作者: Lin, Yi-Han ; Henderson, Mark J. ; Beiko, Jason ; Klonisch, Thomas ; Ippolitov, Danyyl ; Kapoor, Abhijeet ; Del Bigio, Marc R. ; Williams, Darian ; Marugan, Juan J. ; Hombach-Klonisch, Sabine ; Wang, Amy Q. ; Xu, Xin ; Glogowska, Aleksandra ; Calvo, Raul ; Spence, Jeremy ; Thanasupawat, Thatchawan

Abstract:

Brain metastasis occurs in about 50% of all women with metastatic HER2+ breast cancer and confers poor prognosis for patients. Despite effective HER2-targeted treatments of peripheral HER2+ breast cancer with trastuzumab and HER2 inhibitors, limited brain permeability renders these treatments inefficient for HER2+ breast cancer brain metastasis. The scarcity of suitable patient-derived in vivo models for HER2+ breast cancer brain metastasis has curtailed the study of molecular mechanisms that promote growth and therapeutic resistance in brain metastasis. In this study, we generated and characterized a luminal B HER2+ breast cancer brain metastasis cell model (BCBM94) isolated from a patient with HER2+ brain metastasis. Repeated hematogenic xenografting of BCBM94 consistently generated breast cancer brain metastasis in mice. The clinical receptor tyrosine kinase inhibitor (RTKi) lapatinib blocked phosphorylation of all ERBB receptors (ERBB1–4) and induced the intrinsic apoptosis pathway in BCBM94. Neuregulin 1 (Nrg1), an ERBB3/ERBB4 ligand that is abundantly expressed in the brain, abrogated lapatinib-induced apoptosis in HER2+ BCBM94 and BT474 models. ErbB3 signaling pathways that involved PI3K–AKT and the phosphorylation of BAD at serine 136 to prevent apoptosis were essential for Nrg1-induced survival. High-throughput RTKi screening identified the brain-penetrant pan-ErbB inhibitor poziotinib as a highly potent compound that reduced cell viability in HER2+ breast cancer brain metastasis in the presence of NRG1. Two weeks of poziotinib treatment successfully ablated BCBM94 and BT474 HER2+ brain tumors in vivo. In conclusion, this study established a patient-derived HER2+ breast cancer brain metastasis model and identified poziotinib as a highly efficacious RTKi with excellent brain penetrability that eliminated HER2+ breast cancer brain metastasis.Significance: Development of a preclinical patient-derived model to study HER2+ breast cancer brain metastasis enabled the identification of the irreversible pan-ERBB inhibitor poziotinib as highly efficacious in treating brain metastatic tumors.

2025-03-01·Targeted Oncology

HER2 Pathway in Biliary Tract Cancer: A Snapshot of the Current Understanding and Future Directions

Review

作者: Vitiello, Francesco ; Cascinu, Stefano ; Rossari, Federico ; De Cobelli, Francesco ; Camera, Silvia ; Foti, Silvia ; Aldrighetti, Luca ; Casadei-Gardini, Andrea ; Persano, Mara ; Prinzi, Federica Lo ; Rimini, Margherita

Biliary tract cancers (BTCs) are a wide class of malignancies with dismal prognosis. The therapeutic scenario of metastatic BTCs has profoundly changed during recent years. The combination of cisplatin-gemcitabine plus immunotherapy is currently the gold standard in the first line. The more extensive comprehension of the mechanisms at the basis of BTCs and the identification of several molecular alterations has led to the introduction of target-directed therapies in the second line and beyond that have expanded the therapeutic armamentarium alongside the standard FOLFOX regimen, and for the near future, the results of some trials with targeted therapies in first line are expected. HER2 represents a promising therapeutic target detected in BTCs, being overexpressed in approximately 15-20% of cases, with a strong predilection for gallbladder carcinoma and extrahepatic cholangiocarcinoma, although a small proportion of HER2 overexpression can be detected even in intrahepatic cholangiocarcinoma. The efficacy and safety of different HER2 inhibitors have been investigated in several studies in the second line and beyond with encouraging results. This comprehensive review is intended to provide a summary of existing evidence and future perspectives on HER2 altered BTCs.

2025-02-01·Molecular Informatics

Discovery of New HER2 Inhibitors via Computational Docking, Pharmacophore Modeling, and Machine Learning

Article

作者: Mohammad, Haneen ; Taha, Mutasem Omar ; Matrouk, Aseel Yasin ; Daoud, Safa

Abstract:

The human epidermal growth factor receptor 2 (HER2) is a critical oncogene implicated in the development of various aggressive cancers, particularly breast cancer. Discovering novel HER2 inhibitors is crucial for expanding therapeutic options for HER2‐related malignancies. In this study, we present a computational workflow that focuses on generating pharmacophores derived from docked poses of a selected list of 15 diverse, potent HER2 inhibitors, utilizing flexible docking. The resulting pharmacophores, along with other physicochemical molecular descriptors, were then evaluated in a machine learning‐quantitative structure‐activity relationship (ML‐QSAR) analysis against 1,272 HER2 inhibitors. Several machine learning methods were assessed, and a genetic function algorithm (GFA) was employed for feature selection. Ultimately, GFA combined with Bagging and J48Graft classifiers produced the best self‐consistent and predictive models. These models highlighted the significance of two pharmacophores, Hypo_1 and Hypo_2, in distinguishing potent from less active inhibitors. The successful ML‐QSAR models and their associated pharmacophores were used to screen the National Cancer Institute (NCI) database for novel HER2 inhibitors. Three promising anti‐HER2 leads were identified, with the top‐performing lead demonstrating an experimental anti‐HER2 IC50 value of 3.85 μM. Notably, the three inhibitors exhibited distinct chemical scaffolds compared to existing HER2 inhibitors, as indicated by principal component analysis.

项与 HER2 inhibitors(Boehringer Ingelheim) 相关的新闻（医药）

2025-04-28

·Endpoints

Boehringer’s updated results in HER2-mutated lung cancer impress

CHICAGO — Boehringer Ingelheim’s targeted lung cancer drug led to durable responses, according to the latest data from the early-stage trial. The German drugmaker is studying zongertinib in lung cancer with HER2 mutations, which account for 2% to 4% of non-small cell lung cancer cases. As of Nov. 29, a 120 mg dose of the once-daily drug kept cancer at bay for a median of one year in 75 previously treated lung cancer patients. In addition, the median duration of response for those patients was 14 months. The data from the Phase 1b Beamion LUNG-1 study were shared Monday at the American Association for Cancer Research’s annual meeting in Chicago and published the same day in The New England Journal of Medicine . Researchers also shared that 71% of patients in that cohort responded to treatment. The drug’s response rates and the duration of response data “looked really good,” Penn Medicine oncologist Charu Aggarwal told Endpoints News . Aggarwal was not involved in the study. A key feature of zongertinib is that it targets HER2 while sparing EGFR, and it can be a potentially safer option for patients compared to other HER2 inhibitors. Unlike AstraZeneca and Daiichi Sankyo’s Enhertu, “it doesn’t have the risk of ILD [interstitial lung disease], which is a major risk for lung cancer patients,” John Heymach, chair of thoracic/head and neck medical oncology at MD Anderson Cancer Center, said in an interview in advance of the study’s presentation. The most commonly reported adverse event in the study was mild diarrhea, though 17% of patients experienced grade 3 or higher drug-related adverse events like increased liver enzyme levels. Boehringer reported an objective response rate of 71% in February when it announced that the FDA is expected to decide in the third quarter whether to approve zongertinib in advanced HER2-mutant non-small cell lung cancer based on the results of this study. The company is also running a Phase 3 trial called Beamion LUNG-2, studying zongertinib as a first-line option for patients with advanced HER2-mutated lung cancer. When asked about the possibility of FDA delays, Boehringer oncology head Itziar Canamasas said the company is on track with the FDA’s decision date. “We’re monitoring the situation very closely,” she said.

临床结果临床1期临床3期AACR会议临床2期

2024-12-25

·echemi

Zongertinib Tablets Enter Priority Review for Treating HER2-Mutant NSCLC

According to the CDE website on December 25, Boehringer Ingelheim’s (BI) oral HER2 inhibitor Zongertinib tablets (BI 1810631) have been proposed for inclusion in the priority review process. The drug is intended for treating unresectable or metastatic HER2-mutant non-small cell lung cancer (NSCLC) in adult patients who have undergone prior systemic therapy. Zongertinib is a selective HER2 inhibitor that covalently binds to the tyrosine kinase domain (TKD) of both wild-type and mutant HER2 receptors, including those with exon 20 mutations. This enhanced selectivity may lead to better tolerability and efficacy. The drug had previously been granted Breakthrough Therapy Designation by the CDE. In April this year, Boehringer Ingelheim signed a strategic collaboration agreement with China Biopharma. The two companies will leverage their resources to co-develop and commercialize BI's oncology drug pipelines in mainland China, including Zongertinib. Research indicates that 2%-4% of NSCLC patients in China exhibit HER2 gene mutations. Historically, HER2-mutant NSCLC patients have had poor prognoses, with median overall survival (OS) following a stage IV diagnosis at only 1.6–1.9 years and progression-free survival (PFS) shorter than that of EGFR-mutant and ALK/ROS1-rearranged NSCLC patients. Beamion LUNG-1, a Phase Ia/Ib first-in-human open-label trial (NCT04886804), included a Phase Ia dose-escalation study evaluating Zongertinib’s efficacy in patients with advanced/metastatic solid tumors harboring any HER2 alteration. The trial identified 120 mg and 240 mg QD as the recommended expansion doses. As of May 23, 2024, a total of 132 patients in the Ib cohort received Zongertinib at daily doses of 120 mg or 240 mg (n=75/57). Independent Central Review Committee (BICR) evaluations confirmed an objective response rate (ORR) of 66.7%, and tumor reduction of varying magnitudes was observed in 94% of patients across all dose groups.

优先审批临床结果临床1期突破性疗法引进/卖出

2024-06-18

·精准药物

浅析HER2选择性小分子结构特征

这里“HER2选择性”，主要指对EGFRWT的选择性，因二者为同一家族，结合口袋相似性高，之前获批的HER2小分子抑制剂如Lapatinib、Neratinib，都是EGFR/HER2双重抑制剂，由于较强抑制EGFRWT，治疗窗口比较窄，dose上不去。直到2020年Tucatinib获批上市。 Tucatinib是目前唯一上市的选择性HER2小分子抑制剂，由Array公司研发，授权给Seagen (Seattle Genetics)，而后来Array与Seagen先后被辉瑞收购。下图由公众号“新药故事”整理，Lapatinib与Neratinib是EGFR/HER2双抑制剂 (其中Nera为共价分子)，Tucatinib是第一款选择性HER2抑制剂，三者都已上市。后面两个分别为迪哲与赞荣的专利分子，亦是选择性HER2抑制剂。下图也由“新药故事”分享，是一家AI公司Iambic的专利分子，其亦有HER2选择性抑制剂管线。从以上分子可以注意到HER2选择性抑制剂的一处关键，即在第一张图Tucatinib结构式中圈起来的部分。该片段或相似片段被后续HER2选择性分子沿用。包括上面以及下面的例子。下图是Dana-Farber研究中心发表的文献分子，Tucatinib与Neratinib的hybridization。下图是BI公司的分子，前两个是文献分子，第三个已经三期临床。下图是辉瑞公司近日发表的文献分子。综上，可以看出之前highlight过的片段 (或相似片段)，是HER2选择性抑制剂的一个共同特征。下面数据进一步证实五元杂环对HER2选择性的重要。有结合模式就容易理解。杂环指向一处差异残基，其在EGFR中为Cysteine，在HER2中为Serine。在HER2中S783与杂环N形成一个氢键。下图表数据进一步证明该处差异残基的影响。当人为突变EGFR相对应残基C775为Serine (模拟HER2)，与HER2该位点形成氢键的小分子如BI-1622对EGFR的活性明显增强。综上，HER2选择性主要来源于杂环与S783之间形成的氢键，而EGFR中对应位置的残基是C775，即使与杂环形成氢键也弱得多，估算二者差异在3.2-3.9 Kcal/mol之间，对应220-720倍活性差距。而再回头看分子3、4的SAR，加上杂环之后选择性改善一方面由于HER2活性提高，但更因为EGFR活性下降，说明什么呢？请考虑desolvation的影响。最后，目前HER2小分子抑制剂的研发可能主要围绕对EGFRWT选择性及脑渗透两个方面，共价方面有的选择共价有的不共价。分子结构上从个人看到的这些分子 (对该靶点无深入研究)，都沿用了图1 Tucatinib圈起来的片段 (或有改动)，Array公司当年的这一改动 (Tucatinib可能也是在Lapatinib基础上发现的)，不仅成就了一个上市药物，也启发了后来者们。 Iambic的HER2选择性抑制剂，AI设计的？公众号“新药故事” https://www.nature.com/articles/s43018-022-00412-y (2022) 内容来源于网络，如有侵权，请联系删除。

并购临床失败

100 项与 HER2 inhibitors(Boehringer Ingelheim) 相关的药物交易

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