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Chem Commun 2:349–355. https://doi.org/10.1039/C1MD00017A
11. Bradshaw JM, McFarland JM, Paavilainen VO, Bisconte A, Tam D, Phan VT, Romanov S,
Finkle D, Shu J, Patel V, Ton T, Li X, Loughhead DG, Nunn PA, Karr DE, Gerritsen ME,
Funk JO, Owens TD, Verner E, Brameld KA, Hill RJ, Goldstein DM, Taunton J (2015)
Prolonged and tunable residence time using reversible covalent kinase inhibitors. Nat Chem
Biol 11:525–531. https://doi.org/10.1038/nchembio.1817
12. Strelow JM (2017) A perspective on the kinetics of covalent and irreversible inhibition. SLAS
Discov 22:3–20. https://doi.org/10.1177/1087057116671509
13. Schwartz PA, Kuzmic P, Solowiej J, Bergqvist S, Bolanos B, Almaden C, Nagata A, Ryan K,
Feng J, Dalvie D, Kath JC, Xu M, Wani R, Murray BW (2014) Covalent EGFR inhibitor
analysis reveals importance of reversible interactions to potency and mechanisms of drug
resistance. Proc Natl Acad Sci 111:173–178. https://doi.org/10.1073/pnas.1313733111
14. Awoonor-Williams E, Rowley CN (2018) How reactive are druggable cysteines in protein
kinases? J Chem Inf Model 58:1935–1946. https://doi.org/10.1021/acs.jcim.8b00454
15. Leproult E, Barluenga S, Moras D, Wurtz J-M, Winssinger N (2011) Cysteine mapping in
conformationally distinct kinase nucleotide binding sites: application to the design of selective
covalent inhibitors. J Med Chem 54:1347–1355. https://doi.org/10.1021/jm101396q
16. Onufriev AV, Alexov E (2013) Protonation and pK changes in protein–ligand binding. Q Rev
Biophys 46:181–209. https://doi.org/10.1017/S0033583513000024
17. Casimiro-Garcia A, Trujillo JI, Vajdos F, Juba B, Banker ME, Aulabaugh A, Balbo P,
Bauman J, Chrencik J, Coe JW, Czerwinski R, Dowty M, Knafels JD, Kwon S, Leung L,
Liang S, Robinson RP, Telliez J-B, Unwalla R, Yang X, Thorarensen A (2018) Identification
of Cyanamide-based Janus kinase 3 (JAK3) covalent inhibitors. J Med Chem. https://doi.org/
10.1021/acs.jmedchem.8b01308
18. Zhao Z, Liu Q, Bliven S, Xie L, Bourne PE (2017) Determining Cysteines available for
covalent inhibition across the human Kinome. J Med Chem 60:2879–2889. https://doi.org/10.
1021/acs.jmedchem.6b01815
19. Lonsdale R, Ward RA (2018) Structure-based design of targeted covalent inhibitors. Chem
Soc Rev 47:3816–3830. https://doi.org/10.1039/C7CS00220C
20. Backus KM, Correia BE, Lum KM, Forli S, Horning BD, González-Páez GE, Chatterjee S,
Lanning BR, Teijaro JR, Olson AJ, Wolan DW, Cravatt BF (2016) Proteome-wide covalent
ligand discovery in native biological systems. Nature 534:570–574. https://doi.org/10.1038/
nature18002
21. Kathman SG, Xu Z, Statsyuk AV (2014) A fragment-based method to discover irreversible
covalent inhibitors of cysteine proteases. J Med Chem 57:4969–4974. https://doi.org/10.1021/
jm500345q
22. Jöst C, Nitsche C, Scholz T, Roux L, Klein CD (2014) Promiscuity and selectivity in covalent
enzyme inhibition: a systematic study of electrophilic fragments. J Med Chem 57:7590–7599.
https://doi.org/10.1021/jm5006918
23. Zimmermann G, Rieder U, Bajic D, Vanetti S, Chaikuad A, Knapp S, Scheuermann J,
Mattarella M, Neri D (2017) A specific and covalent JNK-1 ligand selected from an encoded
self-assembling chemical library. Chem Eur J 23:8152–8155. https://doi.org/10.1002/chem.
201701644
24. Chan AI, McGregor LM, Jain T, Liu DR (2017) Discovery of a covalent kinase inhibitor from
a DNA-encoded small-molecule library  protein library selection. J Am Chem Soc
139:10192–10195. https://doi.org/10.1021/jacs.7b04880
25. Jackson PA, Widen JC, Harki DA, Brummond KM (2017) Covalent modifiers: a chemical
perspective on the reactivity of α,β-unsaturated carbonyls with thiols via hetero-Michael
addition reactions. J Med Chem 60:839–885. https://doi.org/10.1021/acs.jmedchem.6b00788
26. Bandyopadhyay A, Gao J (2016) Targeting biomolecules with reversible covalent chemistry.
Curr Opin Chem Biol 34:110–116. https://doi.org/10.1016/j.cbpa.2016.08.011
Covalent Kinase Inhibitors: An Overview
85
Chem Commun 2:349–355. https://doi.org/10.1039/C1MD00017A
11. Bradshaw JM, McFarland JM, Paavilainen VO, Bisconte A, Tam D, Phan VT, Romanov S,
Finkle D, Shu J, Patel V, Ton T, Li X, Loughhead DG, Nunn PA, Karr DE, Gerritsen ME,
Funk JO, Owens TD, Verner E, Brameld KA, Hill RJ, Goldstein DM, Taunton J (2015)
Prolonged and tunable residence time using reversible covalent kinase inhibitors. Nat Chem
Biol 11:525–531. https://doi.org/10.1038/nchembio.1817
12. Strelow JM (2017) A perspective on the kinetics of covalent and irreversible inhibition. SLAS
Discov 22:3–20. https://doi.org/10.1177/1087057116671509
13. Schwartz PA, Kuzmic P, Solowiej J, Bergqvist S, Bolanos B, Almaden C, Nagata A, Ryan K,
Feng J, Dalvie D, Kath JC, Xu M, Wani R, Murray BW (2014) Covalent EGFR inhibitor
analysis reveals importance of reversible interactions to potency and mechanisms of drug
resistance. Proc Natl Acad Sci 111:173–178. https://doi.org/10.1073/pnas.1313733111
14. Awoonor-Williams E, Rowley CN (2018) How reactive are druggable cysteines in protein
kinases? J Chem Inf Model 58:1935–1946. https://doi.org/10.1021/acs.jcim.8b00454
15. Leproult E, Barluenga S, Moras D, Wurtz J-M, Winssinger N (2011) Cysteine mapping in
conformationally distinct kinase nucleotide binding sites: application to the design of selective
covalent inhibitors. J Med Chem 54:1347–1355. https://doi.org/10.1021/jm101396q
16. Onufriev AV, Alexov E (2013) Protonation and pK changes in protein–ligand binding. Q Rev
Biophys 46:181–209. https://doi.org/10.1017/S0033583513000024
17. Casimiro-Garcia A, Trujillo JI, Vajdos F, Juba B, Banker ME, Aulabaugh A, Balbo P,
Bauman J, Chrencik J, Coe JW, Czerwinski R, Dowty M, Knafels JD, Kwon S, Leung L,
Liang S, Robinson RP, Telliez J-B, Unwalla R, Yang X, Thorarensen A (2018) Identification
of Cyanamide-based Janus kinase 3 (JAK3) covalent inhibitors. J Med Chem. https://doi.org/
10.1021/acs.jmedchem.8b01308
18. Zhao Z, Liu Q, Bliven S, Xie L, Bourne PE (2017) Determining Cysteines available for
covalent inhibition across the human Kinome. J Med Chem 60:2879–2889. https://doi.org/10.
1021/acs.jmedchem.6b01815
19. Lonsdale R, Ward RA (2018) Structure-based design of targeted covalent inhibitors. Chem
Soc Rev 47:3816–3830. https://doi.org/10.1039/C7CS00220C
20. Backus KM, Correia BE, Lum KM, Forli S, Horning BD, González-Páez GE, Chatterjee S,
Lanning BR, Teijaro JR, Olson AJ, Wolan DW, Cravatt BF (2016) Proteome-wide covalent
ligand discovery in native biological systems. Nature 534:570–574. https://doi.org/10.1038/
nature18002
21. Kathman SG, Xu Z, Statsyuk AV (2014) A fragment-based method to discover irreversible
covalent inhibitors of cysteine proteases. J Med Chem 57:4969–4974. https://doi.org/10.1021/
jm500345q
22. Jöst C, Nitsche C, Scholz T, Roux L, Klein CD (2014) Promiscuity and selectivity in covalent
enzyme inhibition: a systematic study of electrophilic fragments. J Med Chem 57:7590–7599.
https://doi.org/10.1021/jm5006918
23. Zimmermann G, Rieder U, Bajic D, Vanetti S, Chaikuad A, Knapp S, Scheuermann J,
Mattarella M, Neri D (2017) A specific and covalent JNK-1 ligand selected from an encoded
self-assembling chemical library. Chem Eur J 23:8152–8155. https://doi.org/10.1002/chem.
201701644
24. Chan AI, McGregor LM, Jain T, Liu DR (2017) Discovery of a covalent kinase inhibitor from
a DNA-encoded small-molecule library  protein library selection. J Am Chem Soc
139:10192–10195. https://doi.org/10.1021/jacs.7b04880
25. Jackson PA, Widen JC, Harki DA, Brummond KM (2017) Covalent modifiers: a chemical
perspective on the reactivity of α,β-unsaturated carbonyls with thiols via hetero-Michael
addition reactions. J Med Chem 60:839–885. https://doi.org/10.1021/acs.jmedchem.6b00788
26. Bandyopadhyay A, Gao J (2016) Targeting biomolecules with reversible covalent chemistry.
Curr Opin Chem Biol 34:110–116. https://doi.org/10.1016/j.cbpa.2016.08.011
Covalent Kinase Inhibitors: An Overview
85