Bir Kohli P, Maxey RJ, Mendonca R, Mortara K, Murray J, Narukulla R, Shia S, Steffek M,
Ubhayakar S, Ultsch M, van Abbema A, Ward SI, Waszkowycz B, Zak M (2012) Identification
of imidazo-pyrrolopyridines as novel and potent JAK1 inhibitors. J Med Chem 55:5901–5921.
https://doi.org/10.1021/jm300438j
55. Chrencik JE, Patny A, Leung IK, Korniski B, Emmons TL, Hall T, Weinberg RA, Gormley JA,
Williams JM, Day JE, Hirsch JL, Kiefer JR, Leone JW, Fischer HD, Sommers CD, Huang H-C,
Jacobsen EJ, Tenbrink RE, Tomasselli AG, Benson TE (2010) Structural and thermodynamic
characterization of the TYK2 and JAK3 kinase domains in complex with CP-690550 and
CMP-6. J Mol Biol 400:413–433. https://doi.org/10.1016/j.jmb.2010.05.020
56. Robers MB, Dart ML, Woodroofe CC, Zimprich CA, Kirkland TA, Machleidt T, Kupcho KR,
Levin S, Hartnett JR, Zimmerman K, Niles AL, Ohana RF, Daniels DL, Slater M, Wood MG,
Cong M, Cheng Y-Q, Wood KV (2015) Target engagement and drug residence time can
be observed in living cells with BRET. Nat Commun 6:1–10. https://doi.org/10.1038/
ncomms10091
57. Telliez J-B, Dowty ME, Wang L, Jussif J, Lin T, Li L, Moy E, Balbo P, Li W, Zhao Y,
Crouse K, Dickinson C, Symanowicz P, Hegen M, Banker ME, Vincent F, Unwalla R, Liang S,
Gilbert AM, Brown MF, Hayward M, Montgomery J, Yang X, Bauman J, Trujillo JI,
Casimiro-Garcia A, Vajdos FF, Leung L, Geoghegan KF, Quazi A, Xuan D, Jones L, Hett E,
Wright K, Clark JD, Thorarensen A (2016) Discovery of a JAK3-selective inhibitor: functional
differentiation of JAK3-selective inhibition over pan-JAK or JAK1-selective inhibition.
ACS Chem Biol 11:3442–3451. https://doi.org/10.1021/acschembio.6b00677
58. He L, Pei H, Lan T, Tang M, Zhang C, Chen L (2017) Design and synthesis of a highly
selective JAK3 inhibitor for the treatment of rheumatoid arthritis. Arch der Pharm 350:1700194.
https://doi.org/10.1002/ardp.201700194
59. Pei H, He L, Shao M, Yang Z, Ran Y, Li D, Zhou Y, Tang M, Wang T, Gong Y, Chen X,
Yang S, Xiang M, Chen L (2018) Discovery of a highly selective JAK3 inhibitor for the
treatment of rheumatoid arthritis. Sci Rep 8:5273. https://doi.org/10.1038/s41598-018-23569-y
60. He L, Shao M, Wang T, Lan T, Zhang C, Chen L (2018) Design, synthesis, and SAR study
of highly potent, selective, irreversible covalent JAK3 inhibitors. Mol Divers 22:1–16. https://
doi.org/10.1007/s11030-017-9803-2
61. 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
62. Flanagan ME, Abramite JA, Anderson DP, Aulabaugh A, Dahal UP, Gilbert AM,
Li C, Montgomery J, Oppenheimer SR, Ryder T, Schuff BP, Uccello DP, Walker GS, Wu Y,
Brown MF, Chen JM, Hayward MM, Noe MC, Obach RS, Philippe L, Shanmugasundaram V,
Shapiro MJ, Starr J, Stroh J, Che Y (2014) Chemical and computational methods for the
characterization of covalent reactive groups for the prospective design of irreversible inhibitors.
J Med Chem 57:10072–10079. https://doi.org/10.1021/jm501412a
63. Allimuthu D, Adams DJ (2017) 2-Chloropropionamide as a low-reactivity electrophile
for irreversible small-molecule probe identification. ACS Chem Biol 12:2124–2131. https://
doi.org/10.1021/acschembio.7b00424
64. Gehringer M, Forster M, Pfaffenrot E, Bauer SM, Laufer SA (2014) Novel hinge-binding
motifs for Janus kinase 3 inhibitors: a comprehensive structure–activity relationship study
on Tofacitinib Bioisosteres. ChemMedChem 9:2516–2527. https://doi.org/10.1002/cmdc.
201402252
65. Kempson J, Ovalle D, Guo J, Wrobleski ST, Lin S, Spergel SH, Duan JJ-W, Jiang B, Lu Z,
Das J, Yang BV, Hynes J, Wu H, Tokarski J, Sack JS, Khan J, Schieven G, Blatt Y,
Chaudhry C, Salter-Cid LM, Fura A, Barrish JC, Carter PH, Pitts WJ (2017) Discovery of
highly potent, selective, covalent inhibitors of JAK3. Bioorg Med Chem Lett 27:4622–4625.
https://doi.org/10.1016/j.bmcl.2017.09.023
256
M. Gehringer and M. Forster
Ubhayakar S, Ultsch M, van Abbema A, Ward SI, Waszkowycz B, Zak M (2012) Identification
of imidazo-pyrrolopyridines as novel and potent JAK1 inhibitors. J Med Chem 55:5901–5921.
https://doi.org/10.1021/jm300438j
55. Chrencik JE, Patny A, Leung IK, Korniski B, Emmons TL, Hall T, Weinberg RA, Gormley JA,
Williams JM, Day JE, Hirsch JL, Kiefer JR, Leone JW, Fischer HD, Sommers CD, Huang H-C,
Jacobsen EJ, Tenbrink RE, Tomasselli AG, Benson TE (2010) Structural and thermodynamic
characterization of the TYK2 and JAK3 kinase domains in complex with CP-690550 and
CMP-6. J Mol Biol 400:413–433. https://doi.org/10.1016/j.jmb.2010.05.020
56. Robers MB, Dart ML, Woodroofe CC, Zimprich CA, Kirkland TA, Machleidt T, Kupcho KR,
Levin S, Hartnett JR, Zimmerman K, Niles AL, Ohana RF, Daniels DL, Slater M, Wood MG,
Cong M, Cheng Y-Q, Wood KV (2015) Target engagement and drug residence time can
be observed in living cells with BRET. Nat Commun 6:1–10. https://doi.org/10.1038/
ncomms10091
57. Telliez J-B, Dowty ME, Wang L, Jussif J, Lin T, Li L, Moy E, Balbo P, Li W, Zhao Y,
Crouse K, Dickinson C, Symanowicz P, Hegen M, Banker ME, Vincent F, Unwalla R, Liang S,
Gilbert AM, Brown MF, Hayward M, Montgomery J, Yang X, Bauman J, Trujillo JI,
Casimiro-Garcia A, Vajdos FF, Leung L, Geoghegan KF, Quazi A, Xuan D, Jones L, Hett E,
Wright K, Clark JD, Thorarensen A (2016) Discovery of a JAK3-selective inhibitor: functional
differentiation of JAK3-selective inhibition over pan-JAK or JAK1-selective inhibition.
ACS Chem Biol 11:3442–3451. https://doi.org/10.1021/acschembio.6b00677
58. He L, Pei H, Lan T, Tang M, Zhang C, Chen L (2017) Design and synthesis of a highly
selective JAK3 inhibitor for the treatment of rheumatoid arthritis. Arch der Pharm 350:1700194.
https://doi.org/10.1002/ardp.201700194
59. Pei H, He L, Shao M, Yang Z, Ran Y, Li D, Zhou Y, Tang M, Wang T, Gong Y, Chen X,
Yang S, Xiang M, Chen L (2018) Discovery of a highly selective JAK3 inhibitor for the
treatment of rheumatoid arthritis. Sci Rep 8:5273. https://doi.org/10.1038/s41598-018-23569-y
60. He L, Shao M, Wang T, Lan T, Zhang C, Chen L (2018) Design, synthesis, and SAR study
of highly potent, selective, irreversible covalent JAK3 inhibitors. Mol Divers 22:1–16. https://
doi.org/10.1007/s11030-017-9803-2
61. 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
62. Flanagan ME, Abramite JA, Anderson DP, Aulabaugh A, Dahal UP, Gilbert AM,
Li C, Montgomery J, Oppenheimer SR, Ryder T, Schuff BP, Uccello DP, Walker GS, Wu Y,
Brown MF, Chen JM, Hayward MM, Noe MC, Obach RS, Philippe L, Shanmugasundaram V,
Shapiro MJ, Starr J, Stroh J, Che Y (2014) Chemical and computational methods for the
characterization of covalent reactive groups for the prospective design of irreversible inhibitors.
J Med Chem 57:10072–10079. https://doi.org/10.1021/jm501412a
63. Allimuthu D, Adams DJ (2017) 2-Chloropropionamide as a low-reactivity electrophile
for irreversible small-molecule probe identification. ACS Chem Biol 12:2124–2131. https://
doi.org/10.1021/acschembio.7b00424
64. Gehringer M, Forster M, Pfaffenrot E, Bauer SM, Laufer SA (2014) Novel hinge-binding
motifs for Janus kinase 3 inhibitors: a comprehensive structure–activity relationship study
on Tofacitinib Bioisosteres. ChemMedChem 9:2516–2527. https://doi.org/10.1002/cmdc.
201402252
65. Kempson J, Ovalle D, Guo J, Wrobleski ST, Lin S, Spergel SH, Duan JJ-W, Jiang B, Lu Z,
Das J, Yang BV, Hynes J, Wu H, Tokarski J, Sack JS, Khan J, Schieven G, Blatt Y,
Chaudhry C, Salter-Cid LM, Fura A, Barrish JC, Carter PH, Pitts WJ (2017) Discovery of
highly potent, selective, covalent inhibitors of JAK3. Bioorg Med Chem Lett 27:4622–4625.
https://doi.org/10.1016/j.bmcl.2017.09.023
256
M. Gehringer and M. Forster
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