A Phase Ⅱ Study of Chiauranib Plus Albumin-paclitaxel and Gemcitabine as First-line Therapy in Patients With Locally Advanced or Metastatic Pancreatic Ductal Adenocarcinoma

Chiauranib , which simultaneously targets against VEGFR/Aurora B/CSF-1R, several key kinases involved in tumor angiogenesis, tumor cell mitosis, and chronic inflammatory microenvironment.

开始日期2024-08-01

申办/合作机构

深圳微芯生物科技股份有限公司

CTR20220336 / Recruiting临床2期

西奥罗尼胶囊联合卡培他滨在蒽环类和紫杉类治疗失败的晚期三阴性乳腺癌患者中的开放、多中心II期临床研究

主要目的：探索西奥罗尼联合卡培他滨在蒽环类和紫杉类治疗失败的晚期三阴性乳腺癌患者中的初步疗效。次要目的：观察西奥罗尼联合卡培他滨在蒽环类和紫杉类治疗失败的晚期三阴性乳腺癌患者中的安全性；分析西奥罗尼联合卡培他滨用药后的伴随药代动力学（PK）特征。探索性目的：探索潜在生物标志物与初步疗效的关系。

开始日期2023-03-10

申办/合作机构

深圳微芯生物科技股份有限公司

100 项与西奥罗尼相关的临床结果

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100 项与西奥罗尼相关的转化医学

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100 项与西奥罗尼相关的专利（医药）

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项与西奥罗尼相关的文献（医药）

2023-05-09·Cell death & disease

Inhibition of extranodal NK/T-cell lymphoma by Chiauranib through an AIF-dependent pathway and its synergy with L-asparaginase.

Article

作者: Gao, Guoquan ; Huang, Jieye ; Fan, Wei ; Yang, Xia ; Zhou, Ti ; Xie, Jinye ; Li, Zhiming ; Huang, Jiajia ; Yin, Haofan ; Gao, Tianxiao

Extranodal NK/T-cell lymphoma (NKTL) is a rare and aggressive form of extranodal lymphoma with a poor prognosis. Currently, there are very limited treatment options for patients with advanced-stage disease or those with relapsed/recurrent disease. Here we show that Chiauranib, an orally small molecule inhibitor of select serine-threonine kinases (aurora B, VEGFRs, PDGFR, CSF1R, c-Kit), inhibited NKTL cell proliferation, induced cell cycle arrest, as well as suppressed the microvessel density in vitro and in vivo similar as in other types of cancer cells. Surprisingly, Chiauranib unfolded a new effect to induce apoptosis of NKTL cells by triggering AIF-dependent apoptosis other than the traditional cyt-c/caspase mitochondrial apoptosis pathway. The knockdown of AIF in vitro and in vivo dramatically blocked the efficacy of Chiauranib on NKTL. Mechanistically, the release of AIF from mitochondria is due to the upregulation of VDAC1 by the AKT-GSK3β pathway and activation of calcium-dependent m-calpain, which promotes the cleavage of VDAC1 and therefore permits the release of AIF. Notably, the low expression of Bax in both NKTL cells and patient tissues restrained the cyt-c release. It resulted in the inhibition of cyt-c/caspase mitochondrial pathway, suggesting that drugs targeting this traditional pathway may not be effective in NKTL. Furthermore, we found that L-asparaginase triggered CD95 (Fas/Apo-1)-caspase 8-caspase 3 apoptotic pathway in NKTL cells, and combination of Chiauranib and L-asparaginase exhibited a synergistic effect, suggesting a feasibility to combine these two drugs for effective treatment of NKTL. This study demonstrates Chiauranib's positive efficacy toward NKTL through the activation of the AIF-dependent apoptosis pathway for the first time. The novel and multi-targets of Chiauranib and the synergistic effect with L-asparaginase may provide a promising therapy for NKTL patients.

2023-01-01·Exploration of targeted anti-tumor therapy

In silico targeting of colony-stimulating factor-1 receptor: delineating immunotherapy in cancer.

Article

作者: Grose, Richard P ; Raza, Zohaib ; Raza, Afsheen ; Azhar, Zahra

Aim:

Delineate structure-based inhibition of colony-stimulating factor-1 receptor (CSF1R) by small molecule CSF1R inhibitors in clinical development for target identification and potential lead optimization in cancer therapeutics since CSF1R is a novel predictive biomarker for immunotherapy in cancer.

Methods:

Compounds were in silico modelled by induced fit docking protocol in a molecular operating environment (MOE, MOE.v.2015). The 3-dimensional (3D) X-ray crystallized structure of CSF1R kinase (Protein Databank, ID 4R7H) was obtained from Research Collaboratory for Structural Bioinformatics (RSCB) Protein Databank. The 3D conformers of edicotinib, DCC-3014, ARRY-382, BLZ-945, chiauranib, dovitinib, and sorafenib were obtained from PubChem Database. These structures were modelled in Amber10:EHT molecular force field, and quick prep application was used to correct and optimize the structures for missing residues, H-counts, termini capping, and alternates. The binding site was defined within the vicinity of the co-crystallized ligand of CSF1R kinase. The compounds were docked by the triangular matcher placement method and ranked by the London dG scoring function. The docked poses were further refined by the induced fit method. The pose with the lowest binding score (ΔG) was used to model the ligand interaction profile in Discovery Studio Visualizer v17.2. The co-crystallized ligand was docked in its apo conformation, and root-mean-square deviation was computed to validate the docking protocol.

Results:

All 7 CSF1R inhibitors interact with residue Met637 exhibiting selectivity except for edicotinib. The inhibitors maintain CSF1R in an auto-inhibitory conformation by interacting with Asp797 of the Asp-Phe-Gly (DFG) motif and/or hindering the conserved salt bridge formed between Glu633 and Lys616 thus stabilizing the activation loop, or interacting with tryptophan residue (Trp550) in the juxtamembrane domain. DCC-3014, ARRY-382, BLZ-945, and sorafenib bind with the lowest binding energy with CSF1R kinase.

Conclusions:

Pyrimidines are potent inhibitors that interact with CSF1R residues. DCC-3014 and ARRY-382 exhibit exceptional pharmaceutical potential exhibiting great structural stability and affinity.

2020-01-01·American journal of cancer research

Chiauranib selectively inhibits colorectal cancer with KRAS wild-type by modulation of ROS through activating the p53 signaling pathway.

Article

作者: Ma, Caiqi ; Jiang, Ping ; Xie, Jinye ; Luo, Zhaofan ; Yin, Haofan ; Duan, Deyu ; Hong, Honghai ; Jiang, Xi ; Qi, Junhua

Colorectal cancer (CRC) is one of the top three most deadly cancers despite using chemotherapy based on oxaliplatin or irinotecan combined with targeted therapy. Chiauranib has recently been identified to be a promising anticancer candidate with impressive efficacy and safety. However, the role and molecular mechanisms of Chiauranib in the treatment of CRC remain to be elucidated. Our study shows that Chiauranib inhibits cell proliferation and induces apoptosis in KRAS wild-type CRC cells in a dose- and time-dependent manner, but not mutation ones. Meanwhile, Chiauranib increases ROS production in KRAS wild-type CRC cells. Moreover, Chiauranib selectively suppresses KRAS wild-type CRC cells growth in vivo. Mechanistically, Chiauranib inhibits KRAS wild-type CRC cells by triggering ROS production via activating the p53 signaling pathway. Further, KRAS mutation CRC cells are resistant to Chiauranib by increasing Nrf2 to stably elevate the basal antioxidant program and thereby lower intracellular ROS induced by Chiauranib. Our findings provide the rationale for further clinical evaluation of Chiauranib as a therapeutic agent in treating KRAS wild-type CRC.

项与西奥罗尼相关的新闻（医药）

2024-11-04

·医药观澜

微芯生物1类新药获批3期临床，一线治疗小细胞肺癌

11月1日，微芯生物宣布，该公司自主研发的原创新药西奥罗尼联合PD-(L)1单抗及化疗一线治疗广泛期小细胞肺癌的3期临床试验申请获得中国国家药监局（NMPA）批准。西奥罗尼是微芯生物研发的一款新型多靶点抑制剂，可作用于Aurora B、VEGFR、PDGFR、c-Kit和CSF1R多个靶点。广泛期小细胞肺癌（ES-SCLC）是高度恶性的肺癌亚型，长期以来一直是治疗领域的挑战。近年来，免疫治疗极大改变了小细胞肺癌患者的生存结局。然而，与其他肿瘤类型相比，小细胞肺癌患者的长期生存仍有极大的提升空间。根据微芯生物新闻稿介绍，西奥罗尼具有多通路的药理机制，对神经内分泌型肿瘤如小细胞肺癌具有机制针对性的抗肿瘤活性，同时，它通过抗血管和免疫调节活性的双重作用，能够与免疫治疗和化疗产生协同效应。在一线免疫化疗基础上，引入西奥罗尼的新方案有望进一步改善广泛期小细胞肺癌患者长期生存状况，展现出临床治疗潜力。西奥罗尼是微芯生物自主研发和设计的小分子抗肿瘤原创新药，是一种Aurora B选择性抑制剂，可通过抑制肿瘤细胞有丝分裂、抑制肿瘤血管生成和调节肿瘤免疫微环境，发挥综合抗肿瘤作用。其独特的Aurora B抑制活性对于SCLC等神经内分泌肿瘤具有针对性的作用。在作用机制方面，对存在DNA复制及端粒维持功能相关基因活性异常的肿瘤，西奥罗尼通过抑制细胞周期调控激酶Aurora B，或与其他细胞周期抑制化疗药物(如针对DNA 复制、拓扑异构酶、微管蛋白等)联合形成合成致死，形成对肿瘤细胞的增殖抑制；过抑制与血管生成相关的VEGFR 和PDGFR，西奥罗尼可以抑制肿瘤的新生血管形成，从而减少肿瘤的血液供应和生长；通过抑制与免疫细胞增殖活化相关的CSF1R 及DDR，西奥罗尼可以抑制肿瘤局部免疫抑制性细胞，提高机体对肿瘤的免疫监测和免疫清除功能。除此次获批的3期临床试验外，西奥罗尼单药用于小细胞肺癌后线治疗的3期临床试验已完成，Pre NDA正在沟通中。西奥罗尼联合化疗治疗卵巢癌的3期临床试验、单药或联合治疗三阴性乳腺癌、软组织肉瘤和胰腺癌的2期临床试验也在推进中。国际临床方面，西奥罗尼单药治疗小细胞肺癌/实体瘤的1b/2期临床试验在美国开展中。参考资料：[1]西奥罗尼一线治疗广泛期小细胞肺癌III期临床试验申请获批准. Retrieved Nov 1，2024, from https://mp.weixin.qq.com/s/5EI7K4I9E2yaAoZboxNrGw 内容来源于网络，如有侵权，请联系删除。

免疫疗法临床结果

2024-11-02

·医药魔方

西奥罗尼一线治疗广泛期小细胞肺癌III期临床试验申请获批准

11月1日，微芯生物宣布，其自主研发的原创新药西奥罗尼联合PD-(L)1单抗及化疗一线治疗广泛期小细胞肺癌III期临床试验申请获得批准。广泛期小细胞肺癌（ES-SCLC）作为高度恶性的肺癌亚型，长期以来一直是治疗领域的巨大挑战。近年来，免疫治疗极大改变了小细胞肺癌患者的生存结局。然而，与其他肿瘤类型相比，小细胞肺癌患者的长期生存仍有极大的提升空间。西奥罗尼具有多通路的药理机制，对神经内分泌型肿瘤如小细胞肺癌具有机制针对性的抗肿瘤活性，同时，它通过抗血管和免疫调节活性的双重作用，能够与免疫治疗和化疗产生协同效应。在一线免疫化疗基础上，引入西奥罗尼的新方案有望进一步改善广泛期小细胞肺癌患者长期生存状况，展现出巨大的临床治疗潜力。除此次获批的III期临床试验外，西奥罗尼单药用于小细胞肺癌后线治疗的III期临床试验已完成，Pre NDA正在沟通中。西奥罗尼联合化疗治疗卵巢癌的III期临床试验、单药或联合治疗三阴性乳腺癌、软组织肉瘤和胰腺癌的II期临床试验也在推进中。海外临床方面，西奥罗尼单药治疗小细胞肺癌/实体瘤的 Ib/II期临床试验在美国顺利开展中。 ▌关于西奥罗尼西奥罗尼是微芯生物自主研发和设计的小分子抗肿瘤原创新药，是具有全球专利保护的新分子实体。西奥罗尼是一种Aurora B选择性抑制剂，可通过抑制肿瘤细胞有丝分裂、抑制肿瘤血管生成和调节肿瘤免疫微环境，发挥综合抗肿瘤作用。其独特的Aurora B抑制活性对于SCLC等神经内分泌肿瘤具有针对性的作用。对存在DNA复制及端粒维持功能相关基因活性异常的肿瘤，西奥罗尼通过抑制细胞周期调控激酶Aurora B，或与其他细胞周期抑制化疗药物(如针对DNA 复制、拓扑异构酶、微管蛋白等)联合形成合成致死，形成对肿瘤细胞的增殖抑制;通过抑制与血管生成相关的VEGFR 和PDGFR，西奥罗尼可以抑制肿瘤的新生血管形成，从而减少肿瘤的血液供应和生长；通过抑制与免疫细胞增殖活化相关的CSF1R 及DDR，西奥罗尼可以抑制肿瘤局部免疫抑制性细胞，提高机体对肿瘤的免疫监测和免疫清除功能。西奥罗尼的多通路机制在治疗肿瘤方面具有显著优势，展现出相对同类机制药物更优异的药效活性和良好的安全性。 Copyright © 2024 PHARMCUBE. All Rights Reserved. 欢迎转发分享及合理引用，引用时请在显要位置标明文章来源；如需转载，请给微信公众号后台留言或发送消息，并注明公众号名称及ID。免责申明：本微信文章中的信息仅供一般参考之用，不可直接作为决策内容，医药魔方不对任何主体因使用本文内容而导致的任何损失承担责任。

免疫疗法临床3期引进/卖出

2024-11-01

·PRNewswire

The Phase III clinical trial application for first-line treatment of extensive disease small cell lung cancer with Chiauranib has been approved

SHENZHEN, China, Nov. 1, 2024 /PRNewswire/ -- On November 1, Shenzhen Chipscreen Biosciences Co., Ltd. (hereinafter referred to as "Chipscreen Biosciences") and its wholly-owned subsidiary Chengdu Chipscreen Pharmaceutical Ltd., received the "Drug Clinical Trial Approval Notice" approved by the National Medical Products Administration. The company's self-developed original new drug, Chiauranib, combined with PD - (L) 1 monoclonal antibody and standard chemotherapy for the first-line treatment of extensive stage small cell lung cancer, has been approved for phase III clinical trials. Extensive disease small cell lung cancer (ES-SCLC), as a highly aggressive subtype of lung cancer, has long been a huge challenge in the field of treatment. In recent years, chemo-immunotherapy has greatly improved the survival outcomes of patients with small cell lung cancer. However, compared to other types of tumors, there is still great room for improvement in the long-term survival of patients with small cell lung cancer. Chiauranib has a multi pathway pharmacological mechanism and has unique anti-tumor activity against neuroendocrine tumors such as small cell lung cancer. At the same time, it can produce synergistic effects with immunotherapy and chemotherapy through its dual effects of anti-angiogenesis and immune regulatory activity. On the basis of first-line chemo-immunotherapy, the introduction of the new regimen of Chiauranib is expected to further improve the long-term survival of patients with extensive stage small cell lung cancer, demonstrating enormous clinical treatment potential. In addition to the approved Phase III clinical trial, the phase III clinical trial of Chiauranib monotherapy for the later-line treatment of small cell lung cancer has been completed and the Pre NDA is currently under communication. The phase III clinical trial of Chiauranib combined with chemotherapy for ovarian cancer, and the phase II clinical trial of single or combined treatment for triple negative breast cancer, soft tissue sarcoma and pancreatic cancer are also being progressed. In terms of overseas clinical trials, the phase Ib/II clinical trial of Chiauranib monotherapy for small cell lung cancer / solid tumor is in progress in the United States. About Chiauranib Chiauranib is a novel molecular entity independently designed and developed by the Chipscreen Biosciences, with global patent protection. It is a selective inhibitor of Aurora B, a key mitotic regulator. Additionally, Chiauranib targets VEGFR to inhibit tumor angiogenesis, and blocks CSF1R and DDR1 pathways to reduce the infiltration and activity of immunosuppressive cells, thereby enhancing tumor immune microenvironment. Its unique Aurora B inhibitory activity specifically targets neuroendocrine tumors, such as SCLC, making it a novel small molecule anti-tumor drug candidate. Chiauranib exerts a comprehensive anti-tumor effect by a triple-pathway mechanism that simultaneously inhibits tumor angiogenesis, prevents tumor cell mitosis, and modulates the tumor microenvironment. Chiauranib has outperformed drugs with a similar mechanism in overall efficacy and safety profile. About Chipscreen Chipscreen Biosciences is an innovative drug company driven by core technologies with globally competitive pipelines. As a pioneer in drug innovation & development in China, adhering to the concept of "Constant Innovation for Life", we focus on developing revolutionary innovative drugs with new mechanisms of action, to address patients' pressing clinical needs. Our complete industry chain that covers early exploratory discovery through commercialization allows us to provide innovative Chinese drugs for patients worldwide. With a global development strategy based on early-stage research in China, Chipscreen Biosciences has leveraged the top scientists and teams with extensive experience in related fields from the Shenzhen Small Molecule Early R&D Center and Chengdu Small Molecule Early R&D Center to create an integrated technology platform based on AI-driven design and chemical genomics, which spanned the whole process from basic science to clinical translation. We have successfully developed first-in-class and best-in-class innovative drugs. Currently, 2 drugs with 6 indications have been marketed worldwide. In addition, we have launched a number of R&D projects with differentiated advantages and global competitiveness in the five major areas, including malignant tumors, metabolic diseases, autoimmune diseases, central nervous system diseases, and antivirals. Chipscreen Biosciences has formed a global industrial layout consisting of Shenzhen Head Office/R&D Center/GMP production base, Chengdu Regional Head Office/R&D Center/GMP production base, Beijing Branch, Shanghai Branch, and Chipscreen Biosciences (USA) Co., Ltd. Meanwhile, as one of the first batches of national "innovative drug incubation bases" and national high-tech enterprises, Chipscreen Biosciences has independently undertaken many national "863" plans and national major science and technology projects, such as "10th five-year plan", "11th five-year plan", "12th five-year plan" and "13th five-year plan", and National Science and Technology primary Project for Innovative Drug Development. We have filed over 680 invention patents in China and worldwide, with over 200 granted. SOURCE Shenzhen Chipscreen Biosciences Co., Ltd. WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

免疫疗法临床3期临床2期上市批准

100 项与西奥罗尼相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB16124

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
复发性铂耐药性卵巢癌	临床3期	中国	深圳微芯生物科技股份有限公司	2021-12-20
小细胞肺癌复发	临床3期	中国	深圳微芯生物科技股份有限公司	2021-03-05
胰腺导管腺癌	临床2期	中国	深圳微芯生物科技股份有限公司	2024-08-13
转移性胰腺导管腺癌	临床2期	-	深圳微芯生物科技股份有限公司	2024-08-01
晚期恶性实体瘤	临床2期	美国	深圳微芯生物科技股份有限公司	2022-08-26
软组织肉瘤	临床2期	中国	深圳微芯生物科技股份有限公司	2022-08-15
晚期三阴性乳腺癌	临床2期	中国	深圳微芯生物科技股份有限公司	2021-11-05
复发性非霍奇金淋巴瘤	临床2期	中国	深圳微芯生物科技股份有限公司	2019-07-11
复发性卵巢癌	临床2期	中国	深圳微芯生物科技股份有限公司	2019-07-01
晚期肝细胞癌	临床2期	中国	深圳微芯生物科技股份有限公司	2018-04-28

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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


NCT03216343 (AACR2021) 人工标引	临床2期	小细胞肺癌三线	28	Chiauranib	襯醖選獵鑰鏇夢蓋範鏇(淵糧鬱窪膚製蓋餘壓鬱) = 艱積廠糧齋憲艱鑰積獵醖網鹹艱夢構齋鬱鏇夢 (艱願醖網窪願憲選獵壓, 6.06 ~ 36.89) 更多	积极	2021-04-10
NCT02122809 (Pubmed \| J Hematol Oncol) 人工标引	临床1期	HR阳性/HER2低表达实体瘤	18	chiauranib	壓窪糧襯餘艱鹽觸獵夢(膚艱淵壓遞選觸鬱廠衊) = grade 3 hypertension occurred in two patients at 65 mg/day 製衊鬱齋醖淵繭範願窪 (積鬱簾鏇餘壓觸夢網蓋 ) 更多	积极	2019-01-14