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

Chem Sci. 2016 Mar 1;7(3):2322-2330. doi: 10.1039/c5sc03115j.

Oakley B Cox ¹ ² ³, Tobias Krojer ¹, Patrick Collins ³, Octovia Monteiro ¹ ², Romain Talon ¹, Anthony Bradley ¹, Oleg Fedorov ¹ ², Jahangir Amin ⁴, Brian D Marsden ¹ ⁵, John Spencer ⁴, Frank von Delft ¹ ³ ⁶, Paul E Brennan ¹ ²

Affiliations

1 Structural Genomics Consortium (SGC) , University of Oxford , Oxford OX3 7DQ , UK.
2 Target Discovery Institute (TDI) , Nuffield Department of Medicine , University of Oxford , Oxford OX3 7FZ , UK . Email: paul.brennan@sgc.ox.ac.uk.
3 Diamond Light Source (DLS) , Harwell Science and Innovation Campus , Didcot , OX11 0DE , UK . Email: frank.von-delft@diamond.ac.uk.
4 Department of Chemistry , School of Life Sciences , University of Sussex , Brighton , BN1 9QJ , UK.
5 Kennedy Institute of Rheumatology , Nuffield Department of Orthopaedics , Rheumatology and Musculoskeletal Sciences , University of Oxford , Roosevelt Drive, Headington , Oxford OX3 7FY , UK.
6 Department of Biochemistry , University of Johannesburg , Aukland Park 2006 , South Africa.

PMID: 29910922 DOI: 10.1039/c5sc03115j

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.

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