AMG-319(AMG-319) - 药物靶点：PI3Kδ_专利_临床

概要

基本信息

药物类型

小分子化药

别名

靶点

PI3Kδ

作用机制

PI3Kδ抑制剂(磷脂酰肌醇-3激酶δ抑制剂)

治疗领域

肿瘤免疫系统疾病血液及淋巴系统疾病

在研适应症-

非在研适应症

慢性淋巴细胞白血病弥漫性大B细胞淋巴瘤低级别 B 细胞非霍奇金淋巴瘤+ [2]

原研机构

Amgen, Inc.

在研机构-

非在研机构

Amgen, Inc.

最高研发阶段无进展临床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

分子式C21H16FN7

InChIKeyKWRYMZHCQIOOEB-LBPRGKRZSA-N

CAS号1608125-21-8

关联

3

项与 AMG-319 相关的临床试验

NCT02540928 / Terminated临床2期IIT

A Cancer Research UK Randomised, Double Blind, Placebo Controlled Phase IIa Trial of AMG 319 Given Orally as a Neoadjuvant Therapy in Patients With Human Papillomavirus (HPV) Positive and Negative Head and Neck Squamous Cell Carcinoma (HNSCC)

The purpose of this study is to determine whether a drug called AMG 319 has an effect on a patient's own immune response to head and neck cancer squamous cell carcinoma (HNSCC). This study is specifically for patients who are having surgery to treat their HNSCC

开始日期2015-10-01

申办/合作机构

Cancer Research UK

EUCTR2014-004388-20-GB / Not yet recruiting临床2期IIT

A Cancer Research UK randomised, double-blind, placebo-controlled Phase IIa trial of AMG 319 given orally as a neoadjuvant therapy in patients with human papillomavirus (HPV) positive and negative head and neck squamous cell carcinoma (HNSCC)

开始日期2015-06-09

申办/合作机构

Cancer Research UK

NCT01300026 / Completed临床1期

A Phase 1, First-in-Human Study Evaluating the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AMG 319 in Adult Subjects With Relapsed or Refractory Lymphoid Malignancies

This is a multi-center, phase 1, open-label first-in-human study of AMG 319 in subjects with relapsed or refractory lymphoid malignancies. This study consists of two parts. The dose exploration in part 1, studies cohorts of 3 subjects with relapsed or refractory lymphoid malignancies and uses a practical continuous reassessment model [CRM] to guide dose escalation and to define the MTD. The dose expansion in part 2 will enroll 20 subjects with CLL at a dose no higher than the MTD and further explore the safety, PK, and clinical activity of AMG 319 in this patient population.

开始日期2011-04-01

申办/合作机构

Amgen, Inc.

100 项与 AMG-319 相关的临床结果

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100 项与 AMG-319 相关的转化医学

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100 项与 AMG-319 相关的专利（医药）

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7

项与 AMG-319 相关的文献（医药）

2024-02-01·Combinatorial Chemistry & High Throughput Screening

Design, Synthesis and Molecular Docking Studies of Pyrazoline Derivatives as PI3K Inhibitors

Article

作者: Kumar, Arvind ; Singh, Ankit Kumar ; Kumar, Pradeep ; Kumar, Adarsh ; Kumar, Rohit

Aim:Design, synthesis and molecular docking studies of quinoline/naphthalene containing pyrazoline derivatives as PI3K inhibitors.Background:Phosphatidylinositol 3-kinases (PI3Ks) belong to the family of enzymes, which are associated with various cellular functions such as cell growth, proliferation, differentiation etc. Overexpression or any changes in these functions may result in various abnormalities, which in turn cause cancer.Objectives:To perform synthesis and molecular docking studies of quinoline/naphthalene containing pyrazoline derivatives as PI3K inhibitors.Methods:2-Chloroquinoline-3-carbaldehyde was synthesized by a reaction of acetanilide and POCl3. The latter was reacted with substituted acetophenones to synthesize chalcones, which were reacted with substituted phenyl hydrazines to yield pyrazoline derivatives (Series I). Similarly, pchloro benzaldehyde was reacted with 2-acetonapthone to yield chalcone with substituted phenyl hydrazines to yield pyrazoline derivatives (Series II).Results:The synthetic compounds were subjected to molecular modelling experiments using Schrodinger 2016 software and evaluated in silico for their PI3K binding affinities. All the compounds had better docking scores than AMG-319 (-4.36 Kcal/mol) and comparable docking scores with PI-103 (-6.83 Kcal/mol).Conclusion:Compounds 5 and 3 had the best docking scores (-7.85 and -7.17 Kcal/mol, respectively). The synthesized compounds have better docking scores than the reference drug AMG-319. As a result, they might be used as lead molecules in investigating PI3K inhibitors.

2022-05-26·Nature1区 · 综合性期刊

Intermittent PI3Kδ inhibition sustains anti-tumour immunity and curbs irAEs

1区 · 综合性期刊

Article

作者: Kronenberg, Mitchell ; Kelly, Fiona ; Simon, Hayley ; Schache, Andrew Graeme ; McCann, Katy ; Wilson, William ; Jones, Terry M ; Dicker, Martina ; Ottensmeier, Christian H ; Sacco, Joseph J ; Vijayanand, Pandurangan ; Okkenhaug, Klaus ; Ay, Ferhat ; von Witzleben, Adrian ; Shaw, Richard ; Li, Yingcong ; Essame, Louisa ; Friberg, Greg ; Seumois, Gregory ; Paterson, Claire ; Chou, Ting-Fang ; Thomas, Gareth J ; Chudley, Lindsey ; Wang, Alice ; Dobbs, Nicola A ; Mondal, Monalisa ; Davies, Joseph H ; Loadman, Paul M ; Acton, Gary ; Singh, Rabindra P ; Brennan, Peter A ; Ramírez-Suástegui, Ciro ; Eschweiler, Simon ; Halbert, Gavin ; Jeffrey, Danielle ; Lopez-Guadamillas, Elena ; Thomas, Jaya ; McCaul, James Anthony ; Vanhaesebroeck, Bart ; Wood, Oliver ; Hackshaw, Allan ; King, Emma

AbstractPhosphoinositide 3-kinase δ (PI3Kδ) has a key role in lymphocytes, and inhibitors that target this PI3K have been approved for treatment of B cell malignancies1–3. Although studies in mouse models of solid tumours have demonstrated that PI3Kδ inhibitors (PI3Kδi) can induce anti-tumour immunity4,5, its effect on solid tumours in humans remains unclear. Here we assessed the effects of the PI3Kδi AMG319 in human patients with head and neck cancer in a neoadjuvant, double-blind, placebo-controlled randomized phase II trial (EudraCT no. 2014-004388-20). PI3Kδ inhibition decreased the number of tumour-infiltrating regulatory T (Treg) cells and enhanced the cytotoxic potential of tumour-infiltrating T cells. At the tested doses of AMG319, immune-related adverse events (irAEs) required treatment to be discontinued in 12 out of 21 of patients treated with AMG319, suggestive of systemic effects on Treg cells. Accordingly, in mouse models, PI3Kδi decreased the number of Treg cells systemically and caused colitis. Single-cell RNA-sequencing analysis revealed a PI3Kδi-driven loss of tissue-resident colonic ST2 Treg cells, accompanied by expansion of pathogenic T helper 17 (TH17) and type 17 CD8+ T (TC17) cells, which probably contributed to toxicity; this points towards a specific mode of action for the emergence of irAEs. A modified treatment regimen with intermittent dosing of PI3Kδi in mouse models led to a significant decrease in tumour growth without inducing pathogenic T cells in colonic tissue, indicating that alternative dosing regimens might limit toxicity.

2021-06-01·International Immunopharmacology2区 · 医学

Impaired airway epithelial barrier integrity was mediated by PI3Kδ in a mouse model of lipopolysaccharide-induced acute lung injury

2区 · 医学

Article

作者: Li, Jiahui ; Liu, Xingxing ; Tang, Ying ; Tang, Haixiong ; Chen, Junjie ; Chang, Ping ; Lu, Mei ; Yao, Lihong ; Gao, Lijuan ; Wang, Hua ; Liu, Fang

Cell-cell junctions are critical for the maintenance of cellular as well as tissue polarity and integrity. Dysfunction of airway epithelial barrier has been shown to be involved in the pathogenesis of acute lung injury (ALI). Yet the role of phosphatidylinositol 3-kinase delta (PI3Kδ) in dysregulation of airway epithelial barrier integrity in ALI has not been addressed. Mice were subjected to intratracheal instillation of lipopolysaccharide (LPS) to generate a ALI model. Two pharmacological inhibitors of PI3Kδ, IC87114 and AMG319, were respectively given to the mice. Expression of p110δ and its downstream substrate phospho-AKT (Ser473) was increased in LPS-exposed lungs. These increases were inhibited by IC87114 or AMG319. LPS led to pronounced lung injury that was accompanied by significant airway neutrophil recruitment and bronchial epithelial morphological alterations 72 h after exposure. We also found compromised expression of adherens junction protein E-cadherin and tight junction protein claudin-2 in the airway epithelial cells. Treatment with either IC87114 or AMG319 not only attenuated LPS-induced edema, lung injury and neutrophilc inflammation, reduced total protein concentration and IL-6, TNF-α secretion in BALF, but also restored epithelial E-cadherin and claudin-2 expression. In summary, our results showed that LPS can induce a delayed effect on airway epithelial barrier integrity that is mediated by PI3Kδ in a mouse model of ALI.

100 项与 AMG-319 相关的药物交易

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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
慢性淋巴细胞白血病	临床1期	美国	Amgen, Inc.	2011-04-01
弥漫性大B细胞淋巴瘤	临床1期	美国	Amgen, Inc.	2011-04-01
低级别 B 细胞非霍奇金淋巴瘤	临床1期	美国	Amgen, Inc.	2011-04-01
套细胞淋巴瘤	临床1期	美国	Amgen, Inc.	2011-04-01
T细胞淋巴瘤	临床1期	美国	Amgen, Inc.	2011-04-01