Small molecule photocatalysis enables drug target identification via energy transfer

Aaron D. Trowbridge, Ciaran P. Seath, Frances P. Rodriguez-Rivera, Beryl X. Li, Barbara E. Dul, Adam G. Schwaid, Benito F. Buksh, Jacob B. Geri, James V. Oakley, Olugbeminiyi O. Fadeyi, Rob C. Oslund, Keun Ah Ryu, Cory White, Tamara Reyes-Robles, Paul Tawa, Dann L. Parker, David W.C. MacMillan

Research output: Contribution to journalArticlepeer-review

Abstract

Over half of new therapeutic approaches fail in clinical trials due to a lack of target validation. As such, the development of new methods to improve and accelerate the identification of cellular targets, broadly known as target ID, remains a fundamental goal in drug discovery. While advances in sequencing and mass spectrometry technologies have revolutionized drug target ID in recent decades, the corresponding chemical-based approaches have not changed in over 50 y. Consigned to outdated stoichiometric activation modes, modern target ID campaigns are regularly confounded by poor signal-to-noise resulting from limited receptor occupancy and low crosslinking yields, especially when targeting low abundance membrane proteins or multiple protein target engagement. Here, we describe a broadly general platform for photocatalytic small molecule target ID, which is founded upon the catalytic amplification of target-tag crosslinking through the continuous generation of high-energy carbene intermediates via visible light-mediated Dexter energy transfer. By decoupling the reactive warhead tag from the small molecule ligand, catalytic signal amplification results in unprecedented levels of target enrichment, enabling the quantitative target and off target ID of several drugs including (+)-JQ1, paclitaxel (Taxol), dasatinib (Sprycel), as well as two G-protein-coupled receptors—ADORA2A and GPR40.

Original languageEnglish (US)
Article numbere2208077119
JournalProceedings of the National Academy of Sciences of the United States of America
Volume119
Issue number34
DOIs
StatePublished - Aug 23 2022

All Science Journal Classification (ASJC) codes

  • General

Keywords

  • photocatalysis
  • proteomics
  • target identification

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