Delving into the Latest Updates on AZD-8186 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

PI3Kβ x PI3Kδ

Action

inhibitors

Mechanism

PI3Kβ inhibitors(Phosphatidylinositol 3 kinase beta inhibitors), PI3Kδ inhibitors(Phosphatidylinositol 3 kinase delta inhibitors)

Therapeutic Areas

NeoplasmsSkin and Musculoskeletal DiseasesUrogenital Diseases

Active Indication

Advanced breast cancerAdvanced Malignant Solid NeoplasmAdvanced Prostate Carcinoma+ [6]

Inactive Indication

Advanced Gastric AdenocarcinomaSquamous non-small cell lung cancer

Originator Organization

AstraZeneca PLC

Active Organization

National Cancer Institute

Inactive Organization

AstraZeneca PLC

Seoul National University Bundang Hospital

Drug Highest PhasePhase 1

First Approval Date-

Regulation-

Login to view timeline

Structure/Sequence

Molecular FormulaC24H25F2N3O4

InChIKeyLMJFJIDLEAWOQJ-CQSZACIVSA-N

CAS Registry1627494-13-6

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.

Start Date14 May 2019

Sponsor / Collaborator

Seoul National University Bundang Hospital

NCT03218826

/ Active, not recruitingPhase 1IIT

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.

Start Date24 Sep 2018

Sponsor / Collaborator

National Cancer Institute

NCT01884285

/ CompletedPhase 1

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.

Start Date09 Jul 2013

Sponsor / Collaborator

AstraZeneca PLC

100 Clinical Results associated with AZD-8186

Login to view more data

100 Translational Medicine associated with AZD-8186

Login to view more data

100 Patents (Medical) associated with AZD-8186

Login to view more data

66

Literatures (Medical) associated with AZD-8186

01 Mar 2025·Nature Chemical Biology

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

Article

Author: 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.

01 Dec 2024·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

Author: 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.

06 Sep 2024·Oncogene

Cooperative genomic lesions in HRAS-mutant cancers predict resistance to farnesyltransferase inhibitors

Article

Author: Chatila, Walid K ; Saqcena, Mahesh ; Nigam, Aradhya ; Untch, Brian R ; Ho, Alan L ; Walch, Henry ; Schultz, Nikolaus ; Fagin, James A ; Venkatramani, Mandakini ; Krishnamoorthy, Gnana P ; Berman, Katherine

In the clinical development of farnesyltransferase inhibitors (FTIs) for HRAS-mutant tumors, responses varied by cancer type. Co-occurring mutations may affect responses. We aimed to uncover cooperative genetic events specific to HRAS-mutant tumors and to study their effect on sensitivity to FTIs. Using targeted sequencing data from the MSK-IMPACT and Dana-Farber Cancer Institute Genomic Evidence Neoplasia Information Exchange databases, we identified comutations that were observed predominantly in HRAS-mutant versus KRAS-mutant or NRAS-mutant cancers. HRAS-mutant cancers had a higher frequency of coaltered mutations (48.8%) in the MAPK, PI3K, or RTK pathway genes, compared with KRAS-mutant (41.4%) and NRAS-mutant (38.4%) cancers (p < 0.05). Class 3 BRAF, NF1, PTEN, and PIK3CA mutations were more prevalent in HRAS-mutant lineages. To study the effects of comutations on sensitivity to FTIs, Hras^G13R was transfected into "RASless" (Kras^lox/lox/Hras^-/-/Nras^-/-/RERT^ert/ert) mouse embryonic fibroblasts (MEFs), which sensitized nontransfected MEFs to tipifarnib. Comutation in the form of Pten or Nf1 deletion and Pik3ca^H1047R transduction led to resistance to tipifarnib in Hras^G13R-transfected MEFs in the presence or absence of Kras^WT, whereas Braf^G466E transduction led to resistance to tipifarnib only in the presence of Kras^WT. Combined treatment with tipifarnib and MEK inhibition sensitized cells to tipifarnib in all settings, including in MEFs with PI3K pathway comutations. HRAS-mutant tumors demonstrate lineage-dependent MAPK or PI3K pathway alterations, which confer resistance to tipifarnib. The combined use of FTIs and MEK inhibition is a promising strategy for HRAS-mutant tumors.

100 Deals associated with AZD-8186

Login to view more data

External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB15029

R&D Status

10 top R&D records.

Login

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Advanced Gastric Adenocarcinoma	Discovery	South Korea	Seoul National University Bundang Hospital	14 May 2019
Castration-Resistant Prostatic Cancer	Discovery	United States	AstraZeneca PLC	09 Jul 2013
Castration-Resistant Prostatic Cancer	Discovery	United Kingdom	AstraZeneca PLC	09 Jul 2013
Castration-Resistant Prostatic Cancer	Discovery	Spain	AstraZeneca PLC	09 Jul 2013
Castration-Resistant Prostatic Cancer	Discovery	Canada	AstraZeneca PLC	09 Jul 2013
Squamous non-small cell lung cancer	Discovery	United States	AstraZeneca PLC	09 Jul 2013
Squamous non-small cell lung cancer	Discovery	Canada	AstraZeneca PLC	09 Jul 2013
Squamous non-small cell lung cancer	Discovery	United Kingdom	AstraZeneca PLC	09 Jul 2013
Squamous non-small cell lung cancer	Discovery	Spain	AstraZeneca PLC	09 Jul 2013
Solid tumor	Discovery	-	AstraZeneca PLC	-

Login to view more data

Clinical Result

Indication

Phase

Evaluation

View All Results

Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03218826 (CTgov)	Phase 1	Metastatic Solid Tumor \| Advanced Malignant Solid Neoplasm \| Triple Negative Breast Cancer \| Castration-Resistant Prostatic Cancer \| Metastatic breast cancer \| Prostate Cancer, Hereditary, 7 \| Unresectable Solid Neoplasm \| Advanced Prostate Carcinoma \| Advanced breast cancer	23	PI3Kbeta inhibitor AZD8186+docetaxel (Dose Level 1)	pqacxccnrq(exmkhmzaja) = hhtvnhyoci bqsqhrwdvs (jyhcfpoyyf, brfbaegiqb - dpiaqxjvzt) View more	-	21 Sep 2023
NCT03218826 (CTgov)	Phase 1		23	PI3Kbeta inhibitor AZD8186+docetaxel (Dose Level -1)	hdohhdudse(bgtolyrfjh) = asmlypfaho bnoggymgmu (txmiykyoer, anbjcbjvqs - jyilgekvpo) View more	-	21 Sep 2023
NCT01884285 (ESMO2018) Manual	Phase 1/2	Castration-Resistant Prostatic Cancer	52	abiraterone acetate+prednisone+AZD8186	(wnxmvlptmk) = diarrhoea (39%) and nausea (27%) dxlcubwgej (khboicrplp ) View more	Positive	22 Oct 2018
NCT01884285 (ASCO 12017 \| ASCO 22017) Manual	Phase 1	Advanced Malignant Solid Neoplasm	87	AZD-8186	(mdomugyrrw) = 23 SAEs considered alqdttzune (wjkedfynho ) View more	Positive	05 Jun 2017