Delving into the Latest Updates on AMG-319 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

PI3Kδ

Mechanism

PI3Kδ inhibitors(Phosphatidylinositol 3 kinase delta inhibitors)

Therapeutic Areas

NeoplasmsImmune System DiseasesHemic and Lymphatic Diseases

Active Indication-

Inactive Indication

Chronic Lymphocytic LeukemiaDiffuse Large B-Cell LymphomaLow Grade B-Cell Non-Hodgkin's Lymphoma+ [2]

Originator Organization

Amgen, Inc.

Active Organization-

Inactive Organization

Amgen, Inc.

Drug Highest PhasePendingPhase 1

First Approval Date-

Regulation-

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Structure

Molecular FormulaC21H16FN7

InChIKeyKWRYMZHCQIOOEB-LBPRGKRZSA-N

CAS Registry1608125-21-8

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.

Start Date01 Apr 2011

Sponsor / Collaborator

Amgen, Inc.

100 Clinical Results associated with AMG-319

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100 Translational Medicine associated with AMG-319

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100 Patents (Medical) associated with AMG-319

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7

Literatures (Medical) associated with AMG-319

01 Feb 2024·Combinatorial Chemistry & High Throughput Screening

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

Article

Author: 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.

26 May 2022·NatureQ1 · CROSS-FIELD

Intermittent PI3Kδ inhibition sustains anti-tumour immunity and curbs irAEs

Q1 · CROSS-FIELD

Article

Author: 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.

01 Jun 2021·International ImmunopharmacologyQ2 · MEDICINE

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

Q2 · MEDICINE

Article

Author: 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 Deals associated with AMG-319

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Chronic Lymphocytic Leukemia	Phase 1	US	Amgen, Inc.	01 Apr 2011
Diffuse Large B-Cell Lymphoma	Phase 1	US	Amgen, Inc.	01 Apr 2011
Low Grade B-Cell Non-Hodgkin's Lymphoma	Phase 1	US	Amgen, Inc.	01 Apr 2011
Mantle-Cell Lymphoma	Phase 1	US	Amgen, Inc.	01 Apr 2011
T-Cell Lymphoma	Phase 1	US	Amgen, Inc.	01 Apr 2011