TACTIVE-U: AN INTERVENTIONAL SAFETY AND EFFICACY PHASE 1B/2, OPEN-LABEL UMBRELLA STUDY TO INVESTIGATE TOLERABILITY, PK, AND ANTITUMOR ACTIVITY OF VEPDEGESTRANT (ARV-471/PF-07850327), AN ORAL PROTEOLYSIS TARGETING CHIMERA, IN COMBINATION WITH OTHER ANTICANCER TREATMENTS IN PARTICIPANTS AGED 18 AND OLDER WITH ER+ ADVANCED OR METASTATIC BREAST CANCER, SUB-STUDY C (ARV-471 IN COMBINATION WITH SAMURACICLIB)

The purpose of this study is to learn about the safety and effects of the study medicine called vepdegestrant. The safety and effects of vepdegestrant will be see when given with other medicines. Vepdegestrant is studied to see if it can be a possible treatment for advanced metastatic breast cancer. This type of cancer would have spread from where it started (breast) to other parts of the body and would be tough to treat.
The study is seeking for participants who have breast cancer that:
* is hard to treat (advanced) and may have spread to other organs (metastatic). is sensitive to hormonal therapy (it is called estrogen receptor positive).
* is no longer responding to treatments taken before starting this study.
This study is divided into separate sub-studies.
For Sub-Study C:
All the participants will receive vepdegestrant and a medicine called samuraciclib.
Vepdegestrant and samuraciclib will be taken once in a day by mouth. The medicines will be taken at home. The experience of people receiving the study medicines will be studied. This will help see if the study medicine is safe and effective.
Participant will continue to take vepdegestrant and samuraciclib until:
* their cancer is no longer responding, or
* side effects become too severe.
They will have visits at the study clinic about every 4 weeks.

开始日期2024-01-10

申办/合作机构

Pfizer Inc.

[+2]

NCT05963984

/ Completed临床2期

An Open-label, Interventional, Multicenter, Randomized, Phase 2 Study of Fulvestrant With or Without Samuraciclib in Participants With Metastatic or Locally Advanced Hormone Receptor (HR) Positive and Human Epidermal Growth Factor Receptor (HER)2-Negative Breast Cancer (BC)

The purpose of this study is to evaluate the safety and efficacy of samuraciclib in combination with fulvestrant versus fulvestrant alone in adult participants with metastatic or locally advanced Hormone Receptor (HR) positive and Human Epidermal Growth Factor Receptor (HER)2-negative breast cancer.

开始日期2023-11-16

申办/合作机构

Carrick Therapeutics Ltd.

[+1]

NCT05963997

/ Active, not recruiting临床1/2期

A Phase 1b/2 Open-label Study of Samuraciclib in Combination With Elacestrant in Participants With Metastatic or Locally Advanced Hormone Receptor-positive and Human Epidermal Growth Factor Receptor 2-negative Breast Cancer

This is an international, multisite, open-label, Phase 1b/2 study, to confirm safety and efficacy of samuraciclib in combination with elacestrant in adult participants with metastatic or locally advanced Hormone Receptor (HR) positive and Human Epidermal Growth Factor Receptor (HER)2-negative breast cancer.

开始日期2023-10-09

申办/合作机构

Carrick Therapeutics Ltd.

[+1]

100 项与 Samuraciclib hydrochloride 相关的临床结果

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项与 Samuraciclib hydrochloride 相关的文献（医药）

2024-05-01·Clinical cancer research : an official journal of the American Association for Cancer Research

Selective CDK7 Inhibition Suppresses Cell Cycle Progression and MYC Signaling While Enhancing Apoptosis in Therapy-resistant Estrogen Receptor–positive Breast Cancer

Article

作者: Naumenko, Sergey ; Cohen Feit, Gabriella ; Schiff, Rachel ; Guarducci, Cristina ; De Angelis, Carmine ; Bergholz, Johann S. ; Shapiro, Geoffrey I. ; Malorni, Luca ; Jeselsohn, Rinath ; Zhao, Jean J. ; Fraenkel, Ernest ; O'Donnell, Madison ; Grinshpun, Albert ; Feiglin, Ariel ; Hermida-Prado, Francisco ; Russo, Douglas ; Zhang, Qi ; Feit, Avery ; Morlando, Antonio ; Nardone, Agostina ; Leventhal, Mathew Joseph ; Liu, Weihan ; Lim, Elgene ; Nagy, Zsuzsanna ; Nguyen, Quang-Dé ; Freelander, Allegra ; Ma, Wen ; Heraud, Capucine ; Huang, Ying ; Kesten, Nikolas ; Huang, Shixia

Abstract:

Purpose::

Resistance to endocrine therapy (ET) and CDK4/6 inhibitors (CDK4/6i) is a clinical challenge in estrogen receptor (ER)-positive (ER+) breast cancer. Cyclin-dependent kinase 7 (CDK7) is a candidate target in endocrine-resistant ER+ breast cancer models and selective CDK7 inhibitors (CDK7i) are in clinical development for the treatment of ER+ breast cancer. Nonetheless, the precise mechanisms responsible for the activity of CDK7i in ER+ breast cancer remain elusive. Herein, we sought to unravel these mechanisms.

Experimental Design::

We conducted multi-omic analyses in ER+ breast cancer models in vitro and in vivo, including models with different genetic backgrounds. We also performed genome-wide CRISPR/Cas9 knockout screens to identify potential therapeutic vulnerabilities in CDK4/6i-resistant models.

Results::

We found that the on-target antitumor effects of CDK7 inhibition in ER+ breast cancer are in part p53 dependent, and involve cell cycle inhibition and suppression of c-Myc. Moreover, CDK7 inhibition exhibited cytotoxic effects, distinctive from the cytostatic nature of ET and CDK4/6i. CDK7 inhibition resulted in suppression of ER phosphorylation at S118; however, long-term CDK7 inhibition resulted in increased ER signaling, supporting the combination of ET with a CDK7i. Finally, genome-wide CRISPR/Cas9 knockout screens identified CDK7 and MYC signaling as putative vulnerabilities in CDK4/6i resistance, and CDK7 inhibition effectively inhibited CDK4/6i-resistant models.

Conclusions::

Taken together, these findings support the clinical investigation of selective CDK7 inhibition combined with ET to overcome treatment resistance in ER+ breast cancer. In addition, our study highlights the potential of increased c-Myc activity and intact p53 as predictors of sensitivity to CDK7i-based treatments.

2024-04-15·Cancer

Cyclin‐dependent kinase inhibitors enhance programmed cell death protein 1 immune checkpoint blockade efficacy in triple‐negative breast cancer by affecting the immune microenvironment

Article

作者: Wu, Jiayi ; Gao, Lu ; Shao, Xiying ; Wang, Wei ; Wang, Xiaojia

ABSTRACT:

Background:

Clinical studies on programmed death‐ligand 1 (PD‐L1) immune checkpoint inhibitors for treating triple‐negative breast cancer (TNBC) have shown unsatisfactory efficacy due to low tumor‐infiltrating lymphocyte (TIL) levels. Inhibitors targeting cyclin‐dependent kinase (CDK) proteins can affect the immune microenvironment, increase TIL levels, and promote antitumor immunity, thus providing a new direction for TNBC treatment strategies.

Methods:

The authors tested three CDK inhibitors on the TNBC cell lines MDA‐MB‐231 and 4T1 and validated their antitumor effects and impact on the immune microenvironment using multiple detection methods. They verified the efficacy and immune‐related mechanisms of different combination therapy experiments in a 4T1 cell‐transplanted BALB/c mouse model.

Results:

Treatment with CDK inhibitors for 72 hours inhibited cell proliferation, clone formation, migration, and cell‐cycle arrest and induced apoptosis in human breast cancer MDA‐MB‐231 cells and mouse breast cancer 4T1 cells. CDK inhibitors suppressed DNA methylation by downregulating DNMT1, DNMT3a, and DNMT3b expression. These three inhibitors promoted the secretion of various chemokines, enhanced tumor cell antigen presentation, and increased PD‐L1 expression. CDK inhibitors improved the efficacy of immunotherapy in animal models and increased TIL levels.

Conclusions:

Combination therapy with CDK and PD‐L1 immune checkpoint inhibitors affects the immune microenvironment, promotes antitumor immunity, and improves the efficacy of immunotherapy for TNBC.

2023-07-01·Transfusion

Pyrophosphate as a novel anticoagulant for storage of whole blood: A proof‐of‐concept study

Article

作者: Maximilian Feth ; Michael Adam Meledeo ; Gema Barrera ; Evan Ross ; Robert V. Hainline

Abstract:

Background:

Citrate is the only anticoagulant currently Food and Drug Administration (FDA)‐approved for the long‐term storage of blood for transfusion. Citrate inhibits phosphofructokinase and may play a pro‐inflammatory role, suggesting that there may be an advantage to using alternative anticoagulants. Here, we examine the use of pyrophosphate as an anticoagulant.

Study design and methods:

Whole blood samples from healthy donors were anticoagulated either with citrate–phosphate–adenine–dextrose (CPDA‐1) or our novel anticoagulant mixture pyrophosphate‐phosphate–adenine–dextrose (PPDA‐1). Samples were assessed for coagulation capacity by thromboelastography immediately after anticoagulation (T0) with and without recalcification, as well as 5 hours after anticoagulation (T1) with recalcification. Complete blood counts were taken at both timepoints. Flow cytometry to evaluate platelet activation as well as blood smears to evaluate cellular morphology were performed at T1.

Results:

No clotting was detected in samples anticoagulated with either solution without recalcification. After recalcification, clotting function was restored in both groups. R‐Time in recalcified PPDA‐1 samples was shorter than in CPDA‐1 samples. A reduction in platelet count at T1 compared to T0 was observed in both groups. No significant platelet activation was observed in either group at T1. Blood smear indicated platelet clumping in PPDA‐1.

Conclusion:

We have shown initial proof of concept that pyrophosphate functions as an anticoagulant at the dose used in this study, though there is an associated loss of platelets over time that may limit its usefulness for blood storage. Further dose optimization of pyrophosphate may limit or reduce the loss of platelets.

项与 Samuraciclib hydrochloride 相关的新闻（医药）

2025-12-21

·精准药物

小分子大环化：CDK大环抑制剂

早研早知道细胞周期蛋白依赖性激酶（CDK）是细胞周期进程和转录的核心调控因子，若是异常激活，则是癌症的标志性特征，是肿瘤治疗的重要靶点。临床中CDK4/6 抑制剂在 HR+/HER2-乳腺癌治疗中取得成功，但现有抑制剂面临着挑战，如：脱靶毒性、耐药性等。大环化策略通过刚性化分子构象，如利用 U 形结合几何结构，显著提升抑制剂的靶向亲和力、亚型选择性、及药代动力学性质（如，代谢稳定性、口服生物利用度）。近日（Dec. 9），Insilico Medicine 在 Future Medicinal Chemistry 上发文，总结了近10年（2015-2015）CDK抑制剂大环化策略的最新研究进展，追溯了从非环骨架出发的结构修饰改造成大环化合物的过程，并重点介绍了当前疗法关键局限性和潜力。 EARLY R&D TALKING CDK 与大环化 01 1.1 关键CDK 亚型的功能分类 CDK 是丝氨酸/苏氨酸激酶家族，通过与周期蛋白形成异二聚体，调控细胞周期和 RNA 聚合酶 II 介导的转录过程，是细胞增殖和基因表达的关键调控节点。人类基因组编码约 20 种细胞周期蛋白依赖性激酶，大致可分为三大功能组：（1）与细胞周期相关的 CDK：CDK1、2、3、4、6；（2）转录相关的 CDK：CKD7、8、9、10、11、12、13、19、20；（3）非典型 CKD：其余。细胞周期由四个有序阶段组成： G1，细胞生长；S，DNA 合成；G2，有丝分裂准备；M，有丝分裂。这些过程保证 DNA 可靠复制和遗传物质精确分离。除细胞周期功能以外，CDKs还关键地调节转录过程。RNA聚合酶II（RNAPII）依赖的转录在多个水平上受到严格控制，包括起始、暂停、延伸和终止。 1.2 临床进展与核心挑战（1）已获批药物： CDK4/6 抑制剂（palbociclib、ribociclib、abemaciclib），用于 HR+/HER2-乳腺癌一线治疗。（2）在研方向： CDK2/7/9 抑制剂（如 samuraciclib、SY-5609）进入临床； PROTACs（如 CDK2 PROTAC NKT3964）进入 I 期研究。（3）现有药物的核心挑战：挑战1，选择性差：CDK 家族 ATP 结合口袋同源性高（如 CDK2 与 CDK1 结合口袋序列同源性～65%），导致脱靶毒性（如骨髓抑制、胃肠道反应）。挑战性2，耐药性：CDK4/6 抑制剂长期使用后，CDK2/cyclin E 复合物异常激活成为主要耐药机制。 1.3 大环化策略的技术优势大环化合物是至少包含12个原子的环状结构药物实体，作为改善激酶抑制剂药物性质的技术备受关注。与线性化合物相比，大环激酶抑制剂有以下优势：（1）提升结合亲和力通过刚性化 U 形结合构象，降低分子结合时的熵损失，进而提升结合亲和力。（2）增强亚型选择性，减少脱靶利用 CDK 亚型间的微小序列差异，靶向独特的亚型结合口袋，提供机会接触到 ATP 结合位点附近、激酶间保守性较低的区域，从而增强亚型选择性，减少脱靶。（3）改善成药性，提高代谢稳定性、膜通透性、口服生物利用度大环结构减少酶解位点暴露，增强细胞膜渗透性，进而改善药代动力学。（4）克服耐药性通过构象刚性化，减少突变对结合作用的影响，进而针对突变型 CDK克服其耐药性。 EARLY R&D TALKING 代表性 CKD 大环抑制剂 02 2.1 CDK2 抑制剂 CDK2在G1/S期转换和DNA复制中起关键作用。CDK2/细胞周期蛋白E复合物的异常激活被认为是HR+乳腺癌对CDK4/6抑制剂产生耐药的关键机制之一。因此，开发选择性 CDK2 抑制剂，特别是与 CDK4/6抑制剂联合使用，是一种实现更全面的细胞周期抑制和改善治疗结果的潜力策略。开发选择性CDK2抑制剂的主要挑战在于CDK2与CDK1在结合口袋具有约65%的序列同源性，导致大多数临床阶段CDK2抑制剂对CDK1的选择性不足。（1）实例1：QR-6401 Regor Therapeutics 利用生成模型和基于结构的药物设计，从其先导分子PF-07104091出发，通过片段替换和后续的大环化连接头优化，最终得到了大环化合物QR-6401。关键的突破是对化合物2 与 CDK2/周期蛋白E1的共晶结构研究中，发现了 U 形结合取向，将氨基甲酸酯基序与吡啶环通过大环化稳定住构象，进而再经过 ADME 优化。该化合物在CDK2生化分析和OVCAR3细胞实验中表现出相当的效力，IC50 = 0.37 nM，CDK2/CDK1 选择性为 59 倍，口服有效，同时改善了人肝微粒体稳定性，并在异种移植模型中显示出强大的抗肿瘤活性。（2）杭州医学院实例杭州医学院团队基于已报道的大环 CDK2/5/7/9泛抑制剂进行 SAR 研究，通过结构优化改善，改善了选择性和代谢稳定性。此外，多项专利也披露了基于 PF-07104091 分子内环化的大环 CDK2 抑制剂，如下图。 CDK2 大环抑制剂的研究：（1）重点解决了与 CDK1 的高同源性导致的毒性问题。（2）技术应用方面，突出了通过 AI 生成模型，结合基于结构的优化设计的技术整合。 2.2 CDK4/6 抑制剂 CDK4和CDK6是G1/S期转换的关键调节因子。已批准的CDK4/6抑制剂在临床上常因耐药性和剂量限制性毒性而获益有限。（1）Baicreat、Camphor 实例专利中，多家机构分别披露了CDK4/6大环抑制剂，这些化合物显示出纳摩尔级的CDK4/6抑制活性，部分化合物还表现出对其他激酶（如ALK、ROS1）的抑制活性，或相较于大环化前体具有更强的细胞活性。如下图中，杭州Baicreat的化合物11，以及Camphor 制药的化合物12。（2）Insilico Medicine 实例鉴于 CDK2 抑制剂在克服对 CDK4/6 抑制剂的耐药性方面的既定作用，英矽智能采用生成化学方法设计了大环 CDK2/4/6 抑制剂，如下图。从已知的非环抑制剂inixaciclib出发，通过生成式AI工作流程进行环化，并经过多轮优化得到先导化合物16。该化合物表现出强大的酶抑制活性，在癌症细胞系中优于母体化合物，并具有优化的类药性，如改善的肝微粒体稳定性、药代动力学性质和降低的hERG抑制。 CDK4/6 大环抑制剂的研究：（1）旨在克服前体的耐药性和毒性（2）采用生成式 AI 工作流程，对前体进行环化，结构优化改善。 2.3 CDK7 抑制剂 CDK7在细胞周期调控和转录控制中具有双重作用，在多种恶性肿瘤中异常过表达。开发选择性CDK7抑制剂面临ATP口袋在激酶间高度保守的挑战。（1）上海有机所和杭州医学所案例以非环先导化合物CT7001为起点，通过基于结构的晶体结构研究，在大环化策上进行探索，锁定其生物活性构象，得到了选择性、ADME属性得到改善的大环化合物20。（2）Insilico Medicine案例研究人员利用生成式大环化平台重新设计临床CDK7抑制剂SY-5609，以解决熵驱动的结合低效问题。通过预组织其生物活性构象并进行后续优化，得到了化合物24，该化合物保持了强大的抑制活性，改善了细胞活性、渗透性和口服生物利用度，并在异种移植模型中显示出强大的肿瘤生长抑制效果，且可能减轻与母体化合物相关的胃肠道和血液学毒性 CDK7 大环抑制剂的研究：（1）针对转录和细胞周期双重功能，改善相对于 CDK2 的选择性；（2）一方面基于传统的晶体学结构研究，另一方面利用AI生成式大环化平台。 2.4 CDK9 抑制剂 CDK9是mRNA转录延伸的关键调节因子，其失调驱动多种恶性肿瘤的发生。CDK9抑制剂在血液系统恶性肿瘤中显示出显著的临床前景。（1）实例1 为克服奥希替尼耐药的非小细胞肺癌（NSCLC），通过表型筛选发现先导化合物，并利用基于结构的设计和大环化来刚性化分子以提高选择性。经过多轮SAR和ADME优化，最终得到化合物28。该化合物具有优异的CDK9选择性、良好的代谢稳定性和口服生物利用度，在耐药NSCLC的类器官和异种移植模型中有效抑制肿瘤生长，且与BRD4抑制剂JQ1联用显示出协同效应。（2）专利进展拜耳的科学家也披露了选择性大环CDK9激酶抑制剂，其先导化合物显示出卓越的生化效力和延长的靶标停留时间。 CDK9 大环抑制剂的研究：（1）聚焦于克服肿瘤的靶向治疗耐药性；（2）主要通过基于结构的晶体学研究，通过大环化刚性改造，获得高选择性、改善药代性质。 EARLY R&D TALKING 总结与展望 03 CDK在细胞周期进程和转录调控中不可或缺，其异常活性是许多恶性肿瘤的标志。大环化策略已被有效地用于设计靶向CDK2、CDK4/6、CDK7和CDK9的抑制剂，以克服选择性挑战。与需要超出“五规则”大骨架的非激酶靶标不同，大环CDK抑制剂利用相对较小的环并保持较低的分子量。如上表，这些大环化合物与其无环前体相比，通常表现出更高的结合亲和力、改善的选择性和增强的ADME性质。大环化设计过程通常涉及将具有U形结合几何构象的无环抑制剂转化为大环化合物，利用晶体结构分析、分子动力学模拟、和AI驱动生成模型等识别合适的连接位点，系统地设计和优化连接头的化学类型和长度，以预组织其生物活性构象。尽管大环激酶抑制剂的发现取得了重大进展，但尚无大环CDK抑制剂进入临床试验，可能原因包括：（1）SAR复杂性：大环化显著增加了构效关系的复杂性，对细微结构变化高度敏感，其构象预测困难。（2）计算挑战：大环生成策略面临数据稀缺、构象限制的双重性挑战以及设计准确性验证不足等局限性。（3）药代动力学障碍：大环化合物往往表现出不利的药代动力学性质，如溶解性差、代谢清除快、口服生物利用度低。（4）合成复杂性：合成难度可能阻碍大规模生产和快速类似物生成。尽管如此，大环化仍然是提高激酶抑制剂选择性、效力和类药性的有力方法。随着药物化学、AI驱动设计和合成方法的不断进步，开发具有更优生物活性、选择性和药代动力学特征的大环化合物前景可期。参考文献： DOI: 10.1080/17568919.2025.2599648 声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号粉丝群/投稿/授权/广告等请联系公众号助手觉得本文好看，请点这里↓

蛋白降解靶向嵌合体临床结果临床1期

2025-12-10

·carricktherapeutics.com

Carrick Therapeutics Announces Positive Results from Phase 2 Randomized Trial of Samuraciclib in Combination with Fulvestrant in Patients with Hormone Receptor Positive, HER2 Negative Advanced Breast Cancer

Overall response rate (ORR) of 55% and median progression-free survival of 14.5 months in patients without TP53 gene mutation Phase 2 results presented at 2025 San Antonio Breast Cancer Symposium BOSTON, Dec. 10, 2025 (GLOBE NEWSWIRE) -- Carrick Therapeutics Inc., an oncology-focused biopharmaceutical company discovering and developing highly differentiated therapies, today announced positive results from the Phase 2 SUMIT-BC clinical trial evaluating samuraciclib in combination with fulvestrant in patients with second-line advanced hormone receptor positive (HR+) and human epidermal growth factor receptor 2 negative (HER2-) breast cancer who were previously treated with a CDK4/6 inhibitor therapy. The clinical trial results were presented today in a late-breaking poster presentation at the 2025 San Antonio Breast Cancer Symposium (SABCS). Samuraciclib is an oral first-in-class CDK7 inhibitor (CDK7i). “These Phase 2 trial results show that samuraciclib in combination with fulvestrant provided a very notable and clinically meaningful benefit in a broad patient population with HR positive, HER2 negative metastatic breast cancer whose disease progressed following treatment with a CDK4/6 inhibitor. Carrick now has positive efficacy and safety data from three independent clinical trials of samuraciclib in advanced breast cancer,” said Tim Pearson, Chief Executive Officer of Carrick Therapeutics. “The best-in-class PFS and ORR of samuraciclib positions it to be a meaningful therapy that could transform how women with advanced breast cancer are treated following treatment with CDK4/6 inhibitors. We have achieved clinical proof of concept and look forward to advancing samuraciclib into a Phase 3 clinical trial in 2026 to build on these promising results.” Results among study participants without a TP53 gene mutation per baseline circulating tumor DNA (ctDNA), a pre-specified stratification, indicated improved CBR, ORR and mPFS compared to those with the mutation. In the trial, the median PFS of samuraciclib combined with fulvestrant in this TP53wt population was 14.5 months versus 6.8 months with fulvestrant alone, an incremental improvement of 7.7 months. “Identifying the optimal treatment strategy for patients with HR positive, HER2 negative breast cancer following progression on CDK4/6 inhibitor therapy remains a significant clinical challenge,” said Dr. Sonia Pernas, Breast Medical Oncologist at the Catalan Institute of Oncology, L’Hospitalet, Barcelona (Spain), and lead author of the SABCS poster. “The SUMIT-BC results indicate that the combination of samuraciclib and fulvestrant may offer a promising new therapeutic option, with the potential for particularly favorable outcomes in patients with TP53 wild-type tumors.” “We are encouraged by the results of the SUMIT-BC trial of samuraciclib, which demonstrated strong efficacy and durable responses regardless of ESR1 or PI3K mutation status with a tolerable side effect profile,” said Dr. Stuart McIntosh, Chief Medical Officer of Carrick Therapeutics. “SUMIT-BC is now the third study to demonstrate enhanced efficacy in the TP53wt patient population, which makes up 70% of patients in second line setting. The use of baseline ctDNA means this selection biomarker should be straightforward to integrate into clinical practice.” The late-breaking poster presentation at the 2025 San Antonio Breast Cancer Symposium is available on the Posters & Publications page of Carrick Therapeutics’ website. About the Phase 2b SUMIT-BC Trial SUMIT-BC is a randomized, multicenter Phase 2b clinical trial (NCT05963984) evaluating the efficacy and safety of oral samuraciclib (360mg or 240mg) in combination with fulvestrant, an intramuscularly injected selective estrogen receptor degrader (SERD), versus fulvestrant alone in 60 patients with HR+, HER2- locally advanced or metastatic breast cancer who were previously treated with a CDK4/6 inhibitor and aromatase therapy. The primary endpoint is clinical benefit rate, defined as the overall compete response (CR), partial response (PR) or stable disease (SD) ≥ 24-weeks according to RECIST version 1.1 from randomization until disease progression or death due to any cause. Secondary endpoints included objective response rate, duration of response, progression-free survival and safety. About Samuraciclib (CT7001) Samuraciclib is the most advanced cyclin dependent kinase 7 (CDK7) inhibitor in clinical development. Inhibiting CDK7 is a promising therapeutic strategy in cancer, as CDK7 regulates the transcription of cancer-causing genes, promotes uncontrolled cell cycle progression, and promotes resistance to anti-hormone therapy. Samuraciclib, an oral CDK7 inhibitor, has demonstrated a favorable safety profile and encouraging efficacy in early clinical studies in HR+ breast cancer. CDK7 activity mechanistically suppresses the TP53 gene so when CDK7 is inhibited, the activity of p53 is restored thereby further adding to the suppression of tumors by CDK7 inhibition (Reference below). TP53 status is available using commercially available ctDNA tests. Because of its ability to inhibit CDK7, samuraciclib has the potential to treat prostate, pancreatic, small cell lung cancer, triple negative breast (TNBC), ovarian and colorectal cancers. Samuraciclib was discovered by scientists at Imperial College London, in work funded by Cancer Research UK and has been granted Fast Track designation from the U.S. Food and Drug Administration (FDA) for use in combination with fulvestrant for the treatment of CDK4/6i resistant HR+, HER2- advanced breast cancer. About Carrick Therapeutics Carrick Therapeutics is an oncology-focused biopharmaceutical company developing highly differentiated novel therapies that address significant unmet needs. The Company’s lead program, samuraciclib, is a novel oral first-in-class inhibitor of CDK7 currently in multiple Phase 2 clinical trials for metastatic HR+ breast cancer. Additionally, Carrick is developing CT7439, a novel CDK12/13 inhibitor / Cyclin-K glue-degrader, which is currently in a Phase 1 clinical trial. Reference: Wang, Y., Zhang, Z., Mi, X. et al. Elevation of effective p53 expression sensitizes wild-type p53 breast cancer cells to CDK7 inhibitor THZ1. Cell Commun Signal 20, 96 (2022). https://doi.org/10.1186/s12964-022-00837-z For more information about Carrick Therapeutics, please visit www.carricktherapeutics.com Carrick Contacts Carrick Therapeutics Jenny Horsfield, Chief Business Officer jenny.horsfield@carricktherapeutics.com Investors and Media Luke Heagle, Real Chemistry lheagle@realchemistry.com Released December 10, 2025

临床2期临床结果快速通道临床1期

2025-11-13

·医疗科技高峰论坛

AI赋能药物开发的Recursion实践

11月5日，Recursion（纳斯达克股票代码：RXRX），一家领先的临床阶段TechBio公司，致力于解码生物学以彻底改善生活，公布了截至2025年9月30日的第三季度业务更新和财务业绩。 Recursion联合创始人兼首席执行官Chris Gibson表示：“Recursion持续在我们的内部管线、战略合作伙伴关系以及Recursion OS的持续构建和完善方面取得进展。在合作伙伴关系方面，我们自豪地宣布，随着罗氏和基因泰克合作中我们第二张神经图谱的被选择，我们迄今已从合作伙伴处获得超过5亿美元的预付款和里程碑付款，同时我们持续为一些最棘手的疾病领域提供新颖见解并推进项目。这只是我们期望在平台投资上看到回报的开始。凭借强劲的现金储备可支撑至2027年底，我们期待推进我们的管线，并证明构建一个端到端的人工智能赋能平台——将海量专有数据集与行业领先的超算能力和复杂的人工智能模型相结合——是我们行业实现真正变革所需的关键基础设施。” 业务亮点摘要产品组合-内部及合作项目 Recursion首席研发官兼首席商务官Najat Khan表示：“我们在本季度的进展突显了将Recursion OS转化为有意义的管线动力的能力。我们持续推进临床项目，TUPELO研究中的REC-4881将在今年晚些时候获得更多数据。我们还将REC-617推进至其首个联合用药研究，并提名REC-7735为新的开发候选药物。在合作方面，与罗氏和基因泰克交付我们首创的小胶质细胞图谱，彰显了表型组学如何在神经科学和其他复杂疾病领域开辟新疆域。这些大胆而务实的步骤——无论是在我们自己的项目中还是通过合作——在我们努力将平台洞察转化为为患者带来变革性药物的过程中至关重要。” 内部管线更新 REC-617 (CDK7)： Recursion宣布其评估REC-617（一种精准设计的口服CDK7抑制剂）的ELUCIDATE 1/2期试验取得进展。单药剂量递增研究确定了最大耐受剂量（MTD）为每日一次10毫克，显示出可控的安全性特征和与2024年12月更新一致的初步抗肿瘤活性。截至2025年9月29日，29名经过多线治疗的晚期实体瘤患者接受了跨越六个剂量水平的REC-617治疗。治疗通常耐受性良好，最常见的剂量限制性毒性（DLT）是恶心和血小板减少症。≥3级的治疗相关不良事件（TRAE）发生在27.6%的患者（n=8）中，未报告4级/5级TRAE。仅有6.9%（n=2）因TRAE而停药。重要的是，REC-617报告的胃肠道相关毒性发生率与其best-in-class潜力相符。具体而言，REC-617治疗常见的胃肠道毒性为腹泻（69%）、恶心（41%）和呕吐（28%）。Samuraciclib治疗报告的毒性也包括腹泻（82%）、恶心（77%）和呕吐（80%）（Coombes等人，2023）。 REC-617已显示出早期的抗肿瘤活性，包括一例确认的部分缓解和五例疾病稳定。药代动力学数据支持剂量比例暴露、快速吸收和短半衰期（约5小时），这与其作为选择性、可逆CDK7抑制剂的设计一致。 ELUCIDATE研究现已扩展至二线及以上铂耐药卵巢癌（PROC），一个2期单药治疗队列正在进行中，一个1期联合用药组已启动。联合方案包括贝伐珠单抗加紫杉醇或聚乙二醇化脂质体阿霉素（PLD）。Recursion还利用Recursion OS的洞察力探索其他适应症和给药方案以用于扩展队列。 REC-7735 (PI3Kα H1047R)： Recursion宣布了REC-7735的进展，该药物已被提名为开发候选药物，目前正在进行支持新药临床试验申请（IND）的研究。REC-7735是利用Recursion OS生成的精准设计的PI3K⍺ H1047R抑制剂。在临床前研究中，REC-7735在低剂量下表现出显著的肿瘤消退，优于已获批的药物，同时对野生型PI3K⍺保持高选择性（>100倍），以降低剂量限制性高血糖症的风险。凭借差异化的临床前疗效和耐受性特征，REC-7735有潜力成为治疗携带该突变的乳腺癌和其他实体瘤的best-in-class PI3K⍺ H1047R抑制剂。即将到来的里程碑： 1.REC-4881 (MEK1/2)：来自2期TUPELO研究的家族性腺瘤性息肉病（FAP）额外数据预计于2025年12月公布 2.REC-1245 (RBM39)：早期1期安全性和药代动力学（PK）单药数据预计于2026年上半年（1H26）公布 3.REC-3565 (MALT1)：早期1期安全性和PK单药数据预计于2027年上半年（1H27）公布 4.REC-102 (ENPP1)：潜在的1期试验启动预计于2026年下半年（2H26） 5.REC-7735 (PI3Kα H1047R)：潜在的1期试验启动预计于2026年下半年（2H26） 6.Recursion有望在2026年底前获得超过1亿美元的里程碑付款多个项目在未来12个月内正朝着潜在的开发候选药物指定推进通过利用Recursion OS，多个神经科学靶点验证项目正在推进合作研发更新：随着第二张神经图谱的验收以及来自罗氏和基因泰克的3000万美元里程碑付款，Recursion迄今已从其合作伙伴处获得超过5亿美元的预付款和里程碑付款。这一里程碑使Recursion跻身于少数实现如此规模的商业化前生物技术公司之列，突显了其合作战略的实力。这些合作不仅支持Recursion OS的维护和扩展，还提供了接触领先生物制药公司见解的机会，以及未来潜在超过100亿美元的里程碑付款，以及Recursion可能不会独立追求的适应症领域的特许权使用费。罗氏和基因泰克：Recursion宣布已从其合作伙伴罗氏和基因泰克处获得第二笔3000万美元的里程碑付款。该付款是在验收了关于小胶质细胞（对大脑健康至关重要，并与多种神经退行性和神经炎症性疾病相关）的新型全基因组表型图谱（“phenomap”）之后进行的。 a. 该里程碑是一项持续10年以上大型合作的一部分，旨在为神经科学和胃肠肿瘤学领域多达40个项目发现新靶点并开发潜在治疗方法。 b. Recursion、罗氏和基因泰克共同从第一张专注于神经科学的表型图谱中识别出许多可能成为新关注靶点的生物学见解。 c. 罗氏和基因泰克已经选择了一个胃肠肿瘤学的初始项目，并且基于迄今为止合作伙伴已接受的4张全基因组胃肠肿瘤学表型图谱，正在探索额外的潜在靶点/项目。 d. 迄今为止，Recursion通过该合作已获得2.13亿美元的预付款和里程碑付款。赛诺菲： Recursion和赛诺菲继续推进针对肿瘤学和免疫学领域多达15个best-in-class或first-in-class项目的多靶点合作，迄今为止已获得1.3亿美元的预付款和里程碑付款。每个项目都有潜力获得超过3亿美元的里程碑付款。 a. 赛诺菲继续利用整合的Recursion OS 2.0（包括表型组学）来识别新的项目机会。 b. Recursion和赛诺菲正在进一步推进并扩大其在肿瘤学和免疫学领域的联合管线。 c. 多个项目在未来12个月内正朝着潜在的先导化合物系列和开发候选药物指定推进。平台 Recursion OS 2.0：该平台通过在多模态生物学、精准设计和临床开发中整合人工智能，持续推动项目开发——实现更快、更高效、更具创新性的药物发现和开发。 2025年第三季度财务业绩现金状况：截至2025年9月30日，现金、现金等价物及受限现金为6.671亿美元，而截至2024年12月31日为6.030亿美元。截至2025年10月9日（未经审计），现金及现金等价物约为7.85亿美元，此前公司在2025年第三季度和第四季度通过其场内发行（ATM）机制获得了3.875亿美元的净收益，该机制现已完全使用并结束。基于当前的运营计划且无需额外融资，公司预计现金储备可支撑运营至2027年底。收入：总收入（主要包括来自合作协议的收入）在2025年第三季度为520万美元，而2024年第三季度为2610万美元。年度变动的主要原因是2024年8月因第一张表型图谱达成来自罗氏（Roche）和基因泰克（Genentech）的3000万美元里程碑付款，而2025年10月在协议下达成的第二笔3000万美元里程碑（公司预计将在2025年第四季度确认部分作为收入）。研发开支： 2025年第三季度的研发开支为1.211亿美元，而2024年第三季度为7460万美元。增加的驱动因素主要是与收购REC-102（Recursion的ENPP1抑制剂）全部权利相关的购买型知识产权（IPR&D）支出增加，以及公司在2024年11月与Exscientia的业务合并。一般和管理开支： 2025年第三季度的一般和管理开支为4160万美元，而2024年第三季度为3780万美元。与上一期间相比的增加主要源于与Exscientia业务合并后的一般和管理开支纳入。净亏损： 2025年第三季度的净亏损为1.623亿美元，而2024年第三季度的净亏损为9580万美元。运营现金流：截至2025年9月30日的九个月运营活动净现金流为3.257亿美元，而截至2024年9月30日的九个月运营活动净现金流为2.437亿美元。运营现金流使用量增加的主要驱动因素是纳入Exscientia的运营（该业务合并在2024年11月完成）。同时还包括与2025年6月宣布的重组活动相关的770万美元遣散费支付。关于Recursion Recursion（纳斯达克代码：RXRX）是一家处于临床阶段的TechBio公司，通过解码生物学以彻底改善生活而引领行业。其使命的实现依赖于Recursion OS，这是一个跨多种技术构建的平台，持续生成全球最大的专有生物和化学数据集之一。Recursion利用复杂的机器学习算法，从其数据集中提炼出在生物学和化学领域中数万亿个可搜索关系，不受人类偏见的影响。通过掌控大规模实验能力——每周进行高达数百万个湿实验室实验——和大规模计算能力——拥有并运营全球最强大的超级计算机之一，Recursion正将技术、生物学和化学结合起来，以推进医学的未来。 Recursion总部位于盐湖城，是犹他州生命科学行业联盟BioHive的创始成员。公司在蒙特利尔、纽约、伦敦和牛津地区也设有办公室。智药邦

引进/卖出临床1期

100 项与 Samuraciclib hydrochloride 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB16061

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
HR阳性/HER2阴性乳腺癌	临床2期	法国	Carrick Therapeutics Ltd.	2023-10-09
HR阳性/HER2阴性乳腺癌	临床2期	英国	Carrick Therapeutics Ltd.	2023-10-09
局部晚期乳腺癌	临床2期	法国	Carrick Therapeutics Ltd.	2023-10-09
局部晚期乳腺癌	临床2期	英国	Carrick Therapeutics Ltd.	2023-10-09
转移性乳腺癌	临床2期	法国	Carrick Therapeutics Ltd.	2023-10-09
转移性乳腺癌	临床2期	英国	Carrick Therapeutics Ltd.	2023-10-09
晚期恶性实体瘤	临床2期	美国	Carrick Therapeutics Ltd.	2017-11-14
晚期恶性实体瘤	临床2期	英国	Carrick Therapeutics Ltd.	2017-11-14
去势抵抗性前列腺癌	临床2期	美国	Carrick Therapeutics Ltd.	2017-11-14
去势抵抗性前列腺癌	临床2期	英国	Carrick Therapeutics Ltd.	2017-11-14

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临床结果

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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


NCT05963984 (SUMIT-BC, Company_Website) 人工标引	临床2期	HR阳性/HER2阴性乳腺癌 HER2 Negative \| HR Positive	60	Samuraciclib+Fulvestrant	選蓋餘壓網糧網襯繭觸(網餘夢獵齋範觸鏇衊夢) = 鹽憲顧製廠鏇淵鏇餘觸築製願糧鹽鏇鹹鬱糧襯 (選夢繭廠鹹醖憲齋鹽餘 ) 更多	积极	2025-12-10
				Samuraciclib+Fulvestrant (people who TP53 mutation not detected)	選蓋餘壓網糧網襯繭觸(網餘夢獵齋範觸鏇衊夢) = 築顧鹽窪鏇蓋壓鹽顧遞築製願糧鹽鏇鹹鬱糧襯 (選夢繭廠鹹醖憲齋鹽餘 ) 更多
NCT04802759 \| NCT03363893 (CT7001_001 and MORPHEUS, ESMO_BC2025)	临床1/2期	HR阳性乳腺癌	-	SAM 240mg + FUL	鏇蓋廠鏇範製蓋餘齋範(鬱鑰壓窪願醖鏇淵餘顧) = 選壓襯製窪襯壓築鹹艱選簾網衊憲餘艱壓鹽膚 (憲糧願膚齋繭襯繭願積 )	积极	2025-05-14
				SAM 360mg + FUL	鏇蓋廠鏇範製蓋餘齋範(鬱鑰壓窪願醖鏇淵餘顧) = 醖膚壓廠築壓窪壓壓觸選簾網衊憲餘艱壓鹽膚 (憲糧願膚齋繭襯繭願積 )
NCT03363893 (Pubmed \| Nat Commun)	临床1期	晚期乳腺癌	124	samuraciclib (Module 1A)	鬱艱遞構鏇觸蓋襯構範(鑰鹽衊獵築顧糧窪廠構) = dose proportionality (120 mg-480 mg), a half-life of approximately 75 hours, and no fulvestrant interaction 簾夢簾衊壓齋襯製網憲 (糧鹽網窪鑰鑰獵齋糧膚 ) 更多	-	2023-07-24
				samuraciclib (Module 2A)
P1-18-10 (SABCS2022)	临床1期	晚期三阴性乳腺癌	23	Samuraciclib 360mg OD	廠夢襯壓壓鹹觸繭艱範(夢簾觸蓋淵觸簾願淵餘) = following disease progression by RECIST 積鬱築膚觸築選構網艱 (蓋廠糧淵廠積範醖鏇憲 ) 更多	积极	2022-02-15