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

作用方式

抑制剂

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

进展期胃腺癌非小细胞肺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

权益机构-

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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68

项与 AZD-8186 相关的文献（医药）

2025-06-01·Journal of Bone Oncology

A novel bone metastasis-related gene signature for predicting prognosis, anti-androgen resistance, and drug choice in prostate cancer

Article

作者: Li, Yunfan ; Luo, Yu ; Han, Kun ; Wei, Chengcheng ; Liu, Zhangcheng ; Deng, Xiaoqi ; Song, Liangdong ; Su, Shuai ; Wang, Delin ; Zhang, Jindong

ObjectiveProstate cancer (PCa) often metastasizes to the bone, posing a significant clinical challenge. This study aims to develop a bone metastasis-related risk model for PCa.MethodsBone metastasis-related genes (BMRGs) were identified through a combination of differential gene expression analysis and WGCNA using GSE32269 and GSE77930 datasets. Consensus clustering analysis was employed to determine the significance of these genes in molecular subtyping of PCa. LASSO-Cox regression analysis was utilized to construct the bone metastasis-related prognostic gene signature (BMRPS). The predictive performance of BMRPS was assessed using ROC curves, Kaplan-Meier survival curves, and a predictive nomogram. The immune landscape heterogeneity of subgroups was analyzed using CIBERSORT, ESTIMATE, and xCell algorithms. Drug sensitivity and molecular docking analysis were performed to identify drugs associated with BMRPS.ResultsForty-four BMRGs associated with the prognosis of PCa were identified. Consensus clustering revealed the pivotal role of these genes in stratifying PCa into three distinct prognostic clusters. The BMRPS, consisting of 14 BMRGs, demonstrated excellent predictive accuracy for prognosis and served as an independent prognostic factor in PCa. BMRPS effectively predicted the overall survival of bone metastatic PCa and differentiated bone metastasis from other metastatic types. BMRPS showed a close correlation with the immune landscape and immunotherapeutic response biomarkers. Additionally, BMRPS was associated with anti-androgen resistance, and AZD8186 was identified as a potential BMRPS-related drug that holds promise for personalized treatment in PCa.ConclusionBMRPS facilitates the prediction of prognosis and resistance to anti-androgens in PCa. It also offers insights into the molecular mechanisms of bone metastasis and aids in drug selection for the treatment of PCa.

2025-03-01·Nature Chemical Biology

A multiplex single-cell RNA-Seq pharmacotranscriptomics pipeline for drug discovery

Article

作者: Raivola, Juuli ; Piki, Emilia ; Ungureanu, Daniela ; Murumägi, Astrid ; Sharma, Subodh ; Dini, Alice ; Barker, Harlan

AbstractThe gene-regulatory dynamics governing drug responses in cancer are yet to be fully understood. Here, we report a pipeline capable of producing high-throughput pharmacotranscriptomic profiling through live-cell barcoding using antibody–oligonucleotide conjugates. This pipeline combines drug screening with 96-plex single-cell RNA sequencing. We show the potential of this approach by exploring the heterogeneous transcriptional landscape of primary high-grade serous ovarian cancer (HGSOC) cells after treatment with 45 drugs, with 13 distinct classes of mechanisms of action. A subset of phosphatidylinositol 3-OH kinase (PI3K), protein kinase B (AKT) and mammalian target of rapamycin (mTOR) inhibitors induced the activation of receptor tyrosine kinases, such as the epithelial growth factor receptor (EGFR), and this was mediated by the upregulation of caveolin 1 (CAV1). This drug resistance feedback loop could be mitigated by the synergistic action of agents targeting PI3K–AKT–mTOR and EGFR for HGSOC with CAV1 and EGFR expression. Using this workflow could enable the personalized testing of patient-derived tumor samples at single-cell resolution.

2024-12-01·Computational and Structural Biotechnology Journal

Integrating bulk RNA-seq and scRNA-seq analyses revealed the function and clinical value of thrombospondins in colon cancer

Article

作者: Tang, Ying ; Tian, Luyao ; Tang, Ao ; Long, Fei ; Liu, Mingwei ; Chen, Juan ; Li, Jing ; Ding, LiHui

BackgroundActing as mediators in cell-matrix and cell-cell communication, matricellular proteins play a crucial role in cancer progression. Thrombospondins (TSPs), a type of matricellular glycoproteins, are key regulators in cancer biology with multifaceted roles. Although TSPs have been implicated in anti-tumor immunity and epithelial-mesenchymal transition (EMT) in several malignancies, their specific roles to colon cancer remain elusive. Addressing this knowledge gap is essential, as understanding the function of TSPs in colon cancer could identify new therapeutic targets and prognostic markers.MethodsAnalyzing 1981 samples from 10 high-throughput datasets, including six bulk RNA-seq, three scRNA-seq, and one spatial transcriptome dataset, our study investigated the prognostic relevance, risk stratification value, immune heterogeneity, and cellular origin of TSPs, as well as their influence on cancer-associated fibroblasts (CAFs). Utilizing survival analysis, unsupervised clustering, and functional enrichment, along with multiple correlation analyses of the tumor-microenvironment (TME) via Gene Set Variation Analysis (GSVA), spatial localization, Monocle2, and CellPhoneDB, we provided insights into the clinical and cellular implications of TSPs.ResultsFirst, we observed significant upregulation of THBS2 and COMP in colon cancer, both of which displayed significant prognostic value. Additionally, we detected a significant positive correlation between TSPs and immune cells, as well as marker genes of EMT. Second, based on TSPs expression, patients were divided into two clusters with distinct prognoses: the high TSPs expression group (TSPs-H) was characterized by pronounced immune and stromal cell infiltration, and notably elevated T-cell exhaustion scores. Subsequently, we found that THBS2 and COMP may be associated with the differentiation of CAFs into pan-iCAFs and pan-dCAFs, which are known for their heightened matrix remodeling activities. Moreover, THBS2 enhanced CAFs communication with vascular endothelial cells and monocyte-macrophages. CAFs expressing THBS2 (THBS2⁺ CAFs) demonstrated higher scores across multiple signaling pathways, including angiogenic, EMT, Hedgehog, Notch, Wnt, and TGF-β, when compared to THBS2^- CAFs. These observations suggest that THBS2 may be associated with stronger pro-carcinogenic activity in CAFs.ConclusionsThis study revealed the crucial role of TSPs and the significant correlation between THBS2 and CAFs interactions in colon cancer progression, providing valuable insights for targeting TSPs to mitigate cancer progression.

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

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
进展期胃腺癌	临床前	韩国	Seoul National University Bundang Hospital	2019-05-14
三阴性乳腺癌	临床前	英国	AstraZeneca PLC	2013-07-09
三阴性乳腺癌	临床前	美国	AstraZeneca PLC	2013-07-09
三阴性乳腺癌	临床前	西班牙	AstraZeneca PLC	2013-07-09
三阴性乳腺癌	临床前	加拿大	AstraZeneca PLC	2013-07-09
非小细胞肺癌	药物发现	西班牙	AstraZeneca PLC	-
非小细胞肺癌	药物发现	英国	AstraZeneca PLC	-
非小细胞肺癌	药物发现	加拿大	AstraZeneca PLC	-
非小细胞肺癌	药物发现	美国	AstraZeneca PLC	-
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 \| 转移性乳腺癌 \| 去势抵抗性前列腺癌 \| 不可切除的实体瘤 \| 遗传性前列腺癌7型 \| 晚期前列腺癌 \| 晚期乳腺癌	23	PI3Kbeta inhibitor AZD8186+docetaxel (Dose Level 1)	蓋餘齋鏇鏇夢選製願築(遞蓋簾製餘窪艱壓夢築) = 觸範鏇醖範壓糧壓遞糧蓋鑰積蓋壓淵餘鹽壓鏇 (選鏇鏇繭積願選積鏇鏇, 窪醖廠繭觸製觸繭廠簾 ~ 衊鏇鏇製積構膚願衊鹹) 更多	-	2023-09-21
NCT03218826 (CTgov)	临床1期		23	PI3Kbeta inhibitor AZD8186+docetaxel (Dose Level -1)	網襯衊獵築餘夢積鹹醖(繭構膚構衊積積窪顧遞) = 壓網壓簾鏇鹹製夢鬱願獵糧遞網蓋糧範鏇齋憲 (鏇鏇齋簾餘蓋簾獵繭鑰, 鹹鬱範淵鬱顧憲窪淵範 ~ 襯憲積衊願簾繭願積醖) 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	(糧廠齋夢窪製鏇鹹膚範) = diarrhoea (39%) and nausea (27%) 顧憲範積鹹餘壓網繭鹹 (糧構醖餘廠鑰餘夢範鑰 ) 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	(鑰製壓獵構壓夢衊鏇廠) = 23 SAEs considered 鬱壓餘糧淵積築憲襯壓 (遞膚憲觸餘鹽網願鏇構 ) 更多	积极	2017-06-05