AKT/PI3K/mTOR inhibitors(Thryv Therapeutics)(AKT/PI3K/mTOR inhibitors(Thryv Therapeutics)) - 药物靶点：Akt x PI3Kγ x mTOR_在研适应症：实体瘤，痴呆_专利_临床

概要

基本信息

药物类型

基因疗法

别名-

靶点

Akt x PI3Kγ x mTOR

作用机制

Akt 抑制剂(原癌基因蛋白c-akt 抑制剂)、PI3Kγ抑制剂(磷脂酰肌醇-3激酶γ抑制剂)、mTOR抑制剂(丝氨酸/苏氨酸蛋白激酶mTOR抑制剂)

治疗领域

肿瘤神经系统疾病

在研适应症

实体瘤痴呆

非在研适应症-

原研机构

Thryv Therapeutics, Inc.初创企业

在研机构

Amylyx Pharmaceuticals, Inc.

University Hospital Heidelberg

非在研机构-

最高研发阶段临床前

首次获批日期-

最高研发阶段(中国)-

特殊审评-

关联

100 项与 AKT/PI3K/mTOR inhibitors(Thryv Therapeutics) 相关的临床结果

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100 项与 AKT/PI3K/mTOR inhibitors(Thryv Therapeutics) 相关的转化医学

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100 项与 AKT/PI3K/mTOR inhibitors(Thryv Therapeutics) 相关的专利（医药）

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22

项与 AKT/PI3K/mTOR inhibitors(Thryv Therapeutics) 相关的文献（医药）

2025-01-01·JOURNAL OF AFFECTIVE DISORDERS

Electroconvulsive therapy combined with esketamine improved depression through PI3K/AKT/GLT-1 pathway

Article

作者: Xing, Jibin ; Mo, Xingying ; Zheng, Tingwei ; Ji, Jiaming ; Zhang, Jingting ; Zang, Xiangyang ; Zhou, Shaoli ; Chen, Chaojin ; Hu, Jingping

Neuron excitotoxic damage induced by extracellular glutamate accumulation pathologically is one of the main mechanisms of depression. Glutamate transporter-1 (GLT-1) expressed in astrocyte is responsible for glutamate clearance to maintain glutamate balance. Electroconvulsive therapy (ECT) is prevalently recommended for severe depression due to its significant anti-depressant effect. Esketamine could offer advantages of rapid anti-depressant effect and neuron protection. The aim of this study is to investigate the anti-depressant efficacy of esketamine plus ECT, and further to explore the mechanism. Firstly, total 12 patients were randomized into anesthesia with propofol (P) or propofol+esketamine (PK) before ECT. 24-Hamilton Depression Scale (HAMD) was used to evaluate the severity of depression after each ECT. Then, depressive rat model was built using chronic unpredictable mild stress method, and subsequently received infusion of esketamine (5 mg/kg) or saline before ECT treatment (0.5 mA; 100 V) for consecutive 10 days. Tests including sucrose preference test, open field test and forced swimming test were used to evaluate depression-like behaviors. In next experiments, rats were injected with RIL, DHK or LY294002 intracerebroventricularly for continuous 10 days before individual treatment. After the fifth and sixth ECT, PK group displayed lower HAMD score compared to P group. In rat model, we found that esketamine plus ECT could significantly improve depression-like behaviors and decrease glutamate level. Esketamine and ECT could both activate PI3K/Akt/GLT-1 pathway. The GLT-1 agonist RIL made equivalent effect as esketamine plus ECT. Furthermore, after using PI3K/Akt inhibitor LY294002 and GLT-1 inhibitor DHK, esketamine plus ECT could neither improve depression-like symptoms, nor upregulate GLT-1 level. Our present study suggested that esketamine plus ECT could dramatically improve depression symptom. The activation of PI3K/Akt/GLT-1 pathway may be the potential mechanism.

2022-12-01·Cell and Bioscience3区 · 生物学

AKT inhibition in the central nervous system induces signaling defects resulting in psychiatric symptomatology

3区 · 生物学

ArticleOA

作者: Armen, Roger S ; Shaw, Jamie ; Skliris, Antonis ; Pan, Jen Q ; Cottrell, Jeffrey R ; Tsichlis, Philip N ; Tsimberidou, Apostolia-Maria ; Hering, Ursula ; Chan, Tung On ; Vo, Henry Hiep ; Valentine, Alan

Abstract:

Background:

Changes in the expression and activity of the AKT oncogene play an important role in psychiatric disease. We present translational data assessing the role of AKT in psychiatric symptoms.

Methods:

(1) We assessed the protein activity of an AKT3 mutant harboring a PH domain mutation (Q60H) detected in a patient with schizophrenia, the corresponding AKT1 mutant (Q61H), and wild-type AKT1 and AKT3 transduced in AKT-null mouse fibroblasts and modeled the Q61H mutation onto the crystal structure of the Akt1 PH domain. (2) We analyzed the results of earlier genome-wide association studies to determine the distribution of schizophrenia-associated single-nucleotide polymorphisms (SNPs) in the AKT3 gene. (3) We analyzed the psychiatric adverse events (AEs) of patients treated with M2698 (p70S6K/AKT1/AKT3 inhibitor) and with other PI3K/AKT/mTOR pathway inhibitors.

Results:

(1) Proteins encoded by AKT3 (AKT3Q60H) and AKT1 (AKT1Q61H) mutants had lower kinase activity than those encoded by wild-type AKT3 and AKT1, respectively. Molecular modeling of the AKT1-Q61H mutant suggested conformational changes that may reduce the binding of D3-phosphorylated phosphoinositides to the PH domain. (2) We identified multiple SNPs in the AKT3 gene that were strongly associated with schizophrenia (p < 0.5 × 10–8). (3) Psychiatric AEs, mostly insomnia, anxiety, and depression, were noted in 29% of patients treated with M2698. In randomized studies, their incidence was higher in PI3K/AKT/mTOR inhibitor arms compared with placebo arms. All psychiatric AEs were reversible.

Conclusions:

Our data elucidate the incidence and mechanisms of psychiatric AEs in patients treated with PI3K/AKT/mTOR inhibitors and emphasize the need for careful monitoring.

2022-10-01·European review for medical and pharmacological sciences

Efficacy and safety of PI3K/Akt/mTOR inhibitors combined with trastuzumab therapy for HER2-positive breast cancer: a meta-analysis.

Article

作者: Ning, H T ; Huang, B-Q ; Peng, D-S ; Zhu, X-Z

OBJECTIVE:

Activation of the PI3K/AKT/mTOR pathway in patients with HER2-positive breast cancer is associated with acquired resistance to trastuzumab. This randomized controlled trial (RCTs) meta-analysis was designed to evaluate the clinical efficacy and safety of PI3K/Akt/mTOR inhibitors in combination with trastuzumab in HER2-positive breast cancer.

MATERIALS AND METHODS:

We searched on Web of Knowledge, PubMed, Embase, Cochrane, CNKI, and ClinicalTrials.Gov for RCTs comparing PI3K/Akt/mTOR inhibitors plus trastuzumab vs. standard trastuzumab treatments. Pooled estimates of progression-free survival (PFS), pathologic complete response (pCR), and incidence of adverse events were determined.

RESULTS:

5 studies out of 610 were found to be eligible and were included in our analysis (n=1,548 participants). PI3K/Akt/mTOR inhibitors combination with trastuzumab treatments resulted in a statistically significant increase in PFS compared with conventional trastuzumab therapy (HR 0.82; 95% CI: 0.76-0.90; p<0.00001). The new combination treatment was more effective on hormone receptor-negative patients (HR 0.73; 95% CI: 0.58-0.93; p=0.010). In addition, the combination of PI3K/Akt/mTOR inhibitors with trastuzumab slightly increased the risk of some adverse events, such as neutropenia, leukopenia, fatigue, and anemia.

CONCLUSIONS:

The combination treatments of PI3K/Akt/mTOR inhibitors and trastuzumab for PI3K/Akt/mTOR inhibitors combined with trastuzumab treatments for patients with HER2-positive breast cancer can improve median progression-free survival while increasing the incidence of adverse events. It is still controversial based on the current evidence. Due to the limited number and quality of included studies, more high-quality studies are needed for further analysis.

100 项与 AKT/PI3K/mTOR inhibitors(Thryv Therapeutics) 相关的药物交易

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