Article Metrics


Online attention

Aiming to miss a moving target: bromo and extra terminal domain (BET) selectivity in constrained ATAD2 inhibitors

DOI: 10.1021/acs.jmedchem.8b00862 DOI Help

Authors: Paul Bamborough (GlaxoSmithKline) , Chun-Wa Chung (GlaxoSmithKline) , Rebecca C. Furze (GlaxoSmithKline) , Paola Grandi (GlaxoSmithKline) , Anne-Marie Michon (GlaxoSmithKline) , Robert J. Watson (GlaxoSmithKline) , Darren J. Mitchell (GlaxoSmithKline) , Heather Barnett (GlaxoSmithKline) , Rab K. Prinjha (GlaxoSmithKline) , Christina Rau (GlaxoSmithKline) , Robert J. Sheppard (GlaxoSmithKline) , Thilo Werner (GlaxoSmithKline) , Emmanuel H. Demont (GlaxoSmithKline)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: September 2018
Diamond Proposal Number(s): 12279

Abstract: ATAD2 is a cancer-associated protein whose bromodomain has been described as among the least druggable of its class. In our recent disclosure of the first chemical probe against this bromodomain, GSK8814 (6), we described the use of a conformationally constrained methoxy piperidine to gain selectivity over the BET bromodomains. Here we describe an orthogonal conformational restriction strategy of the piperidine ring to give potent and selective tropane inhibitors and show structural insights into why this was more challenging than expected. Greater understanding of why different rational approaches succeeded or failed should help in the future design of selectivity in the bromodomain family.

Journal Keywords: Reaction products; Crystal structure; Inhibitors; Piperidines; Selectivity

Subject Areas: Chemistry, Biology and Bio-materials, Medicine

Instruments: I02-Macromolecular Crystallography

Added On: 26/09/2018 14:15

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)