Prolonged and tunable residence time using reversible covalent kinase inhibitors
J Michael Bradshaw1, Jesse M McFarland2, Ville O Paavilainen2
1Principia Biopharma, South San Francisco, California, USA.
Nature Chemical Biology
|May 26, 2015
Summary
Researchers developed a new strategy using reversible covalent inhibitors to extend drug on-target residence time. This approach, targeting noncatalytic cysteines in Bruton
Area of Science:
- Medicinal Chemistry
- Drug Discovery
- Chemical Biology
Background:
- Prolonged drug on-target residence time is linked to superior therapeutic efficacy.
- General strategies for optimizing drug-target residence time remain underdeveloped.
- Noncatalytic cysteines represent potential targets for covalent inhibition.
Purpose of the Study:
- To develop a generalizable strategy for optimizing drug-target residence time.
- To identify potent and selective inhibitors targeting noncatalytic cysteines.
- To demonstrate the application of this strategy in Bruton's tyrosine kinase (BTK) and fibroblast growth factor receptor (FGFR) kinases.
Main Methods:
- Design and synthesis of reversible covalent inhibitors utilizing an inverted cyanoacrylamide electrophile.
- Inhibition of Bruton's tyrosine kinase (BTK) and fibroblast growth factor receptor (FGFR) kinases.
- Measurement of biochemical and in vivo residence times.
Main Results:
- Identification of potent and selective BTK inhibitors with biochemical residence times ranging from minutes to 7 days.
- Demonstration of prolonged in vivo residence time (>18 hours) for an inverted cyanoacrylamide inhibitor after circulation clearance.
- Discovery of FGFR kinase inhibitors with multi-day residence times, showcasing the approach's generalizability.
Conclusions:
- Targeting noncatalytic cysteines with inverted cyanoacrylamides is a broadly applicable platform.
- This strategy facilitates 'residence time by design' for improved in vivo target engagement.
- The approach offers a novel method for optimizing drug efficacy through extended target binding.
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