2. Academic Validation
  3. Prolonged and tunable residence time using reversible covalent kinase inhibitors

Prolonged and tunable residence time using reversible covalent kinase inhibitors

  • Nat Chem Biol. 2015 Jul;11(7):525-31. doi: 10.1038/nchembio.1817.
J Michael Bradshaw 1,  Jesse M McFarland 2,  Ville O Paavilainen 2,  Angelina Bisconte 1,  Danny Tam 1,  Vernon T Phan 1,  Sergei Romanov 3,  David Finkle 1,  Jin Shu 1,  Vaishali Patel 1,  Tony Ton 1,  Xiaoyan Li 1,  David G Loughhead 1,  Philip A Nunn 1,  Dane E Karr 1,  Mary E Gerritsen 1,  Jens Oliver Funk 1,  Timothy D Owens 1,  Erik Verner 1,  Ken A Brameld 1,  Ronald J Hill 1,  David M Goldstein 1,  Jack Taunton 2
Affiliations

Affiliations

  • 1 Principia Biopharma, South San Francisco, California, USA.
  • 2 Department of Cellular and Molecular Pharmacology and Howard Hughes Medical Institute, University of California, San Francisco, California, USA.
  • 3 Nanosyn Inc., Santa Clara, California, USA.
PMID: 26006010 DOI: 10.1038/nchembio.1817
Abstract

Drugs with prolonged on-target residence times often show superior efficacy, yet general strategies for optimizing drug-target residence time are lacking. Here we made progress toward this elusive goal by targeting a noncatalytic cysteine in Bruton's tyrosine kinase (Btk) with reversible covalent inhibitors. Using an inverted orientation of the cysteine-reactive cyanoacrylamide electrophile, we identified potent and selective Btk inhibitors that demonstrated biochemical residence times spanning from minutes to 7 d. An inverted cyanoacrylamide with prolonged residence time in vivo remained bound to Btk for more than 18 h after clearance from the circulation. The inverted cyanoacrylamide strategy was further used to discover Fibroblast Growth Factor receptor (FGFR) kinase inhibitors with residence times of several days, demonstrating the generalizability of the approach. Targeting of noncatalytic cysteines with inverted cyanoacrylamides may serve as a broadly applicable platform that facilitates 'residence time by design', the ability to modulate and improve the duration of target engagement in vivo.

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