title: Prolonged and tunable residence time using reversible covalent kinase inhibitors.
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.
authors.affiliation: Principia Biopharma, South San Francisco, California, USA.
authors.forename: J Michael
authors.initials: JM
authors.lastname: Bradshaw
authors.affiliation: Department of Cellular and Molecular Pharmacology and Howard Hughes Medical Institute, University of California, San Francisco, California, USA.
authors.forename: Jesse M
authors.identifier: 0000000323933789
authors.initials: JM
authors.lastname: McFarland
authors.affiliation: Department of Cellular and Molecular Pharmacology and Howard Hughes Medical Institute, University of California, San Francisco, California, USA.
authors.forename: Ville O
authors.initials: VO
authors.lastname: Paavilainen
authors.affiliation: Principia Biopharma, South San Francisco, California, USA.
authors.forename: Angelina
authors.initials: A
authors.lastname: Bisconte
authors.affiliation: Principia Biopharma, South San Francisco, California, USA.
authors.forename: Danny
authors.initials: D
authors.lastname: Tam
authors.affiliation: Principia Biopharma, South San Francisco, California, USA.
authors.forename: Vernon T
authors.initials: VT
authors.lastname: Phan
authors.affiliation: Nanosyn Inc., Santa Clara, California, USA.
authors.forename: Sergei
authors.initials: S
authors.lastname: Romanov
authors.affiliation: Principia Biopharma, South San Francisco, California, USA.
authors.forename: David
authors.initials: D
authors.lastname: Finkle
authors.affiliation: Principia Biopharma, South San Francisco, California, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Shu
authors.affiliation: Principia Biopharma, South San Francisco, California, USA.
authors.forename: Vaishali
authors.initials: V
authors.lastname: Patel
authors.affiliation: Principia Biopharma, South San Francisco, California, USA.
authors.forename: Tony
authors.initials: T
authors.lastname: Ton
authors.affiliation: Principia Biopharma, South San Francisco, California, USA.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Li
authors.affiliation: Principia Biopharma, South San Francisco, California, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: Loughhead
authors.affiliation: Principia Biopharma, South San Francisco, California, USA.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Nunn
authors.affiliation: Principia Biopharma, South San Francisco, California, USA.
authors.forename: Dane E
authors.initials: DE
authors.lastname: Karr
authors.affiliation: Principia Biopharma, South San Francisco, California, USA.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Gerritsen
authors.affiliation: Principia Biopharma, South San Francisco, California, USA.
authors.forename: Jens Oliver
authors.initials: JO
authors.lastname: Funk
authors.affiliation: Principia Biopharma, South San Francisco, California, USA.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Owens
authors.affiliation: Principia Biopharma, South San Francisco, California, USA.
authors.forename: Erik
authors.initials: E
authors.lastname: Verner
authors.affiliation: Principia Biopharma, South San Francisco, California, USA.
authors.forename: Ken A
authors.initials: KA
authors.lastname: Brameld
authors.affiliation: Principia Biopharma, South San Francisco, California, USA.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Hill
authors.affiliation: Principia Biopharma, South San Francisco, California, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Goldstein
authors.affiliation: Department of Cellular and Molecular Pharmacology and Howard Hughes Medical Institute, University of California, San Francisco, California, USA.
authors.forename: Jack
authors.initials: J
authors.lastname: Taunton
mesh_terms: D000178:Acrylamides / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D003487:Cyanoacrylates / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D000069439:Dasatinib; D005260:Female; D015870:Gene Expression; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D011743:Pyrimidines / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D061987:Sf9 Cells; D018411:Spodoptera; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013844:Thiazoles / Q000493:pharmacokinetics; D013997:Time Factors
chemical_list: D000178:Acrylamides; D003487:Cyanoacrylates; D008024:Ligands; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011994:Recombinant Proteins; D013844:Thiazoles; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; D000069439:Dasatinib