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One-step synthesis of photoaffinity probes for live-cell MS-based proteomics

DOI: 10.1002/chem.202102036 DOI Help

Authors: David J. Fallon (GlaxoSmithKline R&D; University of Strathclyde) , Stephanie Lehmann (Cellzome GmbH) , Chun‐wa Chung (GlaxoSmithKline R&D) , Alex Phillipou (GlaxoSmithKline R&D) , Christian Eberl (Cellzome GmbH) , Ken G. M. Fantom (GlaxoSmithKline R&D) , Francesca Zappacosta (GlaxoSmithKline R&D) , Vipulkumar K. Patel (GlaxoSmithKline R&D) , Marcus Bantscheff (Cellzome GmbH) , Christopher J. Schofield (University of Oxford) , Nicholas C. O. Tomkinson (University of Strathclyde) , Jacob T. Bush (GlaxoSmithKline R&D)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Chemistry – A European Journal , VOL 71

State: Published (Approved)
Published: September 2021
Diamond Proposal Number(s): 20024

Abstract: We present a one-step Ugi reaction protocol for the expedient synthesis of photoaffinity probes for live-cell MS-based proteomics. The reaction couples an amine affinity function with commonly used photoreactive groups, and a variety of handle functionalities. Using this technology, a series of pan-BET (BET: bromodomain and extra-terminal domain) selective bromodomain photoaffinity probes were obtained by parallel synthesis. Studies on the effects of photoreactive group, linker length and irradiation wavelength on photocrosslinking efficiency provide valuable insights into photoaffinity probe design. Optimal probes were progressed to MS-based proteomics to capture the BET family of proteins from live cells and reveal their potential on- and off-target profiles.

Journal Keywords: bromodomains; epigenetics; MS-based proteomics; multi-component reactions; photoaffinity labelling

Subject Areas: Chemistry, Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 06/10/2021 08:24

Discipline Tags:

Life Sciences & Biotech Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)