Author: Cookson, Rosa ; Kerr, William J ; Reid, Marc ; Bradley, Erin ; Wellaway, Christopher R ; Craggs, Peter D ; Palmer, David S ; Phillipou, Alex ; Rioja, Inmaculada ; Mitchell, Darren J ; Humphreys, Philip G ; Wall, Ian D ; Shah, Rishi R ; Prinjha, Rab K ; Fusani, Lucia ; Demont, Emmanuel H ; Chung, Chun-Wa

Small-molecule-mediated disruption of the protein-protein interactions between acetylated histone tails and the tandem bromodomains of the bromodomain and extra-terminal (BET) family of proteins is an important mechanism of action for the potential modulation of immuno-inflammatory and oncology disease. High-quality chemical probes have proven invaluable in elucidating profound BET bromodomain biology, with seminal publications of both pan- and domain-selective BET family bromodomain inhibitors enabling academic and industrial research. To enrich the toolbox of structurally differentiated N-terminal bromodomain (BD1) BET family chemical probes, this work describes an analysis of the GSK BRD4 bromodomain data set through a lipophilic efficiency lens, which enabled identification of a BD1 domain-biased benzimidazole series. Structure-guided growth targeting a key Asp/His BD1/BD2 switch enabled delivery of GSK023, a high-quality chemical probe with 300-1000-fold BET BD1 domain selectivity and a phenotypic cellular fingerprint consistent with BET bromodomain inhibition.

Pharmaceuticals

The Development and Evaluation of a Novel Highly Selective PET Radiotracer for Targeting BET BD1

Article

Author: Wang, Yanli ; Kang, Leyi ; Wang, Yongle ; Wang, Changning ; Tocci, Darcy ; Xu, Yulong

Background/Objectives: Small molecules that interfere with the interaction between acetylated protein tails and the tandem bromodomains of BET (bromodomain and extra-terminal) family proteins are pivotal in modulating immune/inflammatory and neoplastic diseases. This study aimed to develop a novel PET imaging tracer, [11C]GSK023, that targets the N-terminal bromodomain (BD1) of BET family proteins with high selectivity and potency, thereby enriching the chemical probe toolbox for epigenetic imaging. Methods: [11C]GSK023, a radio-chemical probe, was designed and synthesized to specifically target the BET BD1. In vivo PET imaging evaluations were conducted on rodents, focusing on the tracer’s distribution and binding specificity in various tissues. Blocking studies were performed to confirm the probe’s selectivity and specificity. Results: The evaluations revealed that [11C]GSK023 demonstrated good uptake in peripheral organs with limited brain penetration. Further blocking studies confirmed the probe’s high binding specificity and selectivity for the BET BD1 protein, underscoring its potential utility in epigenetic imaging. Conclusions: The findings suggest that [11C]GSK023 is a promising PET probe for imaging the BET BD1 protein, offering the potential to deepen our understanding of the roles of BET bro-modomains in disease and their application in clinical settings to monitor disease progression and therapeutic responses.

100 Deals associated with GSK-023

R&D Status

Clinical Result

Indication

Phase

Evaluation

View All Results

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Deal

Boost your decision using our deal data.

view full example data

Core Patent

Boost your research with our Core Patent data.

view full example data

Clinical Trial

Identify the latest clinical trials across global registries.

view full example data

Approval

Accelerate your research with the latest regulatory approval information.

view full example data

Regulation

Understand key drug designations in just a few clicks with Synapse.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis


No Data

GSK-023

Overview

Basic Info

Structure

Related

R&D Status

Clinical Result

Translational Medicine

Deal

Core Patent

Clinical Trial

Approval

Regulation