Delving into the Latest Updates on GSK6853 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms-

Target

BRPF1

Mechanism

BRPF1 inhibitors(bromodomain and PHD finger containing 1 inhibitors)

Therapeutic Areas-

Active Indication-

Inactive Indication-

Originator Organization

GSK Plc

Active Organization

GSK Plc

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Structure

Molecular FormulaC22H27N5O3

InChIKeyFQWDVNSBYDXPIO-CQSZACIVSA-N

CAS Registry1910124-24-1

AbstractThe acetylpyrrole scaffold is an acetylated lysine mimic that has been previously explored to develop bromodomain inhibitors. When tested on the hepatoma cell line Huh7 and the breast cancer cell line MDA‐MB‐231, a few compounds in our acetylpyrrole‐thiazole library induced peculiar morphological changes, progressively causing cell death at increasing concentrations. Their evaluation on a panel of human bromodomains revealed concurrent inhibition of BRPF1 and BET bromodomains. To dissect the observed cellular effects, the acetylpyrrole derivatives were compared to JQ1 and GSK6853, chemical probes for the bromodomains of BET and BRPF1, respectively. The appearance of neurite‐like extrusions, accompanied by βIII‐tubulin overexpression, is caused by BET inhibition, with limited effect on cellular viability. Conversely, interference with BRPF1 induces cellular death but not phenotypic alterations. Combined treatment with JQ1 and GSK6853 showed additivity in reducing cellular viability, comparably to the acetylpyrrole‐thiazole‐based BET/BRPF1 inhibitors. In addition, we determined the crystallographic structures of the BRD4 and BRPF1 bromodomains in complex with the acetylpyrrole‐thiazole compounds. The binding modes in the two bromodomains show similar interactions for the acetylpyrrole and different orientations of the moiety that point to the rim of the acetyl‐lysine pocket.

100 Deals associated with GSK6853

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