Another new Zenith publication. It's getting hard to stay caught up with all the good news flowing from Zenith and Resverlogix.
Most BET inhibitors, including ZEN-3694 and apabetalone, bind reversibly to the bromodomains of BET proteins. Covalent inhibitors, described in this recent publication, are irreversible BET inhibitors that may offer improved potency and prolonged BET inhibition relative to reversible BET inhibitors. Zenith has discussed this program before at recent AGMs/Corporate Updates. Nice to see it now published!
DESIGN AND CHARACTERIZATION OF NOVEL COVALENT BROMODOMAIN AND EXTRA-TERMINAL DOMAIN (BET) INHIBITORS TARGETING A METHIONINE
Kharenko O,
Patel RG,
Brown SD,
Calosing C,
White A,
Lakshminarasimhan D,
Suto RK,
Duffy BC,
Kitchen DB,
McLure KG,
Hansen HC,
van der Horst EH,
Young PR.
Abstract
BET proteins are key epigenetic regulators that alter transcription by binding to acetylated lysine (AcLys) residues of histones and transcription factors through bromodomains (BDs). The disruption of this interaction with small molecule bromodomain inhibitors is a promising approach to treat various diseases including cancer, autoimmune and cardiovascular diseases. Covalent inhibitors can potentially offer a more durable target inhibition leading to improved in vivo pharmacology. Here we describe the design of covalent inhibitors of BRD4(BD1) that target a methionine in the binding pocket by attaching an epoxide warhead to a suitably oriented non-covalent inhibitor. Using thermal denaturation, MALDI-TOF mass spectrometry and an X-ray crystal structure, we demonstrate that these inhibitors selectively form a covalent bond with Met149 in BRD4(BD1) but not other bromodomains, and provide durable transcriptional and anti-proliferative activity in cell based assays. Covalent targeting of methionine offers a novel approach to drug discovery for BET proteins and other targets.
