%0 Journal Article %1 Bradshaw2015PharmacophorePanelCovalent %A Bradshaw, J Michael %A McFarland, Jesse M %A Paavilainen, Ville O %A Bisconte, Angelina %A Tam, Danny %A Phan, Vernon T %A Romanov, Sergei %A Finkle, David %A Shu, Jin %A Patel, Vaishali %A Ton, Tony %A Li, Xiaoyan %A Loughhead, David G %A Nunn, Philip A %A Karr, Dane E %A Gerritsen, Mary E %A Funk, Jens Oliver %A Owens, Timothy D %A Verner, Erik %A Brameld, Ken A %A Hill, Ronald J %A Goldstein, David M %A Taunton, Jack %D 2015 %I Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. %J Nat Chem Biol %K covalent-inhibitor irreversible-inhibitor pharmacophore-panel residence-time %N 7 %P 525--531 %T Prolonged and tunable residence time using reversible covalent kinase inhibitors %U http://dx.doi.org/10.1038/nchembio.1817 %V 11 %X 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.

@article{Bradshaw2015PharmacophorePanelCovalent, 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.}, added-at = {2016-06-01T00:29:03.000+0200}, author = {Bradshaw, J Michael and McFarland, Jesse M and Paavilainen, Ville O and Bisconte, Angelina and Tam, Danny and Phan, Vernon T and Romanov, Sergei and Finkle, David and Shu, Jin and Patel, Vaishali and Ton, Tony and Li, Xiaoyan and Loughhead, David G and Nunn, Philip A and Karr, Dane E and Gerritsen, Mary E and Funk, Jens Oliver and Owens, Timothy D and Verner, Erik and Brameld, Ken A and Hill, Ronald J and Goldstein, David M and Taunton, Jack}, biburl = {https://www.bibsonomy.org/bibtex/28f81f88198905c9a64326787b2d93f76/salotz}, description = {Prolonged and tunable residence time using reversible covalent kinase inhibitors : Nature Chemical Biology : Nature Publishing Group}, interhash = {9d56e068b3874bedce053b02432a3476}, intrahash = {8f81f88198905c9a64326787b2d93f76}, issn = {15524450}, journal = {Nat Chem Biol}, keywords = {covalent-inhibitor irreversible-inhibitor pharmacophore-panel residence-time}, month = jul, number = 7, pages = {525--531}, publisher = {Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.}, timestamp = {2016-06-01T00:29:03.000+0200}, title = {Prolonged and tunable residence time using reversible covalent kinase inhibitors}, url = {http://dx.doi.org/10.1038/nchembio.1817}, volume = 11, year = 2015 }