The anaplastic lymphoma kinase (ALK) and the c-Met receptor tyrosine kinase play essential roles in the pathogenesis in multiple human cancers and present emerging targets for cancer treatment. Here, we describe CM-118, a novel lead compound displaying low nanomolar biochemical potency against both ALK and c-Met with selectivity over>90 human kinases. CM-118 potently abrogated hepatocyte growth factor (HGF)-induced c-Met phosphorylation and cell migration, phosphorylation of ALK, EML4-ALK, and ALK resistance mutants in transfected cells. CM-118 inhibited proliferation and/or induced apoptosis in multiple c-Met- and ALK-addicted cancer lines with dose response profile correlating target blockade. We show that the CM-118-induced apoptosis in c-Met-amplified H1993 NSCLC cells involved a rapid suppression of c-Met activity and c-Met-to-EGFR cross-talk, and was profoundly potentiated by EGFR inhibitors as shown by the increased levels of apoptotic proteins cleaved-PARP and Bim as well as reduction of the survival protein Mcl-1. Bim-knockdown or Mcl-1 overexpression each significantly attenuated apoptosis. We also revealed a key role by mTOR in mediating CM-118 action against the EML4-ALK-dependent NSCLC cells. Abrogation of EML4-ALK in H2228 cells profoundly reduced signaling capacity of the rapamycin-sensitive mTOR pathway leading to G 1 cell cycle arrest and mitochondrial hyperpolarization, a metabolic perturbation linked to mTOR inhibition. Depletion of mTOR or mTORC1 inhibited H2228 cell growth, and mTOR inhibitors potentiated CM-118's antitumor activity in vitro and in vivo. Oral administration of CM-118 at a wide range of well tolerated dosages diminished c-Met- and ALK phosphorylation in vivo, and caused tumor regression or growth inhibition in multiple c-Met- and ALK-dependent tumor xenografts in mice. CM-118 exhibits favorable pharmacokinetic and drug metabolism properties hence presents a candidate for clinical evaluation.

2010-04-15·Cancer Research

Abstract 1788: Preclinical development of a selective, potent small molecule ALK inhibitor

作者: Pao, William ; Lovly, Christine M. ; de Stanchina, Elisa ; Liang, Chris

AbstractA chromosomal inversion [inv (2)(p21p23)] resulting in the expression of an oncogenic kinase fusion protein known as EML4-ALK [echinoderm microtubule-associated protein-like 4- anaplastic lymphoma kinase] has been implicated in the pathogenesis of a subset of lung adenocarcinomas. An agent (PF-02341066), originally described as a MET tyrosine kinase inhibitor (TKI) but with “off-target” ALK activity, has demonstrated significant activity in ALK-fusion positive lung cancer patients and is currently in phase II/III clinical trials. In this study, we describe the development and characterization of a novel and highly selective ALK TKI. X-276 (racemic mixture) is an orally bioavailable ATP mimetic that has high selectivity for ALK as assessed by Ambit assays (binding constant 2nM). Treatment of H3122 lung adenocarcinoma cells, which harbor the EML4-ALK E13;A20 fusion product, resulted in potent inhibition of cell growth with an IC50 of 10nM, approximately 10 fold less than the IC50 of H3122 cells treated with a racemic mixture of PF-02341066. Immunoblot analysis confirmed that X-276 inhibited ALK phosphorylation in H3122 cells. Importantly, the IC50 of X-276 in H1993 lung cancer cells, known to be MET-dependent, was >100 fold higher. In addition, the selectivity index of H3122 cells vs. hepatocyte HepG2 cells was >135. Finally, compared to vehicle controls, X-276 delayed the growth of H3122 xenografts in established nude mice by >60%. Collectively, these data show that TKIs can be developed with greater specificity against ALK. Such compounds may lead to the development of ‘second-generation’ ALK TKIs with more potency against ALK-mutant cancers. Future studies will focus on determining the mechanism of acquired resistance to ALK TKIs using these more potent ALK inhibitors.Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1788.

项与 Xcovery, Inc. 相关的新闻（医药）

2022-12-02

·贝达

中国人占93%样本的ALK阳性NSCLC一线证据发布，恩沙替尼eXalt 3亚裔PFS达47.1个月

12月3日，2022MSK- CTONG中美联合研讨大会（MSK- CTONG Symposium 2022）在广州召开。会上，广东省临床试验协会副会长兼秘书长、广东省人民医院肿瘤医院院长周清教授发布了恩沙替尼eXalt 3 全球多中心一线临床研究亚裔疗效数据。恩沙替尼亚裔疗效数据亮点 1.亚裔基线无脑转移人群PFS（无进展生存期）研究者评估结果为47.1个月；独立评审评估结果尚未达到观察终点，未来或可超越研究者评估结果。 2.亚裔基线伴脑转移人群PFS独立评审评估结果为23.9个月。 3.亚裔mITT人群PFS独立评审评估结果为41.5个月。 4.恩沙替尼在基线无脑转移人群中4年OS率达75.7%；基线伴脑转移人群4年OS率达47.7%；总体人群4年OS率达66.3%。本次发布的临床研究数据充分证明了恩沙替尼在亚裔人群中应用于一线治疗，无论患者是否伴有脑转移，均可以获得PFS的显著获益且OS也表现出获益趋势。在基线无脑转移人群中47.1个月的超长PFS再一次夯实了恩沙替尼是ALK阳性NSCLC患者的不二选择。 MSK-CTONG大会结束后，恩沙替尼eXalt 3 全球多中心临床研究中国Leading PI吴一龙教授出席了恩沙替尼亚裔数据首发新闻发布会。吴一龙教授表示：“从今天的数据发布来看，我们可以说恩沙替尼是专门为亚洲人设计的，特别是为中国人设计的ALK TKI。从数据回顾来看，恩沙替尼疗效的提升没有以牺牲安全性为代价，真正做到了疗效持久也同样安全，这也是恩沙替尼亚裔数据公布的意义。” 贝达药业董事长丁列明博士在发布会中介绍了恩沙替尼的研发历程，向主导研发的诸多优秀专家表示感谢，向做出巨大贡献的患者表示敬意。他说，恩沙替尼继去年与埃克替尼共同亮相国家“十三五”科技成就展之后，又在今年党的二十大期间，入选“奋进新时代”主题成就展，社会各界对这个创新成果都充满信心。贝达药业副总裁季东在发布会上向参与eXalt 3临床研究的临床科研团队、患者及患者家属、CRO等合作伙伴致以诚挚的感谢。关于eXalt 3 eXalt 3 研究是一项全球开放多中心随机对照Ⅲ期临床研究，旨在评估盐酸恩沙替尼对比克唑替尼对未经过治疗的（一线）携带ALK阳性NSCLC患者治疗的疗效和安全性。研究全球牵头PI为美国范德堡大学Leora Horn教授，中国牵头PI是广东省人民医院吴一龙教授。研究涉及21个国家和地区的123个研究中心，全球总计入组290名患者，中国入组140名患者。关于盐酸恩沙替尼盐酸恩沙替尼（商品名：贝美纳）是一种新型强效、高选择性的新一代ALK抑制剂，是贝达药业和控股子公司Xcovery共同开发的全新的、拥有完全自主知识产权的创新药。2020年11月，恩沙替尼二线治疗适应症获批上市，成为中国第一个用于治疗ALK突变晚期非小细胞肺癌的国产1类新药，填补了同类药物国产空白，有望成为首个由中国企业主导在全球上市的肺癌靶向创新药。2021年12月，恩沙替尼被纳入国家医保目录。2022年3月，公司基于eXalt 3研究结果申报的恩沙替尼一线治疗适应症获批上市，4月，恩沙替尼术后辅助治疗获批开展临床试验。目前正积极准备一线适应症的国谈。

临床结果临床3期

2022-11-28

·贝达

MSK-CTONG Symposium 2022 |贝达药业盐酸恩沙替尼亚裔疗效数据将公布

2022MSK- CTONG中美联合研讨大会（MSK- CTONG Symposium 2022）将于12月3日在广州召开。本届大会上，贝达药业盐酸恩沙替尼eXalt 3 亚裔疗效数据将由广东省临床试验协会（CTONG）副会长兼秘书长、广东省人民医院周清教授公布。报告题目：盐酸恩沙替尼eXalt 3 研究ALK阳性非小细胞肺癌亚裔人群疗效数据首次发布 eXalt 3 study: First release of Asian population's efficacy inALK-positive non-small cell lung cancer 报告人：广东省临床试验协会（CTONG）副会长兼秘书长、广东省人民医院周清教授报告形式：线上报告报告时间：12月3日上午8:00-10:50 关于盐酸恩沙替尼盐酸恩沙替尼（商品名：贝美纳）是一种新型强效、高选择性的新一代ALK抑制剂，是贝达药业和控股子公司Xcovery共同开发的全新的、拥有完全自主知识产权的创新药。2020年11月，恩沙替尼二线治疗适应症获批上市，成为中国第一个用于治疗ALK突变晚期非小细胞肺癌的国产1类新药，填补了同类药物国产空白，有望成为首个由中国企业主导在全球上市的肺癌靶向创新药。2021年12月，恩沙替尼被纳入国家医保目录。2022年3月，公司基于eXalt 3研究结果申报的恩沙替尼一线治疗适应症获批上市，4月，恩沙替尼术后辅助治疗获批开展临床试验。关于eXalt 3 eXalt 3 研究是一项全球开放多中心随机对照Ⅲ期临床研究，旨在评估盐酸恩沙替尼对比克唑替尼对未经过治疗的（一线）携带ALK阳性NSCLC患者治疗的疗效和安全性。研究全球牵头PI为美国范德堡大学Leora Horn教授，中国牵头PI是广东省人民医院肿瘤医院院长吴一龙教授。研究涉及21个国家和地区的123个研究中心，全球总计入组290名患者，中国入组140名患者。关于CTONG CTONG成立于2007年10月，在广东省人民医院肿瘤医院院长吴一龙教授的带领下，最初国内11所具有一定胸部肿瘤诊疗和科研实力的医疗单位自发联合成立了“中国胸部肿瘤研究协作组，Chinese Thoracic Oncology Group，CTONG”，旨在通过设计、开展多中心临床试验，为胸部肿瘤临床实践提供高级别的循证医学证据。随着CTONG国际、国内学术影响力的迅速提升，国内越来越多的医疗单位希望加入到CTONG组织中，已拥有43个成员单位。从最早的IPASS研究到AURA3研究，从ADJUVANT研究（CTONG 1104）到EMERGING研究（CTONG 1103），从靶向治疗到免疫治疗，在它的引领下，中国在肺癌领域的科研已取得长足进步，获得世界认可。关于MSK MSK——纪念斯隆凯特琳肿瘤中心 (Memorial Sloan Kettering Cancer Center, MSK) 是坐落在纽约曼哈顿岛的世界上最古老和最大的癌症中心，历年在全美最佳医院肿瘤专科类排名中稳居前两位。MSK不仅发现和创造了很多有效的方法来预防、控制甚至治愈癌症，还致力于医学教育项目，让更多的医生和科学家在MSK获得知识和经验，对世界各地的癌症治疗和生物医学研究有着深远的影响。关于MSK- CTONG联合研讨会 MSK-CTONG联合研讨会，是2017年在广东省人民医院肿瘤医院院长吴一龙教授和MSK胸部肿瘤专家、MSK中国及亚太区医生大使Bob L i教授的倡导下，为促进中美胸部肿瘤研究领域的长久战略合作而创办。

上市批准临床3期免疫疗法临床结果

2022-11-16

·PRNewswire

TIGIT Inhibitors Clinical Trial Pipeline Appears Robust with 18+ Key Pharma Players Actively Working in the Space, Estimates DelveInsight

TIGIT Inhibitors clinical trial pipeline constitutes 18+ key companies continuously working towards developing 20+ TIGIT inhibitors drugs, analyzes DelveInsight LAS VEGAS, Nov. 16, 2022 /PRNewswire/ -- DelveInsight's ' TIGIT Inhibitors Competitive Landscape – 2022 ' report provides comprehensive global coverage of available, marketed, and pipeline TIGIT inhibitor drugs in various stages of clinical development, major pharmaceutical companies are working to advance the pipeline space and future growth potential of the TIGIT inhibitors competitive domain. Key Takeaways from the TIGIT Inhibitors Pipeline Report Over 18+ TIGIT inhibitors companies are evaluating 20+ TIGIT inhibitors pipeline therapies in various stages of development, and their anticipated acceptance in the TIGIT inhibitors market would significantly increase market revenue. Leading TIGIT inhibitor companies such as Merck Sharp & Dohme, Bristol-Myers Squibb, BeiGene, Arcus Biosciences, iTeos Therapeutics, Mereo BioPharma, Phio Pharmaceuticals, Bio-Thera Solutions, Compugen, and others are evaluating novel TIGIT inhibitor drugs candidate to improve the treatment landscape. Key TIGIT inhibitor pipeline therapies in various stages of development include Vibostolimab, BMS 986442, Ociperlimab, Domvanalimab, EOS 448, Etigilimab, PH 804-TME, PH 804-ACT, BAT6005, Vibostolimab, M 6223, COM 902, BMS 986442, and others. On September 13, 2022, Akeso, Inc., a China-based biopharmaceutical company focused on the development and commercialization of innovative therapeutic antibodies for Oncology & Immunology, presented encouraging preclinical results in a poster featuring its Fc-mutant anti-TIGIT antibody fused with TGF-RII protein (AK130) at the European Society for Medical Oncology (ESMO) Congress 2022. On May 13, 2022, iTeos Therapeutics stated that it is evaluating whether to conduct additional clinical trials of TIGIT drug EOS-448 with partner GlaxoSmithKline following the failure of a key trial for Roche's rival drug. In December 2021, Bio-Thera Solutions, a commercial-stage pharmaceutical company, announced that dosing has begun in Phase I clinical study to compare the pharmacokinetics and safety of BAT6005, a monoclonal antibody targeting TIGIT in cancer patient volunteers. In June 2021, GlaxoSmithKline and iTeos Therapeutics announced an agreement to co-develop and co-commercialize EOS-448, an anti-TIGIT monoclonal antibody currently in phase I development as a potential treatment for patients with cancer. TIGIT, part of the CD226 checkpoint axis, has demonstrated potential as a promising target for the next generation of immuno-oncology therapies based on compelling preclinical data and a phase II randomized clinical trial. Request a sample and discover the recent advances in the TIGIT inhibitors market @ TIGIT Inhibitors Competitive Landscape Report TIGIT Inhibitors Overview T-cell immunoreceptor with Ig and ITIM domains (TIGIT) is one of the most recently investigated immune checkpoints as an immunotherapeutic target. TIGIT is a transmembrane glycoprotein receptor with an Ig-like V-type domain in its cytoplasmic domain and an ITIM in its extracellular domain. It is found on activated and memory T cells, as well as NK cells and Tregs. Binding to either of its two APC ligands, CD155 (PVR: poliovirus receptor) or CD112 (PVRL2, nectin-2), inhibits maturation and confers a tolerogenic phenotype. TIGIT-blockade clinical trials in cancer have recently begun in large numbers, mostly as combination treatments. TIGIT-Fc fusion protein has been shown to interact with PVR on dendritic cells, increase IL-10 secretion/decrease IL-12 secretion in response to LPS stimulation, and inhibit T cell activation in vivo. Antibodies against TIGIT's interaction with PVR can block its inhibition of NK cytotoxicity, and the activity is directed through its ITIM domain. Find out more about FDA TIGIT inhibitors @ TIGIT Inhibitor Drugs List TIGIT Inhibitors Pipeline Analysis: Drug Profile Ociperlimab: BeiGene BeiGene's Ociperlimab (BGB-A1217) is an investigational humanized monoclonal antibody with high specificity and affinity for TIGIT. Ociperlimab is a cutting-edge, developing anti-TIGIT antibody with an intact IgG Fc binding region for optimal antibody-mediated anti-tumor activity. Ociperlimab binds to TIGIT and prevents it from interacting with poliovirus receptor (CD155) and poliovirus receptor-related 2 (CD112) ligands on tumor cells, activating T cell-mediated antitumor immune responses. BAT6005: Bio-Thera Solutions BAT6005, developed by Bio-Thera Solutions, is a monoclonal antibody that targets TIGIT in cancer patient volunteers. BAT6005 was discovered using Bio-Thera's proprietary IDEAL (Intelligent Design and Engineered Antibody Libraries) platform, and it has normal IgG1 ADCC function. A snapshot of the TIGIT Inhibitors Pipeline Drugs mentioned in the report: Learn more about the TIGIT inhibitor drugs @ TIGIT Inhibitor Trials Scope of the TIGIT Inhibitors Competitive Landscape Report Coverage: Global Key TIGIT Inhibitors Companies: Merck Sharp & Dohme, Bristol-Myers Squibb, BeiGene, Arcus Biosciences, iTeos Therapeutics, Mereo BioPharma, Phio Pharmaceuticals, Bio-Thera Solutions, Compugen, and others Key TIGIT Inhibitors Pipeline Therapies: Vibostolimab, BMS 986442, Ociperlimab, Domvanalimab, EOS 448, Etigilimab, PH 804-TME, PH 804-ACT, BAT6005, Vibostolimab, M 6223, COM 902, BMS 986442, and others. Dive deep for rich insights into TIGIT inhibitor therapy; visit @ FDA-approved TIGIT Inhibitors Table of Contents For further information on the TIGIT inhibitors therapeutics assessment, reach out @ TIGIT Inhibitor Therapy Related Reports Non-Small Cell Lung Cancer (NSCLC) Market Non-Small Cell Lung Cancer Market Insights, Epidemiology and Market Forecast – 2032 report delivers an in-depth understanding of the disease, historical and forecasted epidemiology current treatment practices, emerging drugs, and key non-small cell lung cancer companies, including Novartis Pharmaceuticals, AbbVie, Janssen Pharmaceuticals, Xcovery, Eli Lilly and Company, Sanofi, Pfizer, and others. Non-Small Cell Lung Cancer Epidemiology Forecast Non-Small Cell Lung Cancer Epidemiology Forecast – 2032 report delivers an in-depth understanding of the disease, historical and forecasted non-small cell lung cancer epidemiology in the 7MM, i.e., the United States, EU5 (Germany, Spain, Italy, France, and the United Kingdom), and Japan. Small-cell Lung Cancer Pipeline Small-cell Lung Cancer Pipeline Insight – 2022 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key small-cell lung cancer companies, including Ascentage Pharma, Merck & Co, AstraZeneca, Advenchen Laboratories, Advanced Accelerator Applications, Trillium Therapeutics, Wigen Biomedicine, Linton Pharm, Carrick Therapeutics, among others. Small-cell Lung Cancer Market Small-cell Lung Cancer Market Insights, Epidemiology, and Market Forecast – 2032 report delivers an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key small-cell lung cancer companies, including Ascentage Pharma, Merck & Co, AstraZeneca, Advenchen Laboratories, Advanced Accelerator Applications, Trillium Therapeutics, Wigen Biomedicine, Linton Pharm, Carrick Therapeutics, among others. Extensive Stage Small Cell Lung Cancer Pipeline Extensive Stage Small Cell Lung Cancer Pipeline Insight – 2022 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key extensive stage small cell lung cancer companies, including Eli Lilly and Company, Genentech, Bristol-Myers Squibb, Henlix Biotech, CSPC ZhongQi Pharmaceutical Technology Co., Ltd., BioNTech SE, Xencor, Haihe Biopharma Co., Ltd., Taizhou HoudeAoke Biomedical Co., Ltd, Celgene, among others. Other Trending Reports Goitre Market | Thymus Cancer Market | US Healthcare Outlook Report | Venous Stenosis Market | Negative Pressure Wound Therapy Systems Market | Global Kinase Inhibitor in Autoimmune Diseases Market | Metrorrhagia Market | Dysfunctional Uterine Bleeding Market | Hypereosinophilic Syndrome Market | Age-related Vision Dysfunction Market | Dental Lasers Market | CRISPR Therapies Pipeline Insight | Cell And Gene Therapy For Multiple Myeloma Market | Drug Hypersensitivity Market | Dysthymia Market | Persistent Depressive Disorder Market | Cancer Vaccines Market | Weight Loss/Weight Management (Obesity) Market | Food Allergy Market | Obsessive-Compulsive Disorder Market | Tumor Ablation Market | Physiotherapy Equipment Market | Chimeric Antigen Receptor (CAR) T-Cell Therapy Market | Anti-hypertension Market | Radiofrequency Ablation Devices Market | Global Messenger RNA (mRNA)-based Vaccines and Therapeutics Market | Gastro Intestinal Bleeding Market | Trastuzumab Biosimilars Insight | Varicose Veins Market | Germ Cell Tumor Market | Intracardiac Echocardiography Devices Market | India Healthcare Report | Crows Feet Market | Seborrhoeic Dermatitis Market | Injectable Drug Delivery Devices Market | Structural Heart Devices Market | Substance (Drug) Abuse Market | Insulin Glargine Biosimilar Insight Related Healthcare Blogs TIGIT Inhibitors Market Landscape Small Cell Lung Cancer Treatment Market Global Healthcare Burden NSCLC Poses Lung Cancer and its Increasing Global Burden Related Healthcare Services Healthcare Business Consulting Healthcare Competitive Intelligence Services Healthcare Asset Prioritization Services About DelveInsight DelveInsight is a leading Business Consultant, and Market Research firm focused exclusively on life sciences. Connect with us at LinkedIn Contact Us Shruti Thakur [email protected] +1(919)321-6187 Logo: SOURCE DelveInsight Business Research, LLP

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药物(靶点)	适应症	全球最高研发状态

BPI-442096 ( SHP2 )	实体瘤更多	临床1期
CM-118 ( ALK x c-Met )	非小细胞肺癌更多	临床1期
XV-615 ( PDGFR x VEGFR2 )	眼部疾病更多	无进展
Cancer and inflammation therapeutics(Xcovery) ( ALK )	肿瘤更多	无进展
X-370 ( PI3Kδ )	急性淋巴细胞白血病更多	无进展