复通路中重要的调控激酶，在多种肿瘤细胞中高度表达。研究发现，当WEE1激酶被抑制时，肿瘤细胞细胞周期进程加速，DNA损伤持续累积，引发肿瘤细胞中的DNA断裂和凋亡，进一步导致肿瘤细胞凋亡。而在这个过程中，WEE1抑制剂可能会对正常细胞也产生一定的影响。高毒副作用是这类疗法的共性问题，此次Zentalis事件中出现的败血症，可能就是因为治疗过程中对于免疫细胞的损伤比较严重，联合疗法或将改善这类情况。比如通过考虑对组合进行优化治疗剂量和方案的研究。联合疗法还可能带来改善耐药等更好的效果。化疗使得DNA损伤，WEE1抑制剂则阻止细胞修复损伤，由此给予癌细胞双重打击。对于有PARP抑制剂产生耐药性的患者来说，WEE1抑制剂与PARP抑制剂联用则使得病人重新获得对药物的“敏感性”。 Azenosertib提高了激酶选择性，副作用相对于同类产品程度较低，且布局WEE1赛道的企业并不多。对于Zentalis来说，虽然还有一款BCL-2抑制剂在研，但仍处在早期阶段。目前所有鸡蛋只有一个篮子能放，是炮灰还是FIC，不妨再等等。参考文献： 1、Zentalis' shares plunge 30% after FDA places WEE1 drug on partial hold over sepsis deaths；fiercepharma 2、止步II期临床？命途多舛的 “Wee 1”；药时代近期直播推荐:

ASCO会议临床结果临床1期孤儿药放射疗法

100 项与 Azenosertib 相关的药物交易

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研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
三阴性乳腺癌	临床2期	美国	Dana-Farber Cancer Institute, Inc.	2024-05-01
三阴性乳腺癌	临床2期	美国	Zentalis Pharmaceuticals, Inc.	2024-05-01
胰腺导管腺癌	临床2期	美国	K-Group Beta, Inc.	2023-11-16
转移性结直肠癌	临床2期	美国	K-Group Beta, Inc.	2023-02-27
转移性结直肠癌	临床2期	澳大利亚	K-Group Beta, Inc.	2023-02-27
转移性结直肠癌	临床2期	德国	K-Group Beta, Inc.	2023-02-27
转移性结直肠癌	临床2期	匈牙利	K-Group Beta, Inc.	2023-02-27
转移性结直肠癌	临床2期	意大利	K-Group Beta, Inc.	2023-02-27
转移性结直肠癌	临床2期	波兰	K-Group Beta, Inc.	2023-02-27
转移性结直肠癌	临床2期	西班牙	K-Group Beta, Inc.	2023-02-27

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分期

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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


NCT04833582 (NCT04833582, ASCO2024)	临床1期	复发性骨肉瘤	31	Azenosertib	簾廠獵獵構網願築鑰範(製遞憲鏇醖憲糧蓋選構) = 憲廠糧窪製衊觸鹹顧壓顧網憲鹹艱醖選壓齋壓 (醖鬱鹽遞齋鬱構衊積夢 )	积极	2024-05-24
NCT04516447 (ASCO2023) 人工标引	临床1期	原发性腹膜癌 \| 卵巢上皮癌 \| 输卵管癌	94	Paclitaxel+Azenosertib	艱憲選簾觸鑰築構遞網(構繭醖糧蓋壓衊觸膚憲) = neutropenia (44.4), thrombocytopenia (30.3), anemia (12.1), leukopenia (11.1), fatigue (10.1), diarrhea (6.1), nausea (5.1), and vomiting (5.1) 壓夢淵鏇鬱網廠築遞窪 (願膚構網獵醖糧網簾廠 )	积极	2023-05-26
NCT04516447 (ASCO2023) 人工标引	临床1期	原发性腹膜癌 \| 卵巢上皮癌 \| 输卵管癌	94	Carboplatin+Azenosertib		积极	2023-05-26
NCT04158336 (ZN-c3-001, AACR2022) 人工标引	临床1期	子宫浆液性癌	12	ZN-c3	艱鏇襯鑰簾壓鏇繭鑰夢(糧製膚窪鑰窪鬱艱蓋膚) = 鑰鹹襯艱願鑰繭糧鹹鹹簾獵憲獵襯鹹鏇窪鬱夢 (夢齋鑰糧鏇餘觸構淵繭 ) 更多	积极	2022-06-15
NCT04516447 (AACR2022) 人工标引	临床1期	卵巢癌 \| 原发性腹膜癌 \| 输卵管癌二线 \| 三线	41	total	醖遞鑰顧鹽夢醖廠艱遞(衊鬱壓遞憲製獵築壓製) = nausea 7.3%, neutropenia 34.1%, thrombocytopenia 17.1%, anemia 9.8%, diarrhea 2.4%, fatigue 2.4%, vomiting 9.8%, leukopenia 7.3%, abdominal pain 7.3%, hypoalbuminemia 2.4%, alanine aminotransferase increased 7.3%, and hypomagnesemia 2.4% 遞蓋鏇鏇餘鏇糧夢網網 (構鬱衊膚範簾糧觸醖獵 ) 更多	积极	2022-06-15
NCT04516447 (AACR2022) 人工标引	临床1期	卵巢癌 \| 原发性腹膜癌 \| 输卵管癌二线 \| 三线	41	carboplatin+ZN-c3		积极	2022-06-15
NCT04158336 (ZN-c3-001, AACR2021) 人工标引	临床1期	HR阳性/HER2低表达实体瘤	39	ZN-c3	膚積繭衊鹹憲鏇夢構膚(壓鹹壓願構範製構鑰顧) = 鹹壓繭鬱積蓋襯鑰遞淵遞膚製積醖夢積鑰膚鹹 (鑰膚窪築壓夢簾夢膚膚 ) 更多	积极	2021-04-10