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A poised fragment library enables rapid synthetic expansion yielding the first reported inhibitors of PHIP(2), an atypical bromodomain

DOI: 10.1039/C5SC03115J DOI Help

Authors: Oakley B Cox (University of Oxford) , Tobias Krojer (Oxford University SGC) , Patrick Collins (Diamond Light Source) , Octovia Monteiro (University of Oxford) , Romain Talon (University of Oxford) , Anthony Bradley (University of Oxford) , Oleg Fedorov (University of Oxford) , Jahangir Amin (University of Sussex) , Brian D. Marsden (University of Oxford) , John Spencer (University of Sussex) , Frank Von Delft (Diamond Light Source) , Paul E. Brennan (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Chemical Science

State: Published (Approved)
Published: December 2015
Diamond Proposal Number(s): 5073 , 11175

Open Access Open Access

Abstract: Research into the chemical biology of bromodomains has been driven by the development of acetyl-lysine mimetics. The ligands are typically anchored by binding to a highly conserved asparagine residue. Atypical bromodomains, for which the asparagine is mutated, have thus far proven elusive targets, including PHIP(2) whose parent protein, PHIP, has been linked to disease progression in diabetes and cancers. The PHIP(2) binding site contains a threonine in place of asparagine, and solution screening have yielded no convincing hits. We have overcome this hurdle by combining the sensitivity of X-ray crystallography, used as the primary fragment screen, with a strategy for rapid follow-up synthesis using a chemically-poised fragment library, which allows hits to be readily modified by parallel chemistry both peripherally and in the core. Our approach yielded the first reported hit compounds of PHIP(2) with measurable IC50 values by an AlphaScreen competition assay. The follow-up libraries of four poised fragment hits improved potency into the sub-mM range while showing good ligand efficiency and detailed structural data.

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

Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 25/01/2016 16:46


Discipline Tags:

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

Technical Tags:

Diffraction Macromolecular Crystallography (MX)