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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acrylamides / chemical synthesis
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Acrylamides / pharmacokinetics*
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Agammaglobulinaemia Tyrosine Kinase
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Animals
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B-Lymphocytes / drug effects*
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B-Lymphocytes / enzymology
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B-Lymphocytes / pathology
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Cell Line, Tumor
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Crystallography, X-Ray
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Cyanoacrylates / chemical synthesis
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Cyanoacrylates / pharmacokinetics*
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Dasatinib
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Female
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Gene Expression
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Humans
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Ligands
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Molecular Docking Simulation
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / pharmacokinetics*
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Protein Structure, Tertiary
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Protein-Tyrosine Kinases / antagonists & inhibitors*
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Protein-Tyrosine Kinases / chemistry
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Protein-Tyrosine Kinases / genetics
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Pyrimidines / pharmacokinetics
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Rats
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Rats, Sprague-Dawley
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Recombinant Proteins / chemistry
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Recombinant Proteins / genetics
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Sf9 Cells
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Spodoptera
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Structure-Activity Relationship
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Substrate Specificity
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Thiazoles / pharmacokinetics
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Time Factors
Substances
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Acrylamides
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Cyanoacrylates
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Ligands
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Protein Kinase Inhibitors
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Pyrimidines
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Recombinant Proteins
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Thiazoles
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Protein-Tyrosine Kinases
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Agammaglobulinaemia Tyrosine Kinase
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BTK protein, human
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Dasatinib
Associated data
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PubChem-Substance/250230078
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PubChem-Substance/250230079
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PubChem-Substance/250230080
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PubChem-Substance/250230081
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PubChem-Substance/250230082
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PubChem-Substance/250230083
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PubChem-Substance/250230084
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PubChem-Substance/250230085
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PubChem-Substance/250230086
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PubChem-Substance/250230087
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PubChem-Substance/250230088
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PubChem-Substance/250230089
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PubChem-Substance/250230090
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PubChem-Substance/250230091
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PubChem-Substance/250230092
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PubChem-Substance/250230093
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PubChem-Substance/250230094
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PubChem-Substance/250230095
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PubChem-Substance/250230096
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PubChem-Substance/250230097
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PubChem-Substance/250230098
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PubChem-Substance/250230099
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PubChem-Substance/250230100
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PubChem-Substance/250230101
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PubChem-Substance/250230102
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PubChem-Substance/250230115
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PubChem-Substance/250230120
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PubChem-Substance/250230121
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PubChem-Substance/250230122
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PubChem-Substance/250230123