A Phase 1, Open-Label, Multicenter Study to Evaluate the Safety and Efficacy of the Oral Cyclin A/B-RxL Inhibitor CID-078 in Patients With Advanced Solid Tumor Malignancies

This is a first-in-human, multicenter, open-label, phase 1 study to evaluate safety, tolerability, and efficacy of CID-078, a Cyclin A/B-RxL inhibitor, in patients with advanced solid tumors.

开始日期2024-08-14

申办/合作机构

Circle Pharma, Inc.

100 项与 Cyclin A/B抑制剂(Circle) 相关的临床结果

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100 项与 Cyclin A/B抑制剂(Circle) 相关的转化医学

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100 项与 Cyclin A/B抑制剂(Circle) 相关的专利（医药）

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项与 Cyclin A/B抑制剂(Circle) 相关的文献（医药）

2024-07-31·Journal of Agricultural and Food Chemistry

Identification of Sarmentosin as a Key Bioactive from Blackcurrants (Ribes nigrum) for Inhibiting Platelet Monoamine Oxidase in Humans

Article

作者: Walker, Edward G ; Ngametua, Nayer ; Günther, Catrin S ; Kanon, Alexander P ; Trower, Tania M ; Cooney, Janine M ; Bloor, Stephen J ; Lomiwes, Dominic ; Lo, Kim ; Jensen, Dwayne A ; Sawyer, Greg ; Hedderley, Duncan

Previous clinical studies indicate that monoamine oxidase-B (MAO-B) inhibition by blackcurrants must be predominantly attributed to bioactives other than anthocyanins. In this natural products discovery study, MAO-A/B inhibitory phytochemicals were isolated from blackcurrants, and a double-blind crossover study investigated the efficacy of freeze-dried whole-fruit blackcurrant powder in inhibiting MAO-B compared with blackcurrant juice in healthy adults. Platelet MAO-B inhibition was comparable between powder (89% ± 6) and juice (91% ± 4), and it was positively correlated with MAO-modulated plasma catecholamines, subjective alertness, and reduced mental fatigue, assessed using the Bond-Lader questionnaire. Sarmentosin, a nitrile glycoside, and its hydroxycinnamoyl esters were identified as novel MAO-A/B inhibitors from blackcurrant in vitro, and sarmentosin was demonstrated to inhibit platelet MAO-B activity in vivo. These findings confirm sarmentosin as the primary bioactive for MAO-A/B inhibition in blackcurrants, as well as its bioavailability and stability during freeze-drying, and suggest that consuming blackcurrant powder and juice may positively affect mood in healthy adults.

2024-05-01·Journal of Chromatography B

Simultaneous mass spectrometric quantification of trace amines, their precursors and metabolites

Article

作者: van der Ley, Claude P ; Kema, Ido P ; van Faassen, Martijn ; de Bruyn, Krisztina ; Diekman, Eugene F

OBJECTIVESTrace amines are powerful neuromodulators influencing the release and reuptake of catecholamines. These low concentrated endogenous amines impact mood, cognition, and hormone regulation. Dysregulation of trace amines have been associated with a variety of diseases, such as schizophrenia, Parkinson's disease, migraine, depression and more. Succesfull simultaneous quantification of trace amines, their precursors and metabolites would benefit both research and patient care. Since these compounds have various functional groups and are present in biological matrices with large concentration difference, their simultaneous quantification is an analytical challenge. Our goal was to develop a highly sensitive LC-MS/MS assay to simultaneously quantify trace amines, their precursors and metabolites in plasma.METHODSOur method is based on a simple two-step in-matrix derivatization protocol: propionic anhydride (PA) and 3-Ethyl-1-[3-(dimethylamino)propyl]carbodiimide (EDC) in combination with 2,2,2-trifluoroethylamine (TFEA) followed by online solid phase extraction combined with LC-MS/MS. Fifteen metabolites can be measured simultaneously, three precursors, eight trace amines and four metabolites. Validation of this method was performed according to international validation guidelines. The pre-analytical stability of trace amines was assessed.RESULTSThis novel method was successful in quantifying trace amines, their precursors, and metabolites in plasma. Using just 50 µl human plasma, we were able to accomplish limit of quantification for 2-phenylethylamine and N-methyl-phenylethylamine of 0.2 nmol/L and 0.1 nmol/L for tyramine and n-methyltyramine. Inter-and intra-assay imprecision was < 15 % for all analytes. Stability assessment showed susceptibility of certain trace amines e.g. 2-phenylethylamine and N-methyl-phenylethylamine to enzymatic degradation in plasma. The addition of the monoamine oxidase inhibitor pargyline to plasma prevented this enzymatic degradation.CONCLUSIONSWe developed a novel LC-MS/MS method that1) uses a new double derivatization technique, 2) is automated with online SPE, 3) uses far less sample volume then previous methods and 4) detects more components in the same sample (eight trace amines, three precursors, and four metabolites) with high specificity and selectivity. Furthermore, addition of MAO A/B inhibitor prevents degradation and guarantees more accurate quantification of trace amines.

2021-04-01·Current Microbiology4区 · 生物学

Whole-Genome Sequence Analysis of Paenibacillus alvei JR949 Revealed Biosynthetic Gene Clusters Coding for Novel Antimicrobials

4区 · 生物学

Article

作者: Karthikeyan, Raman ; Rajendhran, Jeyaprakash ; Mahalakshmi, Balasubramanian ; Sivakumar, Ramamoorthy ; Pranav, Parameswaran Sree

The increased prevalence of multidrug-resistant pathogens poses a significant clinical threat, and hence, the discovery of novel antibiotics is the need of the hour. Several attempts are being made worldwide to screen and identify newer antibiotics from various microbial sources. The genus Paenibacillus is known for its biosynthetic potential and metabolic versatility in producing several secondary metabolites. In this study, we isolated Paenibacillus alvei strain JR949 from the soil, which exhibited antimicrobial activity against Enteropathogenic Escherichia coli (EPEC), Pseudomonas aeruginosa (PAO1), and methicillin-resistant Staphylococcus aureus (MRSA). The whole genome of this strain was sequenced using the Illumina platform. The genome mining of the draft genome sequence revealed a total of 31 biological gene clusters (BGCs) responsible for the synthesis of secondary metabolites. The construction of the similarity network of the BGCs and the comparative analysis with the genetically related strains aided the identification of metabolites produced by this strain. We identified BGCs coding for paenibactin, paenibacterin, anabaenopeptin NZ857, icosalide A/B, polymyxin, and bicornutinA1/A2 with 100% similarity. The BGCs with lower sequence similarity to paenibacterin, polymyxin B, colistin A/B, pellasoren, tridecaptin, pelgipeptin, and marthiapeptide were also identified. Furthermore, 13 putative NRPS BGCs, 3 NRPS-T1PKS hybrid clusters, a T1PKS, and a bacteriocin BGC were identified with very low similarity (≤ 25%) or no similarity with known antibiotics. Further experimental investigations may result in the discovery of novel antimicrobial drugs.

项与 Cyclin A/B抑制剂(Circle) 相关的新闻（医药）

2024-10-23

·BioSpace

Circle Pharma’s First-in-Class Oral Macrocycle Cyclin A/B RxL Inhibitor, CID-078, Preclinical Data Highlighted at the 36th EORTC-NCI-AACR Symposium

SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)-- #BreastCancer --Circle Pharma, a clinical-stage biopharmaceutical company dedicated to discovering and developing a new generation of macrocycle therapies, today announced that preclinical data from its lead candidate, CID-078, a first-in-class oral macrocycle cyclin A/B RxL inhibitor, has been selected for a late-breaking poster presentation at the 36th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, also known as the Triple Meeting. The symposium is taking place from October 23-25, 2024, in Barcelona, Spain. Poster presentation details are below: Author: Wang et al. Title: CID-078, a First-in-Class Oral Macrocycle Cyclin A/B RxL Inhibitor, Demonstrates Anti-Tumor Activity in ESF-driven Cancers Abstract Number: PB-515 Session Title: Late breaking posters Date and Time: October 23, 2024 (6 a.m. EST/12 p.m. CEST) to October 25, 2024 (11 a.m. EST/5 p.m. CEST) The digital poster can be viewed here. The pre-clinical data shows CID-078 demonstrated single-agent tumor activity across tumor cell line and in vivo models with dysregulated cell cycle (CDK-RB-E2F) function. Notably, tumor regressions were observed in small-cell lung cancer (SCLC), non-small-cell lung cancer (NSCLC), and triple-negative breast cancer (TNBC) preclinical models. Within specific indications, CID-078 single agent activity was correlated with RB1 mutation, high E2F target, or G2M checkpoint hallmark pathway scores. The cumulative pre-clinical data suggests that CID-078 holds promise as a monotherapy for patients with these cancers. A multi-center phase 1 clinical trial (NCT06577987) is currently enrolling patients. About CID-078 CID-078 is an orally bioavailable macrocycle with dual cyclin A and B RxL inhibitory activity that selectively targets tumor cells with oncogenic alterations that cause cell cycle dysregulation. In biochemical and cellular studies, Circle Pharma’s cyclin A/B RxL inhibitors have been shown to potently and selectively disrupt the protein-to-protein interaction between cyclins A and B and their key substrates and modulators, including E2F (a substrate of cyclin A) and Myt1 (a modulator of cyclin B). Preclinical studies have demonstrated the ability of these cyclin A/B RxL inhibitors to cause single-agent tumor regressions in multiple in vivo models. A multi-center phase 1 clinical trial ( NCT06577987 ) is currently enrolling patients. About Circle Pharma, Inc. South San Francisco-based Circle Pharma is advancing the discovery and development of intrinsically cell-permeable macrocycles that can be delivered by multiple routes, including oral administration. Circle Pharma’s MXMO™ platform combines structure-based rational drug design and advanced synthetic chemistry to develop a new generation of macrocycle therapies for challenging targets to address unmet clinical needs. Circle Pharma is focusing its development efforts on cyclins, which are master regulators of the machinery that controls the progression of cells through the cell cycle and are key drivers in many cancers. To learn more about Circle Pharma, please visit . Contacts Media Contact: Roslyn Patterson 650.825.4099 roslyn.patterson@circlepharma.com

临床1期AACR会议

2024-10-17

·创鉴汇

AI制药领域35家公司Q3获得融资

今年的诺贝尔奖相继揭晓，人工智能（AI）无疑成为了焦点。AI学者不仅摘得了2024年诺贝尔物理学奖，诺贝尔化学奖也颁发给了三位与AI相关领域的科学家。谷歌DeepMind公司的Demis Hassabis博士和John Jumper博士，因其在蛋白质结构预测领域的突破性贡献获奖，他们的研究解决了这一领域50年来的重大挑战。与此同时，华盛顿大学的David Baker教授则因其在计算蛋白设计方面的卓越成就获此殊荣。这些AI驱动的科研成果极大地推动了生物医药领域的科学发现，也彰显了AI在制药领域的潜力和价值。在此背景下，AI制药行业也迎来了蓬勃发展。仅在2024年第三季度，全球至少有35家AI制药公司获得了总计超过10亿美元的融资。值得关注的亮点包括：早期融资占比过半：早期融资（B轮及以前）事件占比近70%；全球共有8家AI制药企业获A轮融资，总融资额超2亿美元，8家初创企业获得种子轮融资，总金额超5000万美元。 Flagship Pioneering先后推出两家新锐公司：Flagship分别投资5000万美元，孵化出了AI助力的基因药物递送平台Mirai Bio和可编程生物制剂研发公司Abiologics。公司类型多元：获得融资的公司中，业务类型涵盖小分子药物发现到细胞疗法研发的众多药物类型，并且以打造AI技术平台的平台型公司和专注于AI辅助药物管线发现的研发型公司数量平分秋色。 BioAge Labs成功登陆纳斯达克，IPO募资1.98亿美元 BioAge Labs是一家抗衰老研究公司，目前共有3个研究方向：代谢和肌肉衰老、免疫衰老和大脑衰老。公司致力于通过绘制人类衰老图谱并利用独有的AI药物发现平台，以开发治疗疾病和延长健康寿命的创新药物。BioAge Labs的主要候选药物Azelaprag是一种口服小分子药物，属于Apelin受体激动剂。该产品正在与礼来GLP-1/GI受体激动剂Tizepatide联合开展减肥2期临床试验，它还将于明年上半年与诺和诺德减肥产品Wegovy联合进入2期试验。 9月26日，BioAge Labs在纳斯达克上市，募资1.98亿美元，该融资所得将用于推动其减肥管线的临床试验。 Outpace Bio完成1.44亿美元B轮融资 Outpace Bio是一家细胞疗法公司，利用人工智能蛋白质设计对免疫细胞进行编程，以改善实体瘤患者体内功能。公司的技术平台致力于利用人工智能，设计具有自然界中没有的全新功能的蛋白和调控回路。并且利用这些全新蛋白和调控回路精密调节细胞的分化状态以及信号通路，从而让它们在合适的时间产生合适的作用。 Outpace Bio的主打项目OPB-101是一种针对间皮素的CAR-T细胞，利用Outpace的专有技术OUTSMART、OUTLAST、OUTSPACER和OUTSAFE进行增强，计划于2025年获得IND许可并首次在晚期铂耐药性上皮性卵巢癌、输卵管癌或原发性腹膜癌患者进行给药。 8月1日，公司宣布完成超额认购的B轮融资，筹集1.44亿美元，获得的资金将用于推进多种T细胞候选疗法，以期在实体肿瘤治疗中获得早期临床概念验证。此外，这些资金还将支持Outpace利用其模块化技术平台扩展未来的产品线。 Superluminal Medicines完成1.2亿美元A轮融资成立于2023年，Superluminal Medicines是一家致力于推动小分子药物研发的速度和准确性的开发差异化药物管线的生成生物和化学公司。公司利用深厚的生物学和化学专业知识、机器学习以及专有的大数据基础设施，快速开发创建候选化合物。平台采用预测-设计-测试架构，精确模拟蛋白质形状，并设计高度选择性的化合物，以达到治疗效果。公司由业内领先的AI药物发现上市公司Schrödinger前高管Cony D'Cruz先生和知名风投RA Capital Management的Ajay Yekkirala先生共同创立。目前，Superluminal的开发重点集中于高价值的G蛋白偶联受体（GPCR）靶点药物的开发。 9月9日，Superluminal Medicines公司宣布完成1.2亿美元的A轮融资。获得资金将用于支持该公司的主打在研项目进入临床开发，并增加针对GPCR靶点的小分子药物发现项目。 Circle Pharma完成9000万美元D轮融资 Circle Pharma是一家致力于包括口服等多种给药途径的细胞渗透性大环化合物的发现和开发的生物技术公司，其MXMO平台结合了基于结构的合理药物设计和先进的合成化学，开发了新一代大环疗法，用于靶向具有挑战性的靶点。目前公司将开发重点放在细胞周期蛋白上，这类蛋白是控制细胞在细胞周期中进展机制的主要调节器，也是许多癌症的关键驱动因素。 9月3日，Circle Pharma宣布完成9000万美元的D轮融资，此轮融资的资金将用于资助其细胞周期蛋白A/B（cyclin A/B）RxL抑制剂CID-078的临床开发。CID-078是一种多肽类抗肿瘤药物，目前处于早期临床阶段。 CytoReason获得8000万美元战略投资 CytoReason是一家致力于开发计算疾病模型的技术公司。该公司使用来自医药合作伙伴的真实数据来构建组织和细胞的特定模型以模拟各种疾病，然后利用其机器学习AI探索这些模型，能够突出不同患者群体和治疗方法之间的差异，潜在地为候选新药确定更有效的进攻路径。 CytoReason的平台是由70名经验丰富的生物学家、生物信息学家和数据工程师组成的多学科团队开发的。该平台使医药和生物技术公司能够优先考虑新目标、寻找生物标志物并预测哪些患者可能对新疗法产生最佳的反应，从而缩短试验阶段、降低开发成本并增加药物获批的可能性。 7月17日，公司宣布获得OurCrowd、英伟达（NVIDIA）、辉瑞（Pfizer）和赛默飞世尔（Thermo Fisher Scientific）总计8000万美元的融资。CytoReason将利用这笔投资将其模型的应用扩展到其他适应症，增加其专有的分子和临床数据。 Mirai Bio获5000万美元A轮融资 Mirai由Flagship Pioneering于2021年创立，旨在提供开源技术平台，与生物技术公司合作开发优化的基因药物（genetic medicines）。公司的技术平台包括高通量自动化、体内多重筛选、机器学习等前沿技术，能够产生大量数据并且通过优化的迭代循环，同时优化基因药物的递送、设计和生产，提高疗法开发的成功率和开发速度。 9月28日，公司宣布获得Flagship Pioneering的5000万美元A轮投资，资金将用于促进该公司技术平台的开发，以及在多个疾病治疗领域和治疗模式中加速基因药物的开发。 Flagship推出新锐公司Abiologics Abiologics是一家通过创造名为Synteins的可编程药物，重新定义生物制品的公司。Synteins是一种在自然界中不存在的全新药物类型，它通过计算设计生成，并使用新型的合成构建块，赋予其独特的特性，能够为各类疾病患者提供变革性的治疗。该公司的技术平台依托先进的生成式人工智能，从头计算设计Synteins，使用广泛的人工构建模块，突破了目前生物制品仅依赖20种天然氨基酸的局限。Synteins能够被编程从而与几乎所有治疗靶点相互作用，并且巧妙地规避身体的自然免疫防御机制。 7月24日，Flagship Pioneering初步承诺投资5000万美元以推进该公司的平台并开发多样化的药物管线，初步重点是肿瘤学和免疫学适应症。读者们请星标⭐创鉴汇，第一时间收到推送免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文由药明康德内容团队根据公开资料整理编辑，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转发/复制至其他平台。转发授权请在「创鉴汇」微信公众号留言联系我们。更多数据内容推荐点击“在看”，分享创鉴汇健康新动态

临床申请临床2期细胞疗法IPO临床1期

2024-10-15

·PipelineReview

Circle Pharma Announces First Patients Dosed in Phase 1 Clinical Trial of First-in-Class Oral Cyclin A/B RxL Inhibitor CID-078 for Advanced Solid Tumors

SOUTH SAN FRANCISCO, CA, USA I October 15, 2024 I Circle Pharma, Inc., a clinical-stage biopharmaceutical company dedicated to discovering and developing a new generation of macrocycle therapies, announced today that the first patient cohort has been dosed in the phase 1 trial of CID-078, the company’s first-in-class oral cyclin A/B RxL inhibitor. The trial will evaluate CID-078 in patients with advanced solid tumors, including tumors with elevated E2F transcription factor activity, such as small cell lung cancer, triple negative breast cancer and ER+ HER-2- breast cancer following CDK 4/6-inhibitor therapy. “We are thrilled that the IND for CID-078 was cleared at the end of the 30-day regulatory review period and that CID-078 has now moved into human dosing at a consortium of world class cancer centers. This will allow our investigators to generate clinical proof-of-concept data which will inform CID-078’s potential impact in settings of high unmet medical need as well as validate Circle Pharma’s proprietary MXMO™ macrocycle platform for difficult-to-drug targets in cancer and other serious diseases,” said David J. Earp, JD, Ph.D., CEO of Circle Pharma. CID-078 is designed to selectively inhibit key protein-to-protein interactions involving cyclins A and B, both of which have been implicated in the proliferation and survival of cancer cells. The research program builds on work performed in the laboratory of Nobel Laureate and Circle Pharma’s Scientific Advisory Board Chair, William G. Kaelin Jr., MD, who demonstrated synthetic lethality through the disruption of these cyclins in settings of dysregulated cell cycle control and elevated E2F activity. Geoffrey Shapiro, MD, Ph.D., senior vice president, Development Therapeutics at Dana-Farber Cancer Institute and professor of medicine at Harvard University, stated, “Disrupting the ability of E2F-driven cancer cells to turn off E2F at the appropriate time in the cell cycle has been shown to selectively induce apoptosis. Until now there hasn’t been a selective therapeutic agent to exploit this observation and so I am extremely excited to see Circle Pharma’s cyclin A/B RxL inhibitor move into the clinic.” All patients in the cohort are enrolled at The START Center for Cancer Research, Midwest, Grand Rapids, MI. Other clinical sites currently open include The START Center for Cancer Research, West Valley City, UT, and NEXT Oncology in San Antonio, TX. Additional clinical sites are planned to open soon. Circle Pharma’s Phase 1 clinical trial (NCT06577987) is an open label, multi-center dose escalation and expansion study that is expected to enroll up to 100 patients. The study will evaluate the safety, pharmacokinetics and pharmacodynamics of CID-078 as well as preliminary anti-tumor activity in solid tumors. Circle Pharma anticipates reporting preliminary safety and anti-tumor data from the Phase 1 study in 2025. About CID-078, Circle Pharma’s Cyclin A/B RxL Inhibitor Program CID-078 is an investigational orally bioavailable macrocycle with dual cyclin A and B RxL inhibitory activity that selectively targets tumor cells with oncogenic alterations that cause cell cycle dysregulation. In biochemical and cellular studies, Circle Pharma’s investigational cyclin A/B RxL inhibitors have been shown to potently and selectively disrupt the protein-to-protein interaction between cyclins A and B and their key substrates and modulators, including E2F (a substrate of cyclin A) and Myt1 (a modulator of cyclin B). Preclinical studies have demonstrated the ability of these cyclin A/B RxL inhibitors to cause single-agent tumor regressions in multiple xenograft models. Based on these findings CID-078 has progressed to a Phase 1 clinical study (NCT06577987). About Circle Pharma, Inc. South San Francisco-based Circle Pharma is advancing the discovery and development of intrinsically cell-permeable macrocycles that can be delivered by multiple routes, including oral administration. Circle Pharma’s MXMO™ platform combines structure-based rational drug design and advanced synthetic chemistry to develop a new generation of macrocycle therapies for challenging targets to address unmet clinical needs. Circle Pharma is focusing its development efforts on cyclins, which are master regulators of the machinery that controls the progression of cells through the cell cycle and are key drivers in many cancers. To learn more about Circle Pharma, please visit www.circlepharma.com . SOURCE: Circle Pharma

临床1期

100 项与 Cyclin A/B抑制剂(Circle) 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
晚期恶性实体瘤	临床1期	美国	Circle Pharma, Inc.	2024-08-14
肺癌	临床1期	美国	Circle Pharma, Inc.	2024-08-14
转移性实体瘤	临床1期	美国	Circle Pharma, Inc.	2024-08-14
神经内分泌癌	临床1期	美国	Circle Pharma, Inc.	2024-08-14
三阴性乳腺癌	临床1期	美国	Circle Pharma, Inc.	2024-08-14
ER低表达乳腺癌	临床申请	美国	Circle Pharma, Inc.	2024-07-01
HR阳性乳腺癌	临床申请	美国	Circle Pharma, Inc.	2024-07-01
小细胞肺癌	临床申请	美国	Circle Pharma, Inc.	2024-07-01
非小细胞肺癌	临床前	美国	Circle Pharma, Inc.	2023-07-19
胰腺癌	临床前	美国	Circle Pharma, Inc.	2023-07-19