Epidermal growth factor receptor (EGFR) signaling plays a key role in regulating epidermal cell proliferation, survival, and differentiation. Keratins form a scaffold with epidermal desmosomes that involves ErbB/ EGFR signaling and keratin deficiency makes keratinocytes more sensitive to EGFR activation. Erlotinib, an EGFR inhibitor, was approved 20 years ago for cancer treatment and is generally used at 150 mg daily in adults >50 kg. While gastrointestinal and cutaneous side effects commonly occur at doses of 150 mg, adverse events occur less often at lower doses. We first reported erlotinib as effective for Olmsted syndrome, a rare hereditary EDD with painful PPK that results from variants in TRPV3. Erlotinib is now the treatment of choice for children and adults with Olmsted syndrome. Erlotinib is thought to inhibit formation of a complex that includes TRPV3, EGFR, and its primary skin-based ligand, TGF-a, which in turn regulates keratinocyte proliferation and differentiation. High-throughput screening to identify compounds that stabilize keratin filaments have also pointed to the EGFR pathway for targeting. Reviews and recent case reports have suggested the benefit of erlotinib for PC,
Given these preliminary data, we hypothesize that EGFR activation is a characteristic feature of keratinopathies. Further, we expect that oral low-dose erlotinib will improve the scaling and skin thickening of the spectrum of keratinopathies and be tolerated by most patients. For those who experience pain, particularly from plantar involvement, we predict that erlotinib therapy will improve mobility and pain. Finally, we aim to find the mechanism by which erlotinib improves the phenotypes of the various keratinopathies to better understand these disorders and predict response. We will look specifically at the impact on differentiation vs. hyperproliferation and barrier function, as well as the immune modulatory effects of the erlotinib using a multi-omics approach.

开始日期2025-12-01

申办/合作机构

Northwestern University

[+1]

NCT04172779 / Not yet recruiting临床2期IIT

Phase IIa Single-arm Clinical Trial of Hepatocellular Carcinoma Chemoprevention With Low-dose Erlotinib in Patients With Liver Cirrhosis

This phase IIa trial studies long-term low-dose erlotinib hydrochloride treatment to assess its efficacy and safety to prevent development of hepatocellular carcinoma in patients with liver cirrhosis.

开始日期2025-07-01

申办/合作机构

The University of Texas Southwestern Medical Center

[+1]

NCT06630325 / Not yet recruiting临床2期IIT

Serial Measurements of Molecular and Architectural Responses to Therapy (SMMART): Adaptive Clinical Treatment (ACT)

This phase II trial tests the how well a precision medicine approach (serial measurements of molecular and architectural response to therapy [SMMART])-adaptive clinical treatment [ACT]) works in treating patients with sarcoma, prostate, breast, ovarian or pancreatic cancer that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced). SMMART testing uses genetic and protein tests to learn how cancer changes and to understand what drugs may work against a person's cancer or why drugs stop working. These test results are reviewed by a group of physicians and scientists during a SMMART tumor board who then recommend precision therapy.

开始日期2025-01-01

申办/合作机构

OHSU Knight Cancer Institute

[+3]

100 项与 EGFR L858R x EGFR 相关的临床结果

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100 项与 EGFR L858R x EGFR 相关的转化医学

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0 项与 EGFR L858R x EGFR 相关的专利（医药）

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773

项与 EGFR L858R x EGFR 相关的文献（医药）

2024-12-01·European Journal of Medicinal Chemistry

Design, synthesis, and biological evaluation of diphenyl ether substituted quinazolin-4-amine derivatives as potent EGFRL858R/T790M/C797S inhibitors

Article

作者: Mei, Wenyi ; He, Huan ; Dou, Dou ; Jiang, Wenzhe ; Li, Wenjie ; Zhang, Chen ; Zhang, Xingsen ; Wang, Caolin ; Li, Honglin ; Diao, Yanyan ; Wumaier, Gulinuer ; Xie, Lijuan ; Zhao, Zhenjiang ; Sha, Wenjie ; Qiao, Yunjin ; Li, Shengqing ; Chen, Zhuo ; Wang, Jie ; Wu, Lingkang ; Xu, Yufang ; Zhu, Lili

Epidermal growth factor receptor (EGFR) is a validated target for non-small-cell lung cancer (NSCLC). However, the treatment for EGFR-C797S mutation induced by third-generation EGFR inhibitors remains a concern. Therefore, the development of the fourth-generation EGFR inhibitors to overcome the EGFR-C797S mutation has great potential for clinical treatment. In this article, we designed and synthesized a series of diphenyl ether substituted quinazolin-4-amine derivatives that simultaneously occupy the ATP binding pocket and the allosteric site of EGFR. Among the newly synthesized compounds, 9d displayed excellent kinase activity against EGFR^{L858R/T790M/C797S} with an IC₅₀ value of 0.005 μM, and exhibited anti-proliferation activity in BaF3-EGFR^{L858R/T790M/C797S} cells with the IC₅₀ value of 0.865 μM. Furthermore, 9d could suppress phosphorylation of EGFR and induce cell apoptosis and cycle arrest at G2 phase in a dose-dependent manner in BaF3-EGFR^{L858R/T790M/C797S} cells. More importantly, 9d displayed significant antitumor effects in BaF3-EGFR^{L858R/T790M/C797S} xenograft mouse model (30 mg/kg, TGI = 71.14 %). All the results indicated compound 9d might be a novel fourth-generation EGFR inhibitor for further development in overcoming the EGFR-C797S resistance mutation.

2024-11-01·European Journal of Medicinal Chemistry

Novel EGFR inhibitors against resistant L858R/T790M/C797S mutant for intervention of non-small cell lung cancer

Article

作者: Yang, Shuang ; Shi, Yi ; Wang, Xiaoxue ; Zeng, Beilei ; Fan, Yan ; Xu, Kejia ; Qiu, Wenrui ; Ma, Yakun ; Bai, Yuting ; Qin, Zhongxiang

To overcome C797S mutation, the latest and most common resistance mechanism in the clinical treatment of third-generation EGFR inhibitor, a novel series of substituted 6-(2-aminopyrimidine)-indole derivatives were designed and synthesized. Through the structure-activity relationship (SAR) study, compound 11eg was identified as a novel and potent EGFR ^{L858R/T790M/C797S} inhibitor (IC₅₀ = 0.053 μM) but had a weak effect on EGFR^WT (IC₅₀ = 1.05 μM). 11eg significantly inhibited the proliferation of the non-small cell lung cancer (NSCLC) cells harboring EGFR^{L858R/T790M/C797S} with an IC₅₀ of 0.052 μM. 11eg also showed potent inhibitory activity against other NSCLC cell lines harboring main EGFR mutants. Furthermore, 11eg exhibited much superior activity in arresting cell cycle and inducing apoptosis of NSCLC cells with mutant EGFR^C797S. It blocked cellular EGFR signaling. Importantly, 11eg markedly suppressed the tumor growth in in vivo xenograft mouse model with good safety. Additionally, 11eg displayed good microsomal stability. These results demonstrated the potential of 11eg with novel scaffold as a promising lead compound targeting EGFR^C797S to guide in-depth structural optimization.

2024-11-01·Bioorganic & Medicinal Chemistry

Design, preparation and biological evaluation of new Rociletinib-inspired analogs as irreversible EGFR inhibitors to treat non-small-cell-lung cancer

Article

作者: Konsue, Adchata ; Paul Gleeson, M. ; Pickering, James D. ; Britton, Robert G ; Jones, Donald J L ; Lamtha, Thomanai ; Gleeson, Duangkamol ; Choowongkomon, Kiattawee ; Jones, Donald J.L. ; Gleeson, M Paul ; Pickering, James D ; Britton, Robert G.

Epidermal growth factor receptor (EGFR) kinase has been implicated in the uncontrolled cell growth associated with non-small cell lung cancer (NSCLC). This has prompted the development of 3 generations of EGFR inhibitors over the last 2 decades due to the rapid development of drug resistance issues caused by clinical mutations, including T790M, L858R and the double mutant T790M & L858R. In this work we report the design, preparation and biological assessment of new irreversible 2,4-diaminopyrimidine-based inhibitors of EGFR kinase. Twenty new compounds have been prepared and evaluated which incorporate a range of electrophilic moieties. These include acrylamide, 2-chloroacetamide and (2E)-3-phenylprop-2-enamide, to allow reaction with residue Cys797. In addition, more polar groups have been incorporated to provide a better balance of physical properties than clinical candidate Rociletinib. Inhibitory activities against EGFR wildtype (WT) and EGFR T790M & L858R have been evaluated along with cytotoxicity against EGFR-overexpressing (A549, A431) and normal cell lines (HepG2). Selectivity against JAK3 kinase as well as physicochemical properties determination (logD_7.4 and phosphate buffer solubility) have been used to profile the compounds. We have identified 20, 21 and 23 as potent mutant EGFR inhibitors (≤20 nM), with comparable or better selectivity over WT EGFR, and lower activity at JAK3, than Osimertinib or Rociletinib. Compounds 21 displayed the best combination of EGFR mutant activity, JAK3 selectivity, cellular activity and physicochemical properties. Finally, kinetic studies on 21 were performed, confirming a covalent mechanism of action at EGFR.

189

项与 EGFR L858R x EGFR 相关的新闻（医药）

2024-10-29

·精准药物

药物筛选中心对外提供EGFR抑制剂筛选服务

咨询合作药物筛选中心（暨南大学），隶属于暨南大学药学院公共科研平台。中心拥有Echo550微量液体超声转移工作站等先进的自动化药物筛选仪器，前期支撑的多个激酶抑制剂已经产业转化及发表JMC等高水平论文。目前，筛选中心建有激酶、蛋白酶等相关靶标的筛选和研究，每天能够完成数万次的新药筛选反应。已建立的药物筛选模型 1）激酶：EGFR, EGFR (T790M), EGFR(L858R), EGFR(L861Q), EGFR(T790ML858R), EGFR(D746-750), EGFR(D746-750/T790M) 2）肿瘤细胞模型：基于Ba/F3的敏感和耐药模型； 3）肿瘤移植瘤模型体内药效；对外服务 1）体外激酶活性； 2) 体外细胞活性； 3）体外降解活性； 4) 机制研究； 5）体内抗肿瘤药效； 6）小鼠、大鼠体内PK； 7）蛋白表达、共晶等。咨询合作

2024-10-23

·翰森制药

翰森制药阿美乐®联合化疗治疗EGFR突变晚期肺癌的Ⅲ期注册试验取得积极结果

阿美乐®联合化疗在EGFR突变的晚期肺癌患者中显示出在无进展生存期具有统计学显著性和临床意义的改善。 2024年10月22日，翰森制药集团有限公司（翰森制药，03692.HK），中国领先的创新驱动型制药公司今日宣布，评估阿美乐®（甲磺酸阿美替尼片），翰森制药自主研发的1类创新药——第三代表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI），联合化疗作为局部晚期（IIIB-IIIC期）或转移性（IV期）EGFR突变非小细胞肺癌（NSCLC）患者的一线治疗方案的Ⅲ期注册试验AENEAS2，达到了其主要终点即无进展生存期（PFS）。根据盲态独立中心评审，AENEAS2Ⅲ期研究数据表明，阿美乐®联合化疗的患者在疾病进展或死亡的风险方面，风险降低超过50%，具有统计学显著性。阿美乐®联合化疗的中位无进展生存期延长至超过2年。安全性结果与此前研究中已确立的各药物的安全性特征一致，未发现新的安全性信号。 AENEAS2代表了一项突破性的研究，展示了在一线EGFR突变NSCLC患者治疗方面的重大进展，并突出了阿美乐®在提高该人群疗效中的潜力。这些具有统计学显著性和临床意义的结果进一步强调了阿美乐®在治疗EGFR突变NSCLC患者中的潜力。我们期待在即将举行的医学会议上分享这些激动人心的发现。来自AENAES2研究的这些积极结果为晚期EGFR突变肺癌患者带来新的联合治疗选择。无进展生存期的显著改善进一步凸显了阿美乐®联合化疗的潜力。我们将继续致力于满足EGFR突变非小细胞肺癌患者未被满足的医疗需求。继阿美乐®在AENAESⅢ期研究中作为一线单药治疗成功展示其疗效后，来自AENAES2的数据证明了阿美乐®联合化疗作为潜在一线治疗的有效性。该试验的详细数据将在未来医学会议上发布及向监管机构递交。阿美乐®（甲磺酸阿美替尼片）是中国首个原研的三代EGFR-TKI类创新药。2020年3月，阿美乐®获批用于既往经EGFR-TKI治疗进展且T790M突变阳性的局部晚期或转移性NSCLC患者，并于2023年1月成功续约纳入2022版国家医保目录。2021年12月，阿美乐®获批用于具有EGFR外显子19缺失或外显子21(L858R)置换突变阳性的局部晚期或转移性NSCLC成人患者的一线治疗，并于2023年1月被纳入2022版国家医保目录。2024年7月，阿美乐®用于具有EGFR外显子19缺失或外显子21(L858R)置换突变阳性的NSCLC成人患者肿瘤切除术后的辅助治疗上市许可申请（NDA）获中国国家药品监督管理局（NMPA）受理。2024年8月，阿美乐®用于含铂根治性放化疗后未出现疾病进展的不可切除的局部晚期EGFR外显子19缺失或外显子21(L858R)置换突变的NSCLC患者治疗NDA获NMPA受理。 AENEAS2是一项随机、开放标签、多中心、Ⅲ期试验，共纳入624名局部晚期（IIIB-IIIC期）或转移性（IV期）EGFRm NSCLC患者。患者每个周期接受每日一次的阿美乐®（甲磺酸阿美替尼片 110毫克）口服片剂，与每三周一次化疗（培美曲塞500mg/m2加顺铂75mg/m2或卡铂（AUC5））联合治疗，共四个周期，随后每三周进行一次阿美乐®与培美曲塞维持治疗。肺癌在中国仍然是癌症发病率和死亡率的首要原因。根据2022年的统计数据，中国约有106万新肺癌病例，占所有恶性肿瘤的22.0%，有74万癌症相关死亡，占所有癌症死亡的28.5%1。其中，非小细胞肺癌（NSCLC）是最常见的类型，占所有诊断的85%2。EGFR突变的患者对EGFR酪氨酸激酶抑制剂（EGFR-TKIs）特别敏感，这是一类阻断促进肿瘤生长的特定信号通路的靶向疗法3。翰森制药是中国领先的创新驱动型制药企业，下属豪森药业、常州恒邦药业、翰森生物医药等子公司，重点关注抗肿瘤、抗感染、中枢神经系统、代谢及自身免疫等重大疾病治疗领域，致力于通过持续创新提高人类生命质量。截至2024上半年，公司已上市7款创新药，创新产品营收占比达77.4%。公司连续多年位居全球制药企业百强、中国医药研发产品线最佳工业企业前3强，是国家重点高新技术企业、国家技术创新示范企业。公司于2019年6月在香港联交所挂牌上市（股票代码：03692.HK）。内容来源于网络，如有侵权，请联系删除。

临床成功申请上市临床结果

2024-09-26

·Endpoints

AstraZeneca's lung cancer blockbuster Tagrisso wins label expansion in early-stage EGFR patients

AstraZeneca’s blockbuster lung cancer treatment Tagrisso scored a new FDA approval on Thursday in certain EGFR-mutated early-stage patients whose non-small cell lung cancer has not spread, but can’t be removed through surgery. The company’s immunotherapy Imfinzi has been a standard treatment in this population, according to Mohit Manrao, the senior VP of AstraZeneca’s US oncology business unit. But he said that EGFR-mutated patients are likely to do better on a targeted therapy like Tagrisso. Otherwise known as osimertinib, Tagrisso is now approved for use after chemoradiotherapy in unresectable, stage 3 patients with exon 19 deletions or exon 21 (L858R) mutations, two of the most common non-small cell lung cancer mutations. Of 200,000 patients in the US diagnosed with lung cancer each year, 80% to 85% have non-small cell lung cancer, and 15% of those patients have EGFR mutations, Manrao said. The approval came earlier than expected. AstraZeneca previously said the FDA would likely announce a decision in the fourth quarter of 2024. Tagrisso is already approved for use as a monotherapy in metastatic non-small cell lung cancer patients, as an adjuvant treatment in patients with early-stage cancer after surgery, and in combination with chemotherapy in more advanced patients. “Tagrisso is the backbone now available to every patient at every stage, which has been our mission with this drug, given the impact it has on those patients,” Manrao told Endpoints News. Tagrisso is also the backbone of AstraZeneca’s oncology portfolio, generating the unit’s highest 2023 sales at nearly $5.8 billion. Imfinzi was close behind, at $4.2 billion. The approval was based on Phase 3 data which suggested Tagrisso reduced patients’ risk of disease progression or death by 84% compared to placebo (p<0.001). Median progression-free survival was 39.1 months in the Tagrisso arm versus 5.6 months in the placebo arm. Overall survival data were not mature at the time of the readout, Manrao said, adding that AstraZeneca will follow up. “Hopefully at some point when the data is mature enough — it’s an event-driven rate — we will be able to show more information,” he said.

上市批准免疫疗法临床结果临床3期