主要目的：研究健康受试者在空腹/餐后状态下，单次口服由北京康立生医药技术开发有限公司的达可替尼片15mg（受试制剂）和辉瑞制药（Pfizer Limited/Europe MA EEIG）为持证商的达可替尼片15mg（Dacomitinib Tablets/ Vizimpro®/多泽润®)，参比制剂）的相对生物利用度，评价受试制剂和参比制剂的生物等效性。次要目的：通过不良事件发生率、实验室检验结果、生命体征和体格检查等的变化情况观察受试制剂和参比制剂在中国健康受试者中的安全性和耐受性。

开始日期2024-12-23

申办/合作机构

北京康立生医药技术开发有限公司

NCT06075615

/ WithdrawnN/A

A Multicenter, Observational Study to Describe the Effectiveness and Treatment Patterns of Dacomitinib Among Epidermal Growth Factor Receptor Mutation-Positive Non-Small Cell Lung Cancer Patients With Brain Metastasis

The purpose of this study is to learn about dacomitinib for the possible treatment of lung cancer which has spread to other parts of the body.
This study is seeking participants who:
* have lung cancer that has reached at least the brain.
* have a type of gene called epidermoid growth factor receptor. A gene is a part of your DNA that has instructions for making things your body needs to work.
* have not received any treatment before.
All participants in this study will receive dacomitnib 1 time a day. Dacomitinib is a tablet that is taken by mouth at home. They can continue to take dacomitnib until their cancer is no longer responding. The study will look at the experiences of people receiving the study medicine. This will help to see if the study medicine is safe and effective.

开始日期2024-09-30

申办/合作机构

Pfizer Inc.

CTR20234208

/ CompletedN/A

健康受试者在空腹和餐后状态下单次口服达可替尼片的人体生物等效性试验

1.主要目的：以山东朗诺制药有限公司生产的达可替尼片为受试制剂（T），以Pfizer Europe MA EEIG持证，Pfizer Manufacturing Deutschland GmbH生产的达可替尼片（商品名：VIZIMPRO®）为参比制剂（R），评估健康受试者在空腹和餐后状态下单次给药受试制剂和参比制剂的药代动力学特征。 2. 次要目的：考察健康受试者给药受试制剂和参比制剂后的安全性。

开始日期2023-12-30

申办/合作机构

山东朗诺制药有限公司

100 项与达可替尼相关的临床结果

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100 项与达可替尼相关的转化医学

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100 项与达可替尼相关的专利（医药）

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项与达可替尼相关的文献（医药）

2025-11-01·JOURNAL OF MOLECULAR GRAPHICS & MODELLING

In silico discovery of multi-target small molecules and efficient siRNA design to overcome drug resistance in breast cancer via local therapy

Article

作者: Hashemi, Seyed Mohammad Javad ; Feizi-Dehnayebi, Mehran ; Mellati, Amir ; Ghalehnoei, Hossein ; Akhtari, Javad ; Barzegar, Ali

In this study, we designed an efficient siRNA for PKMYT1 gene knockdown and evaluated the binding affinity of various natural small molecules to key proteins associated with breast cancer through molecular docking and molecular dynamics (MD) simulations. Subsequently, among these molecules, The small molecule, SCHEMBL7562664, was introduced as a "golden ligand" that showed potent multi-target activity as an antagonist for aromatase, estrogen receptor α, HER2, and PARP10, and as an agonist for MT2 and STING. Next, MD simulations of six protein- golden ligand complexes (PDB IDs: 4QXQ, 5GS4, 5JL6, 5LX6, 6ME6, and 7PCD), performed with GROMACS over 100 ns at 298.15 K, provided valuable information about their structural dynamics. Analysis of the radius of gyration (Rg) revealed that, while five complexes (7PCD, 5GS4, 5LX6, 4QXQ, and 5JL6) maintained compact structures (Rg between 1.7 and 2.3 nm), the 6ME6 complex exhibited a more extended and flexible conformation (average Rg ∼3.4 nm). Complementary RMSD analysis confirmed that most complexes rapidly stabilized with minimal deviations (generally <0.3 nm), whereas the 6ME6 complex showed higher variability, reaching up to 0.67 nm. Furthermore, Binding free energy calculations using MM-GBSA and PBSA methods further supported these findings, with energies ranging from -21.45 ± 2.28 kcal/mol (5LX6) to -39.79 ± 1.34 kcal/mol (6ME6), indicating an optimal balance between intrinsic interactions and desolvation costs in the 6ME6 and 5JL6 systems. Based on DFT results, the golden ligand showed higher stability and lower reactivity compared to control ligands such as aromatase, tamoxifen, and dacomitinib, potentially leading to reduced off-target interactions and a more favorable safety profile. The integration of these data underscores the therapeutic potential of SCHEMBL7562664 as a multi-target agent for breast cancer, with promising pharmacokinetic properties that can be optimized for local treatment by incorporation into a 3D scaffold.

2025-10-01·CELLULAR SIGNALLING

Acetaldehyde dehydrogenase 1A1 upregulation drives dacomitinib-induced skin toxicity through mitochondrial dysfunction and keratinocyte apoptosis

Article

作者: Ma, Xinyue ; Tan, Lili ; Chen, Xinyi ; Zhou, Wanying ; Yang, Yiting ; Yang, Dihong ; Wang, Jiaqi ; Li, Huidan ; Fang, Luo ; Mei, Yuqing ; Xu, Gaoqi

Dacomitinib is a pan-human epidermal growth factor receptor (HER) tyrosine kinase inhibitor (TKI), approved for the first-line treatment of non-small cell lung cancer (NSCLC) with human epidermal growth factor receptor 1(EGFR)-sensitive mutations. The use of dacomitinib is limited because of its cutaneous toxicity. Since the exact mechanism of dacomitinib-induced cutaneous toxicity is unknown, effective targeted prophylaxis and therapy remain unavailable. Our study established an animal model of dacomitinib-induced cutaneous toxicity and found that dacomitinib induced mitochondrial dysfunction and apoptosis in keratinocytes with enhanced secretion of inflammatory factors. Mechanistically, we found that the retinoid pathway in keratinocytes was activated by dacomitinib, with significant upregulation of the key enzyme acetaldehyde dehydrogenase 1A1 (ALDH1A1), which appears to be a key factor in cutaneous toxicity. ALDH1A1 knockdown reversed the apoptosis and mitochondrial dysfunction caused by dacomitinib in keratinocytes, suggesting its potential as a therapeutic target. Furthermore, silibinin was shown to mitigate dacomitinib-induced cutaneous toxicity by reducing ALDH1A1. Overall, this study highlights the critical role of ALDH1A1 in drug-induced cutaneous toxicity and its potential as an interventional target.

2025-07-03·JOURNAL OF DRUG TARGETING

Epidermal growth factor receptors unveiled: a comprehensive survey on mutations, clinical insights of global inhibitors, and emergence of heterocyclic derivatives as EGFR inhibitors

Review

作者: Pasha, Ismail ; H P, Gagana ; B L, Kavya ; Shivanandappa, Thippeswamy Boreddy ; K N, Purushotham ; K M, Gagana ; Hussain, Shalam M. ; Pasha, T. Y. ; Ahmed, Mohammed Muqtader ; C, Manojmouli ; Rahamathulla, Mohamed

Mutations that overexpress the epidermal growth factor receptor (EGFR) are linked to cancers like breast (15-20%), head and neck (10-15%), colorectal (5-8%), and non-small cell lung cancer (10-50%), especially in East Asian populations. EGFR activation stimulates 'RAS/RAF/MEK/ERK, PI3K/Akt, and MAPK' pathways, which enhance cell division, survival, angiogenesis, and tumour growth while inhibiting apoptosis and metastasis. Secondary mutations (e.g. 'T790M', 'C797S'), off-target effects, and resistance due to alternate pathway activation reduce the efficacy of currently available EGFR inhibitors. To address these issues, 'novel heterocyclic inhibitors with structural versatility were developed to improve selectivity and binding affinity for mutant EGFR forms'. These new EGFR reduce side effects, enhance pharmacokinetics, and enhance therapeutic efficacy at low concentrations. This review focuses on 'EGFR mutations in various cancers' detailing the biochemical effects, clinical profiles, and binding interactions of globally approved EGFR inhibitors. Furthermore, it focuses into recent progress in nano-formulations and the development of heterocyclic derivatives that can successfully 'target mutant EGFRs' through varied synthesis methods. These inhibitors have the potential to have better binding affinities, selectivity's, and less side-effect. Further research required to refine the structures and develop nanoformulations of EGFR-targeted therapeutics in order to improve therapeutic efficiency and, provide more effective cancer treatments.

项与达可替尼相关的新闻（医药）

2025-06-23

·CPHI制药在线

老靶点EGFR在肺癌领域的创新韧性

关注并星标CPHI制药在线近日，翰森制药宣布，其第三代EGFR-TKI阿美替尼（Aumseqa）的上市许可申请，已获英国药品和健康产品管理局 (MHRA）批准，作为单药治疗成人局部晚期或转移性非小细胞肺癌（NSCLC）且具有激活的EGFR突变的患者的一线治疗，以及成人局部晚期或转移性EGFR T790M突变阳性NSCLC患者的治疗，成为首个出海欧洲的中国原研三代EGFR-TKI。从NDA受理到获批，阿美替尼历经了三年的漫长等待。阿美替尼的成功出海，再次彰显了EGFR这一老靶点的创新韧性。EGFR的作用机制EGFR（表皮生长因子受体）是一个跨膜酪氨酸激酶受体，对于细胞增殖、迁移、分化等都发挥着关键作用。当EGFR与表皮生长因子（EGF）结合后，可参与细胞正常生长和分裂，是人体表皮细胞的调控开关。TKI（酪氨酸激酶抑制剂）是一组通过多种抑制模式破坏蛋白激酶信号转导通路的药物。EGFR-TKI可通过竞争性抑制EGFR的ATP结合位点，阻断EGFR的自磷酸化和下游信号通路的激活，实现抑制肿瘤细胞的增殖、存活和诱导肿瘤细胞凋亡的治疗目的。EGFR基因在非小细胞肺癌（NSCLC）中的总体发生率为17.2%。但在包括中国在内的东南亚地区，其发生率则高达40%-60%。因此，EGFR-TKI成为NSCLC领域的主流治疗药物。从EGFR发现至今，EGFR-TKI已历经三代更迭。如今，第四代已箭在弦上，另外还有其他技术路线产品正在临床阶段。EGFR-TKI的造富能力有多强？2002年，阿斯利康的吉非替尼（Gefitinib）在日本获批上市，开启了EGFR-TKI时代。目前，已经历三代更迭，代表产品分别是：第一代：吉非替尼、厄洛替尼、埃克替尼；第二代：阿法替尼、达可替尼；第三代：奥希替尼、阿美替尼、伏美替尼、贝福替尼、奥莫替尼、兰泽替尼、瑞齐替尼。吉非替尼上市首年销售额便达到6700万美元，2003年获FDA批准上市，销售额暴涨240%，高达2.28亿美元。罗氏的厄洛替尼于2004年获得FDA批准后，销售额也一路高涨，2013年达到销售额巅峰13.39亿法郎（14.58亿美元）。2015年11月，阿斯利康的奥希替尼（Tagrisso）获FDA批准上市，用于单药一线治疗外显子19缺失（EGFR ex19del）或外显子21 L858R突变（EGFR ex21 L858R）的局部晚期或转移性非小细胞肺癌（NSCLC）患者，开启了三代EGFR-TKI治疗时代。目前，该药物已获批5项适应症。奥希替尼自上市以来销售额稳步上升，2018年被批准一线疗法后销售额突飞猛进，2021年首次突破50亿美元大关，2023年全球销售额达到57.99亿美元，2024年全球销售额达到65.80亿美元，成为阿斯利康第二大畅销药。成立于2003年的贝达药业，更是凭借中国第一个自主研发的EGFR-TKI-盐酸埃克替尼（商品名：凯美纳），成为国内首个销售额破十亿的创新药。目前成为主流的三代EGFR-TKI依然面临着严峻的肿瘤耐药挑战，在经奥希替尼二线治疗后出现耐药的NSCLC患者中，大约10%-26%的患者存在EGFR C797S耐药性突变。EGFR-TKI与肺癌的对抗之战已然来到第四阶段。"后EGFR时代"之战目前第四代EGFR-TKI大战已经打响，全球约有20多款四代EGFR-TKI进入临床，其中以Black Diamond Therapeutics的BDTX-1535的数据最为亮眼。BDTX-1535是一种中枢神经系统渗透剂第四代不可逆（共价）EGFR抑制剂，可靶向第三代EGFR TKI获得性和内在耐药性突变，对野生型EGFR有选择性，同时有很好的渗脑作用。在II期研究中，接受每日1次200mg BDTX-1535治疗的EGFR突变型NSCLC患者有42%（8/19）实现了客观缓解（ORR）。为了克服EGFR-TKI耐药难题，行业还开发了EGFR抗体、EGFR ADC、EGFR PROTAC等方向产品。EGFR抗体的研发很早就开始了，但在肺癌治疗领域一直未能成功，这是因为EGFR信号通路的激活依赖于配体介导的EGFR受体二聚化，EGFR单抗可以与EGFR胞外区结合，抑制配体介导的受体二聚化，从而抑制EGFR信号传递。而EGFR突变发生在胞内区，因此EGFR单抗无法阻止EGFR信号传递。2015年，首款EGFR单抗necitumumab获批用于治疗NSCLC，不过疗效非常有限。2021年5月，强生的EGFR/cMET双抗埃万妥单抗以I期试验结果获得FDA加速批准，用于治疗铂化疗后进展的EGFR 20ins突变的局部晚期或转移性NSCLC，成为首个成功进入肺癌领域的EGFR抗体疗法。在EGFR单抗的基础上，ADC技术带来了新的突破。乐普生物的EGFR ADC新药维贝柯妥塔单抗（MRG003）是国内进展最快的，由EGFR靶向单抗与强效的微管抑制剂MMAE分子通过vc链接体偶联而成，维贝柯妥塔单抗针对肺癌的适应症正在临床研究中。PROTAC作为一种具有新结构新机制的肿瘤靶向药物，可以降解整个蛋白而不仅仅是抑制酶活性，因此可能克服耐药性问题，是EGFR赛道一个理想的成药方向。全球已有20多个PROTAC药物进入临床研究，包括海思科的EGFR PROTAC药物HSK40118和贝达药业/C4 Therapeutics的EGFR PROTAC药物CFT8919，正在开展临床试验，用于治疗不可手术的、携带EGFR突变的晚期NSCLC患者。历久弥新的EGFR靶点，在一代代技术更迭下，演绎着属于自己的创新韧性。参考来源： 1.翰森制药公告 2.Dawei Hong, Bizhong Zhou, Bei Zhang, Hao Ren, Liquan Zhu, Guowan Zheng, Minghua Ge, Jingyan Ge, Recent advances in the development of EGFR degraders: PROTACs and LYTACs, European Journal of Medicinal Chemistry Volume 239, 5 September 2022, 114533. 3.Specific non-genetic IAP-based protein erasers (SNIPERs) as a potential therapeutic strategy. Eur J Med Chem 2021;216:113247.END来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~

上市批准申请上市医药出海

2025-06-17

·PRNewswire

Lung Cancer Research Foundation Announces Request for Proposals Focused on Curing EGFR Mutant Lung Cancers

New Team Science Award is $1.5 million Over Three Years NEW YORK, June 17, 2025 /PRNewswire/ -- The Lung Cancer Research Foundation (LCRF) announces today a new funding mechanism: the 2025 LCRF Team Science Award on Advancing Therapies Toward Curing EGFR Mutated Lung Cancers. The Request for Proposals is now open for submissions. Designed to bring together scientific teams to accomplish innovative breakthroughs, this team science award must include at least two projects directed at understanding and treatment of resistant or persistent disease in EGFR mutated lung cancer. Lung cancer is responsible for more deaths worldwide than any other cancer, accounting for an estimated 124,730 deaths annually in the United States alone.1 In the last 10 to 15 years, accelerated clinical trials and FDA approvals of targeted therapies for non-small cell lung carcinoma have been possible in part due to advances in molecular profiling of tumors. Many of these targeted therapies are directed against oncogenic drivers. Epidermal growth factor receptor (EGFR) mutations were the first oncogenic drivers that were successfully targeted with the use of tyrosine kinase inhibitors (TKIs). Subsequently additional oncogenic driver alterations in EML4-ALK, BRAF, RET, KRAS G12C, HER2, MET, NTRK, ROS1 and NRG1 were identified along with corresponding therapeutic options for treatment. Several TKIs including gefitinib, erlotinib, afatinib, dacomitinib, and osimertinib have been approved by the FDA for the treatment of EGFR mutated (EGFRmut+) Non Small Cell Lung Cancer (NSCLC.) Despite substantial progress in the treatment of EGFRmut+ lung cancer, available treatments are not curative, and resistance invariably develops. Sometimes biopsies are repeated to identify the source of resistance to potentially evaluate patients for additional targeted therapy. Usually, at some point in time chemotherapy is employed to treat the disease. Immunotherapy in the form of PD-1/PD-L1 inhibitors has revolutionized the treatment of many forms of lung cancer but has not proven effective in the treatment of most oncogene-driven lung cancers. Given that therapeutic options available to date are not curative, there is a need for novel approaches to treat these lung cancers and improve outcomes for patients with the ultimate intention of cure. This grant mechanism will focus on furthering the development of novel therapies for patients with EGFRmut+ NSCLC. "There has been so much scientific discovery in EGFR mutated lung cancer, and with the development of targeted treatments, patients are living longer," said Benay Taub, lung cancer survivor. "However, even with the best of circumstances, resistance develops and we need patients to have more treatment options. The goal of this award is to support a team of committed researchers in pursuit of improved treatments and outcomes for lung cancer patients and hopefully, one day, a cure." "EGFR discoveries were the start of oncogene-driven treatment and while the science has made great strides, there is still a significant need for more to be discovered," says Dr. Antoinette Wozniak, Chief Scientific Officer for LCRF. "Our commitment to people affected by lung cancer is simple: continue to fund research that pushes the boundaries of what is known to what is possible – toward a cure. This award will hopefully move the science in that direction." "Tomorrow's breakthroughs are made possible by research that happens today," emphasized David Carbone, MD, PhD, Director, Translational Therapeutics Program, The Ohio State University Wexner Medical Center and member of LCRF's Scientific Advisory Board. "Taking a team approach to combatting resistance in EGFR mutant lung cancer promises to accelerate the pace of discovery." This new Team Science Award is made possible by a generous private donation from Benay and Steven Taub. Their visionary support reflects a deep belief in the power of collaboration to drive scientific discovery. Submissions to the Request for Proposals will be reviewed through a two-step process: Letters of Intent will be accepted until midnight on July 29, 2025; if selected, projects will then be chosen to submit full proposals. All applications will be subject to a rigorous review by LCRF's Scientific Advisory Board. More details about the Request for Proposal, along with eligibility, requirements, and deadlines can be found at LCRF.org/FundingOpportunities. Siegel RL, Giaquinto AM, Jemal A. CA: A Cancer Journal for Clinicians, Vol 24,Issue 1, Jan/Feb 2024 About the Lung Cancer Research Foundation (LCRF) The Lung Cancer Research Foundation® (LCRF) is the leading nonprofit organization focused on funding innovative, high-reward research with the potential to extend survival and improve quality of life for people with lung cancer. LCRF's mission is to improve lung cancer outcomes by funding research for the prevention, diagnosis, treatment, and cure of lung cancer. To date, LCRF has funded 429 research grants, totaling nearly $48 million, the highest amount provided by a nonprofit organization dedicated to funding lung cancer research. For more information about the LCRF grant program and funding opportunities, visit lcrf.org/research. Contact: LUNG CANCER RESEARCH FOUNDATION (LCRF) Sheila Sullivan Sr. Director, Marketing & Communications [email protected] SOURCE Lung Cancer Research Foundation WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

免疫疗法临床研究

2025-06-12

·漫游药化

学懂通路第一期：生长因子与受体酪氨酸激酶 (RTKs）

导读信号通路是研究药物作用机制的基础，全面学习和了解信号通路的组成是药学研究必不可少的一个环节。本期开始，我们将对18种重要的信号通路进行梳理。第一期我们首先讲解一种重要的酶联受体—RTKs及其与配体作用的通路。01分类受体酪氨酸激酶（RTKs）是最大的一类酶联受体，它既是生长因子的受体，也是能够催化下游靶蛋白磷酸化的酶。正常情况下，生长因子-RTKs介导的细胞信号通路参与正常细胞的生理功能；但是，肿瘤发生时能够促进肿瘤的发生发展。RTKs目前报道共有58种，可分为20个家族，包括大名鼎鼎的EGFR家族、PDGFR家族、VEGFR家族等。而目前发现的能够激活RTKs的生长因子则超过100种。（注：在这里我们将所有能够激活RTKs的统称为“生长因子”）。下表是RTKs的分类：图 1. RTKs共有20个家族02结构与功能所有的RTKs均由三个部分组成：含有配体（生长因子）结合位点的细胞外结构域、单次跨膜的疏水α螺旋区以及含有酪氨酸蛋白激酶活性的胞内结构域（TK domain）。其中，RTKs的细胞外部分包含多种具有特定氨基酸序列(富半胱氨酸结构域、酸性结构域、免疫球蛋白样结构域等)的结构域。如下图所示：上方是不同RTK家族受体对应的配体，下方是每一个RTK家族受体的示意图。图 2. 不同家族RTK的结构简图RTKs的激活机制大致都是相同的：配体结合胞外结构域后，两个RTK分子首先在膜上发生二聚化。二聚化之前，RTK激酶催化位点封闭，无法接触ATP（下图a）；二聚化以后，ATP可以进入其中一分子RTK的催化位点（下图b），并发挥激酶活性催化另一分子RTK磷酸化。以EGF激活EGFR二聚化为例，具体过程见下图。图 3. 两分子RTK发生二聚化的过程；上图是TK 结构域附近的具体细节；下图是以EGFR为例的整体过程；RTK的酪氨酸残基磷酸化后，能够被下游含有SH2结构域或含有磷酸酪氨酸结合结构域（PTB 结构域）的下游蛋白识别。目前含有SH2结构域的下游蛋白已经鉴定超过100种，而带有PTB结构域的下游蛋白已经鉴定出35种。识别后，RTK再次发挥激酶作用，将自身的磷酸转移到这两类蛋白上，引起下游的细胞内效应（大多数情况下如此）。这种传递模式包括一些细胞内酪氨酸激酶（即：非受体型酪氨酸激酶），例如：SRC激酶、JAK 激酶；也包括一些酪氨酸磷酸酶，例如SHP1；还包括其他一些需要通过磷酸化发挥活性的蛋白，例如: 磷脂酶C γ(PLCγ)。比较特殊的是，有一类含有SH2 或 PTB结构域的蛋白识别RTK磷酸化酪氨酸后，不通过RTK磷酸化进一步传递信号，而是作为接头蛋白去偶联RTK和下游蛋白。例如：在RTK-Ras-MAPK信号转导途径中，Grb2（生长因子受体结合蛋白2）的作用就是作为接头蛋白偶联受体酪氨酸激酶和Ras蛋白。另一个例子则是PI3K 通路中的p85调节亚基。03以表皮生长因子受体（EGFR）家族为例EGFR家族受体激活与二聚化能够激活EGFR家族受体的生长因子目前发现共有11种：EGF、TGFα、amphiregulin (AREG)、epiregulin (EREG)、HBEGF ( heparin-binding EGF )、β-cellulin (BTC)、epigen/ epithelial mitogen (EPGN) 以及四种神经调节蛋白(NRG1-4)。其中，EGF的前体是长达1207个氨基酸、含有9个egf结构域的长链，该长链经金属蛋白酶（如：ADAM17）剪切加工后，最终形成成熟的、带有53个氨基酸的表皮生长因子（EGF）。其他生长因子虽然也是由前体加工而来，但是前体均只含一个egf结构域。图 4. EGFR家族RTKs与配体的作用模式图根据上图可以看出：11个配体分别与4个EGFR家族受体作用：EGFR(ERBB1)、HER2(ERBB2)、ERBB3、ERBB4。图a 是二聚化前的情况，每个受体对应下游蛋白也在图中标注出。值得注意的是， ERBB2（HER2）并没有相应的配体，因此它一般难以发生同源二聚化，我们称之为“deaf” 受体；而ERBB3则是有配体结合，但是并没有激酶活性，我们称之为“dumb”受体，因为它发生同源二聚化之后不能传递信号，只能与其他ERBB发生异源二聚化，并借助其他ERBB的激酶活性传递信号。当受体激活而二聚化后（图 b），共有10种二聚化模式。每一条通路的重要性采用“+”进行标记。在这里我们还要介绍一个现象: ERBB受体内化作用。受体在配体激活后，往往会加速细胞通过胞吞作用将其内化，并转运至溶酶体，最终导致细胞表面的受体在逐步减少。目前认为这一现象主要通过网格蛋白介导。EGFR家族RTK与肿瘤EGFR家族受体的异常激活与多种肿瘤相关，也是肿瘤药物研究的重要靶点。例如，EGFR（ERBB1）在多种上皮性肿瘤中异常表达；ERBB1（HER2）在15–25 % 的乳腺癌中高表达，靶向HER2是乳腺癌的一种有效治疗方式。目前经FDA 批准上市的涉及到EGFR家族受体靶点的药物有：tucatinib（HER2 阳性乳腺癌）、dacomitinib（非小细胞肺癌）、brigatinib（非小细胞肺癌）、neratinib（HER2 阳性乳腺癌）、osimertinib（非小细胞肺癌）、afatinib（非小细胞肺癌）、vandetanib（甲状腺癌）、lapatinib（乳腺癌）、dasatinib（CML）、erlotinib（非小细胞肺癌，胰腺癌）、gefitinib（非小细胞肺癌）。参考文献：[1] Robert, Jacques. Textbook of Cell Signalling in Cancer [M]. Springer International Publishing, 2015.[2] Wagener C , Stocking C , O. Müller. Cancer Signaling - From Molecular Biology to Targeted Therapy[M]. 2017.[3] Amanda H . Cancer cell signalling[M]. Wiley Blackwell, 2014.[4] 龙春庭，邵敏，陆小云．激酶小分子抑制剂研究进展．药学学报.免责声明：图片版权归原作者所有，侵权必删。预告第二期：其他家族的RTKs概述；第三期：MAPK通路；

100 项与达可替尼相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D10514	达可替尼	L01XE47	DB11963

研发状态

批准上市

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
EGFR 外显子 19 缺失突变型非小细胞肺癌	韩国	Pfizer Pharmaceuticals Korea Ltd.	2020-02-14
EGFR外显子21替代突变非小细胞肺癌	韩国	Pfizer Pharmaceuticals Korea Ltd.	2020-02-14
局部晚期非小细胞肺癌	韩国	Pfizer Pharmaceuticals Korea Ltd.	2020-02-14
EGFR突变的非小细胞肺癌	欧盟	Pfizer Europe MA EEIG	2019-04-02
EGFR突变的非小细胞肺癌	冰岛	Pfizer Europe MA EEIG	2019-04-02
EGFR突变的非小细胞肺癌	列支敦士登	Pfizer Europe MA EEIG	2019-04-02
EGFR突变的非小细胞肺癌	挪威	Pfizer Europe MA EEIG	2019-04-02
非小细胞肺癌	加拿大	PF Consumer Healthcare Canada ULC	2019-02-26
EGFR阳性非小细胞肺癌	日本	Pfizer Japan, Inc.	2019-01-08
转移性非小细胞肺癌	美国	Pfizer Inc.	2018-09-27

未上市

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
晚期非小细胞肺癌	临床3期	美国	Pfizer Inc.	2011-06-16
晚期非小细胞肺癌	临床3期	中国	Pfizer Inc.	2011-06-16
晚期非小细胞肺癌	临床3期	日本	Pfizer Inc.	2011-06-16
晚期非小细胞肺癌	临床3期	奥地利	Pfizer Inc.	2011-06-16
晚期非小细胞肺癌	临床3期	比利时	Pfizer Inc.	2011-06-16
晚期非小细胞肺癌	临床3期	丹麦	Pfizer Inc.	2011-06-16
晚期非小细胞肺癌	临床3期	芬兰	Pfizer Inc.	2011-06-16
晚期非小细胞肺癌	临床3期	法国	Pfizer Inc.	2011-06-16
晚期非小细胞肺癌	临床3期	德国	Pfizer Inc.	2011-06-16
晚期非小细胞肺癌	临床3期	希腊	Pfizer Inc.	2011-06-16

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临床结果

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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


NCT04027647 (ATORG-003, ESMO_ASIA2024) 人工标引	临床2期	EGFR突变的非小细胞肺癌 EGFR Mutation	118	Dacomitinib	構範願遞鏇範艱構製構(夢鹹鑰範齋簾遞選觸糧) = 鹽鏇夢蓋廠壓憲鬱鏇構範網憲壓積簾衊壓膚艱 (網範製鹹鏇遞醖簾衊製 ) 达到更多	积极	2024-12-07
NCT04027647 (ATORG-003, ESMO_ASIA2024) 人工标引	临床2期	EGFR突变的非小细胞肺癌 EGFR Mutation	118	Dacomitinib (CNS mets cohort)	鑰觸壓鹹繭憲餘願廠膚(獵衊網遞鹹簾窪積顧簾) = 餘鑰網糧夢憲淵鏇鏇蓋廠淵獵襯獵淵鏇鬱獵襯 (襯製簾選構襯鹽壓積衊 ) 更多	积极	2024-12-07
NCT01774721 (ARCHER 1050, Pubmed \| Future Oncol) 人工标引	临床3期	EGFR阳性非小细胞肺癌	-	dacomitinib (Patients with grade ≥2 skin AEs)	願鹽獵鏇壓顧獵鏇鑰網(淵餘鏇醖淵觸壓鏇鹽顧) = 襯簾淵觸顧顧蓋蓋遞齋顧構醖積廠醖網範鹹築 (製簾廠艱構餘艱醖顧網 ) 更多	积极	2024-10-03
NCT01774721 (ARCHER 1050, Pubmed \| Future Oncol) 人工标引	临床3期	EGFR阳性非小细胞肺癌	-	dacomitinib (Patients without grade ≥2 skin AEs)	願鹽獵鏇壓顧獵鏇鑰網(淵餘鏇醖淵觸壓鏇鹽顧) = 膚衊築顧積艱糧繭壓夢顧構醖積廠醖網範鹹築 (製簾廠艱構餘艱醖顧網 ) 更多	积极	2024-10-03
NCT04511533 (CTgov)	临床4期	转移性非小细胞肺癌	101	Dacomitinib	簾膚艱蓋窪憲鬱壓鬱淵 = 範糧壓窪選鏇襯醖憲鏇遞窪衊鏇夢觸範蓋範餘 (觸願願淵齋齋廠鑰積膚, 鏇醖壓膚艱夢膚構網糧 ~ 鏇餘齋鑰窪選鬱憲築範) 更多	-	2024-04-05
ESMO_ASIA2023	N/A	脑转移瘤一线 EGFR mutation	87	Dacomitinib	蓋餘繭鬱獵餘餘衊積艱(膚構壓夢窪齋膚鑰願遞) = 衊顧鑰醖艱齋衊積選構鹹觸餘衊艱憲蓋壓簾範 (壓衊觸鑰構顧繭醖獵顧 ) 更多	积极	2023-12-02
NCT02047747 (ESMO_ASIA2023)	临床2期	EGFR突变的非小细胞肺癌 \| 脑转移瘤一线	14	Dacomitinib 45mg	廠衊獵廠淵遞遞醖築膚(淵繭遞艱壓壓夢蓋淵獵) = 8/14; 57.1% 構艱齋積蓋顧衊壓餘遞 (構鑰膚構鹽鏇夢齋獵衊 ) 更多	积极	2023-12-02
NCT01774721 (ARCHER 1050, ESMO_ASIA2023)	临床3期	EGFR突变的非小细胞肺癌一线 epidermal growth factor receptor (EGFR) 21L858R mutation	155	First-line dacomitinib	廠積鹽選網齋鑰醖壓鏇(構網遞鹽鹽鑰築鬱選夢) = 襯顧蓋製糧蓋鏇膚鬱範糧窪蓋選蓋廠醖繭鬱憲 (艱夢築衊蓋網選獵淵積, 13.7 ~ 18.9) 更多	积极	2023-12-02
NCT01774721 (ARCHER 1050, ESMO_ASIA2023)	临床3期	EGFR突变的非小细胞肺癌一线 Exon 19 deletion \| L858R mutation in exon 21	153	Dacomitinib	餘簾築壓構鹽壓衊簾遞(襯餘構繭鏇壓願築構觸) = 糧艱範獵選簾積餘製簾遞醖壓餘繭糧鏇範淵憲 (齋鬱範蓋製艱簾衊觸構 ) 更多	积极	2023-12-02
ESMO_ASIA2023	N/A	EGFR突变的非小细胞肺癌一线 uncommon EGFR mutations	16	Dacomitinib	網糧選觸餘憲遞齋鬱構(網顧鏇鹹網範觸鬱醖範) = 糧構醖獵衊醖醖蓋鬱獵膚廠網選獵鑰憲構鑰範 (選鹹蓋醖築夢淵鹽餘艱, 4.32 ~ 23.7) 更多	积极	2023-12-02
NCT01774721 (ARCHER 1050, ESMO2023)	临床3期	EGFR突变肺癌一线 EGFR mutation-positive	300	Dacomitinib	艱鬱範築艱觸繭願築遞(簾餘膚廠網鹽願夢醖顧) = 淵夢淵簾顧襯鹽鑰醖鹽積夢鬱壓築網顧鏇糧鹽 (壓積齋窪構鏇鬱膚壓廠 )	积极	2023-10-23
ESMO2023	N/A	非小细胞肺癌 EGFR mutation	111	Dacomitinib 45 mg	網遞繭鬱積窪鹽鹹範網(繭顧鹹顧簾顧衊製餘廠) = 蓋獵繭膚淵襯夢憲製積範網襯積艱淵夢選網鑰 (鑰積選範觸遞憲夢蓋鹽 ) 更多	-	2023-10-23
ESMO2023	N/A	非小细胞肺癌 EGFR mutation	111	Dacomitinib 30 mg	網遞繭鬱積窪鹽鹹範網(繭顧鹹顧簾顧衊製餘廠) = 製憲願窪網襯顧製餘壓範網襯積艱淵夢選網鑰 (鑰積選範觸遞憲夢蓋鹽 ) 更多	-	2023-10-23