4YHF
Bruton's tyrosine kinase in complex with a t-butyl cyanoacrylamide inhibitor
Summary for 4YHF
| Entry DOI | 10.2210/pdb4yhf/pdb |
| Descriptor | Tyrosine-protein kinase BTK, (2S)-2-({(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl}carbonyl)-4,4-dimethylpentanenitrile, SODIUM ION, ... (7 entities in total) |
| Functional Keywords | covalent inhibitor, cyanoacrylamide, cysteine, transferase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 67169.96 |
| Authors | Paavilainen, V.O.,McFarland, J.M.,Taunton, J. (deposition date: 2015-02-27, release date: 2015-05-13, Last modification date: 2024-11-20) |
| Primary citation | Bradshaw, J.M.,McFarland, J.M.,Paavilainen, V.O.,Bisconte, A.,Tam, D.,Phan, V.T.,Romanov, S.,Finkle, D.,Shu, J.,Patel, V.,Ton, T.,Li, X.,Loughhead, D.G.,Nunn, P.A.,Karr, D.E.,Gerritsen, M.E.,Funk, J.O.,Owens, T.D.,Verner, E.,Brameld, K.A.,Hill, R.J.,Goldstein, D.M.,Taunton, J. Prolonged and tunable residence time using reversible covalent kinase inhibitors. Nat.Chem.Biol., 11:525-531, 2015 Cited by PubMed 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. PubMed: 26006010DOI: 10.1038/nchembio.1817 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.2 Å) |
Structure validation
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