AZD-8186(AZD-8186) - 药物靶点：PI3Kβ x PI3Kδ_在研适应症：晚期乳腺癌，晚期恶性实体瘤，晚期前列腺癌_专利_临床

概要

基本信息

药物类型

小分子化药

别名

靶点

PI3Kβ x PI3Kδ

作用机制

PI3Kβ抑制剂(磷脂酰肌醇-3激酶β抑制剂)、PI3Kδ抑制剂(磷脂酰肌醇-3激酶δ抑制剂)

治疗领域

肿瘤皮肤和肌肉骨骼疾病泌尿生殖系统疾病

在研适应症

晚期乳腺癌晚期恶性实体瘤晚期前列腺癌+ [6]

非在研适应症

进展期胃腺癌鳞状非小细胞肺癌

原研机构

AstraZeneca PLC

在研机构

National Cancer Institute

非在研机构

AstraZeneca PLC

Seoul National University Bundang Hospital

最高研发阶段临床1期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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结构/序列

分子式C24H25F2N3O4

InChIKeyLMJFJIDLEAWOQJ-CQSZACIVSA-N

CAS号1627494-13-6

关联

3

项与 AZD-8186 相关的临床试验

NCT04001569

/ Unknown status临床1/2期IIT

Phase1b/2 Study of AZD8186 in Combination With Paclitaxel in Patients With Advanced Gastric Cancer

AZD8186 is an orally-dosed, selective Phosphatidylinositol 3-kinase (PI3K) β/δ inhibitor that binds to PI3Kβ and PI3Kδ, and inhibits kinase activity and downstream pathways in vitro and in vivo. AZD8186 has shown significant anti-tumor activity in PTEN-deficient preclinical models, including prostate, triple negative breast cancer, squamous lung and germinal center diffuse large B-cell lymphoma models. PTEN deficiency is reported in approximately 20% of patients with gastric cancer and in 35-48% of those with human epidermal growth factor receptor 2(HER2)-positive gastric cancer. To date, there have been no clinical trials with AZD8186 alone or in combination with paclitaxel in advanced gastric cancer. Therefore, it is very important to conduct clinical trials of combination therapy of AZD8186 and paclitaxel in patients with metastatic/recurrent gastric cancer who have failed previous therapy, and to identify the clinical factors and biomarkers that predict effects of the combination therapy.
The purpose of the study is to define the maximal tolerated dose (MTD) and recommended phase 2 dose (RP2D) of paclitaxel and AZD8186 combination therapy in patients with advanced tumors and to evaluate the efficacy of paclitaxel and AZD8186 combination therapy as a second-line therapy in patients with advanced gastric cancer with PTEN aberrations. This study is divided into Phase 1b and Phase 2.

开始日期2019-05-14

申办/合作机构

Seoul National University Bundang Hospital

NCT03218826

/ Active, not recruiting临床1期IIT

A Phase I Study of AZD8186 in Combination With Docetaxel in Patients With PTEN Mutated or PIK3CB Mutated Advanced Solid Tumors, Potentially Amenable to Docetaxel

This phase I trial studies the side effects and best dose of PI3Kbeta inhibitor AZD8186 when given together with docetaxel in treating patients with solid tumors with PTEN or PIK3CB mutations that have spread to other places in the body (metastatic) or cannot be removed by surgery. PI3Kbeta inhibitor AZD8186 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as docetaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving PI3Kbeta inhibitor AZD8186 and docetaxel may work better in treating patients with solid tumors.

开始日期2018-09-24

申办/合作机构

National Cancer Institute

NCT01884285

/ Completed临床1期

A Phase I, Open-label, Multicentre Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Preliminary Anti-tumour Activity of AZD8186 in Patients With Advanced Castration-resistant Prostate Cancer (CRPC), Squamous Non-Small Cell Lung Cancer (sqNSCLC), Triple Negative Breast Cancer (TNBC) and Patients With Known PTEN-deficient/Mutated or PIK3CB Mutated/ Amplified Advanced Solid Malignancies as Monotherapy and in Combination With Abiraterone Acetate or AZD2014

This is a phase I, open-label, multicentre study of AZD8186 administered orally in patients with advanced castrate-resistant prostate cancer (CRPC), squamous non-small cell lung cancer (sqNSCLC), triple negative breast cancer (TNBC) and known PTEN-deficient/mutated or PIK3CB mutated/amplified advanced solid malignancies as monotherapy and in combination with abiraterone acetate or AZD2014.

开始日期2013-07-09

申办/合作机构

AstraZeneca PLC

100 项与 AZD-8186 相关的临床结果

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100 项与 AZD-8186 相关的转化医学

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100 项与 AZD-8186 相关的专利（医药）

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30

项与 AZD-8186 相关的文献（医药）

2024-07-01·Translational Cancer Research

Systematic analysis of TREM2 and its carcinogenesis in pancreatic cancer

Article

作者: Huang, Wentao ; He, Jun ; Qin, Lei ; Wu, Nuwa ; Yu, Wangjianfei ; Zheng, Wanting ; Tian, Siyun ; Hua, Ruheng

BackgroundTriggering receptor expressed on myeloid cells 2 (TREM2), a transmembrane immunoglobulin-superfamily receptor, is expressed primarily on cells such as macrophages and dendritic cells. TREM2 has been shown to be associated with diseases such as neurodegeneration, fatty liver, obesity, and atherosclerosis. Currently, it has become one of the hotspots in oncology research. However, the role of TREM2 in pan-cancer, especially pancreatic cancer, remains unclear.MethodsWe used the Tumor-immune System Interactions Database (TISIDB) to explore TREM2 expression differences, Tumor Immune Single-cell Hub 2 (TISCH2) to explore TREM2 expression distribution, Tumor IMmune Estimation Resource 2.0 (TIMER 2.0) to explore immune infiltration, cBio Cancer Genomics Portal (cBioPortal) to explore genetic variation, Genomics of Drug Sensitivity in Cancer (GDSC) to explore drug resistance, and Kaplan-Meier plotter database to explore the relationship between TREM2 and prognosis in pancreatic cancer. In addition, we used The Cancer Genome Atlas-pancreatic adenocarcinoma (TCGA-PAAD) and normal pancreas samples from the Genotype-Tissue Expression (GTEx) databases to explore the relationship between TREM2 and lymph node metastasis. We verified the protein level of TREM2 in pancreatic cancer by Human Protein Atlas (HPA) and western blotting and detected the colocalization of TREM2 with malignant cell markers by multiplex immunohistochemistry (mIHC). Finally, we identified the tumor-promoting role of TREM2 in pancreatic cancer via in vitro experiments, such as cell cycle assays, colony formation assays, and transwell migration and invasion assays.ResultsOur results showed that TREM2 was differentially expressed in various tumors according to different molecular and immune subtypes of pan-cancer. It was found that TREM2 was mainly expressed in monocytes/macrophages. In addition, our study showed that TREM2 expression was closely associated with macrophages in the tumor microenvironment (TME) of pan-cancer. TREM2 was shown to be related to anti-inflammatory and immunosuppressive effects in most cancers. Furthermore, we found that amplification was the main somatic mutation of TREM2 in pan-cancer. Further correlational analysis revealed a significant negative association of TREM2 expression with sensitivity to AZD8186, which is a selective inhibitor of PI3K, but not gemcitabine and paclitaxel. Finally, through the knockdown and overexpression of TREM2, our findings verified that TREM2 on cancer cells promoted the progression of PAAD.ConclusionsIn conclusion, our comprehensive analysis identified that TREM2 expression level was correlated with the TME and the immunosuppressive effects. In particular, our study indicated that TREM2 was involved in the progression of pancreatic cancer.

2024-04-04·The Oncologist

Correction to: AZD8186 in Combination With Paclitaxel in Patients With Advanced Gastric Cancer: Results From a Phase Ib/II Study (KCSG ST18-20)

2024-02-01·Biomedicine & Pharmacotherapy

β1 integrin mediates unresponsiveness to PI3Kα inhibition for radiochemosensitization of 3D HNSCC models

Article

作者: Borodins, Olegs ; Korovina, Irina ; Cordes, Nils ; Willers, Henning ; Seifert, Michael ; Elser, Marc

Phosphoinositide 3-kinase (PI3K)-α represents a key intracellular signal transducer involved in the regulation of key cell functions such as cell survival and proliferation. Excessive activation of PI3Kα is considered one of the major determinants of cancer therapy resistance. Despite preclinical and clinical evaluation of PI3Kα inhibitors in various tumor entities, including head and neck squamous cell carcinoma (HNSCC), it remains elusive how conventional radiochemotherapy can be enhanced by concurrent PI3K inhibitors and how PI3K deactivation mechanistically exerts its effects. Here, we investigated the radiochemosensitizing potential and adaptation mechanisms of four PI3K inhibitors, Alpelisib, Copanlisib, AZD8186, and Idelalisib in eight HNSCC models grown under physiological, three-dimensional matrix conditions. We demonstrate that Alpelisib, Copanlisib and AZD8186 but not Idelalisib enhance radio- and radiochemosensitivity in the majority of HNSCC cell models (= responders) in a manner independent of PIK3CA mutation status. However, Alpelisib promotes MAPK signaling in non-responders compared to responders without profound impact on Akt, NFκB, TGFβ, JAK/STAT signaling and DNA repair. Bioinformatic analyses identified unique gene mutations associated with extracellular matrix to be more frequent in non-responder cell models than in responders. Finally, we demonstrate that targeting of the cell adhesion molecule β1 integrin on top of Alpelisib sensitizes non-responders to radiochemotherapy. Taken together, our study demonstrates the sensitizing potential of Alpelisib and other PI3K inhibitors in HNSCC models and uncovers a novel β1 integrin-dependent mechanism that may prove useful in overcoming resistance to PI3K inhibitors.

100 项与 AZD-8186 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB15029

研发状态

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适应症	最高研发状态	国家/地区	公司	日期
进展期胃腺癌	药物发现	韩国	Seoul National University Bundang Hospital	2019-05-14
去势抵抗性前列腺癌	药物发现	美国	AstraZeneca PLC	2013-07-09
去势抵抗性前列腺癌	药物发现	英国	AstraZeneca PLC	2013-07-09
去势抵抗性前列腺癌	药物发现	西班牙	AstraZeneca PLC	2013-07-09
去势抵抗性前列腺癌	药物发现	加拿大	AstraZeneca PLC	2013-07-09
鳞状非小细胞肺癌	药物发现	英国	AstraZeneca PLC	2013-07-09
鳞状非小细胞肺癌	药物发现	美国	AstraZeneca PLC	2013-07-09
鳞状非小细胞肺癌	药物发现	加拿大	AstraZeneca PLC	2013-07-09
鳞状非小细胞肺癌	药物发现	西班牙	AstraZeneca PLC	2013-07-09
实体瘤	药物发现	-	AstraZeneca PLC	-

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临床结果

适应症

分期

评价

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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


NCT03218826 (CTgov)	临床1期	转移性实体瘤 \| 晚期恶性实体瘤 \| 三阴性乳腺癌 \| 去势抵抗性前列腺癌 \| 转移性乳腺癌 \| 遗传性前列腺癌7型 \| 不可切除的实体瘤 \| 晚期前列腺癌 \| 晚期乳腺癌	23	PI3Kbeta inhibitor AZD8186+docetaxel (Dose Level 1)	鹹壓網鑰艱製鹽鬱鏇鹽(觸齋壓憲鑰繭廠簾簾鑰) = 鬱鑰築醖網範鏇選積衊選構鏇艱膚衊壓壓築築 (壓鏇襯壓壓窪積遞蓋範, 願繭鏇窪夢鑰鹹獵艱淵 ~ 網鬱遞艱積選鏇膚廠築) 更多	-	2023-09-21
NCT03218826 (CTgov)	临床1期		23	PI3Kbeta inhibitor AZD8186+docetaxel (Dose Level -1)	鏇膚鬱艱製醖範鹽構蓋(製艱範獵夢齋窪齋艱壓) = 積鑰簾構夢鹽簾衊窪憲窪壓醖餘顧積膚衊窪網 (艱膚鹹窪網糧壓衊餘窪, 鑰願糧築獵淵齋憲鏇齋 ~ 蓋遞鬱蓋鑰餘鹽製衊鑰) 更多	-	2023-09-21
NCT01884285 (ESMO2018) 人工标引	临床1/2期	去势抵抗性前列腺癌	52	abiraterone acetate+prednisone+AZD8186	(製襯蓋願淵顧蓋艱壓壓) = diarrhoea (39%) and nausea (27%) 構齋鹹醖選廠壓範繭膚 (齋衊淵夢夢積蓋鹽廠獵 ) 更多	积极	2018-10-22
NCT01884285 (ASCO 12017 \| ASCO 22017) 人工标引	临床1期	晚期恶性实体瘤	87	AZD-8186	(憲願網構衊鏇積鑰鬱衊) = 23 SAEs considered 蓋繭糧鬱窪構艱願觸蓋 (窪艱糧壓蓋夢蓋鬱襯鬱 ) 更多	积极	2017-06-05