(Decernotinib): a potent and selective Janus kinase 3 inhibitor for the treatment of autoimmune
diseases. J Med Chem 58:7195–7216. https://doi.org/10.1021/acs.jmedchem.5b00301
26. Soth M, Hermann JC, Yee C, Alam M, Barnett JW, Berry P, Browner MF, Frank K,
Frauchiger S, Harris S, He Y, Hekmat-Nejad M, Hendricks T, Henningsen R, Hilgenkamp R,
Ho H, Hoffman A, Hsu P-Y, Hu D-Q, Itano A, Jaime-Figueroa S, Jahangir A, Jin S,
Kuglstatter A, Kutach AK, Liao C, Lynch S, Menke J, Niu L, Patel V, Railkar A, Roy D,
Shao A, Shaw D, Steiner S, Sun Y, Tan S-L, Wang S, Vu MD (2013) 3-Amido pyrrolopyrazine
JAK kinase inhibitors: development of a JAK3 vs JAK1 selective inhibitor and evaluation in
cellular and in vivo models. J Med Chem 56:345–356. https://doi.org/10.1021/jm301646k
27. Gehringer M, Pfaffenrot E, Bauer S, Laufer SA (2014) Design and synthesis of tricyclic JAK3
inhibitors with picomolar affinities as novel molecular probes. ChemMedChem 9:277–281.
https://doi.org/10.1002/cmdc.201300520
28. Nakajima Y, Aoyama N, Takahashi F, Sasaki H, Hatanaka K, Moritomo A, Inami M, Ito M,
Nakamura K, Nakamori F, Inoue T, Shirakami S (2016) Design, synthesis, and evaluation of
4,6-diaminonicotinamide derivatives as novel and potent immunomodulators targeting JAK3.
Bioorg Med Chem 24:4711–4722. https://doi.org/10.1016/j.bmc.2016.08.007
29. Haan C, Rolvering C, Raulf F, Kapp M, Drückes P, Thoma G, Behrmann I, Zerwes H-G (2011)
Jak1 has a dominant role over Jak3 in signal transduction through γc-containing cytokine
receptors. Chem Biol 18:314–323. https://doi.org/10.1016/j.chembiol.2011.01.012
30. Thorarensen A, Banker ME, Fensome A, Telliez J-B, Juba B, Vincent F, Czerwinski RM,
Casimiro-Garcia A (2014) ATP-mediated Kinome selectivity: the missing link in understanding
the contribution of individual JAK kinase isoforms to cellular signaling. ACS Chem Biol
9:1552. https://doi.org/10.1021/cb5002125
31. Yoshida T, Kakizuka A, Imamura H (2016) BTeam, a novel BRET-based biosensor for the
accurate quantification of ATP concentration within living cells. Sci Rep 6:39618. https://doi.
org/10.1038/srep39618
32. Leonard WJ, Mitra S, Lin J-X (2016) Immunology: JAK3 inhibition—is it sufficient? Nat Chem
Biol 12:308–310. https://doi.org/10.1038/nchembio.2066
33. Chaikuad A, Koch P, Laufer SA, Knapp S (2018) The cysteinome of protein kinases as a target
in drug development. Angew Chem Int Ed 57:4372–4385. https://doi.org/10.1002/anie.
201707875
34. Fry DW, Bridges AJ, Denny WA, Doherty A, Greis KD, Hicks JL, Hook KE,
Keller PR, Leopold WR, Loo JA, McNamara DJ, Nelson JM, Sherwood V, Smaill JB,
Trumpp-Kallmeyer S, Dobrusin EM (1998) Specific, irreversible inactivation of the
epidermal growth factor receptor and erbB2, by a new class of tyrosine kinase inhibitor.
PNAS 95:12022–12027. https://doi.org/10.1073/pnas.95.20.12022
35. Thorarensen A, Dowty ME, Banker ME, Juba B, Jussif J, Lin T, Vincent F, Czerwinski RM,
Casimiro-Garcia A, Unwalla R, Trujillo JI, Liang S, Balbo P, Che Y, Gilbert AM,
Brown MF, Hayward M, Montgomery J, Leung L, Yang X, Soucy S, Hegen M, Coe J,
Langille J, Vajdos F, Chrencik J, Telliez J-B (2017) Design of a Janus Kinase 3 (JAK3)
specific inhibitor 1-((2S,5R)-5-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin1-yl)prop-2-en-1-one (PF-06651600) allowing for the interrogation of JAK3 signaling in
humans. J Med Chem 60:1971–1993. https://doi.org/10.1021/acs.jmedchem.6b01694
36. Hanks SK, Hunter T (1995) Protein kinases 6. The eukaryotic protein kinase superfamily:
kinase (catalytic) domain structure and classification. FASEB J 9:576–596
37. Brown GR, Bamford AM, Bowyer J, James DS, Rankine N, Tang E, Torr V, Culbert EJ (2000)
Naphthyl ketones: a new class of Janus kinase 3 inhibitors. Bioorg Med Chem Lett 10:575–579.
https://doi.org/10.1016/S0960-894X(00)00051-2
38. Stepkowski SM, Kao J, Wang M-E, Tejpal N, Podder H, Furian L, Dimmock J, Jha A, Das U,
Kahan BD, Kirken RA (2005) The Mannich base NC1153 promotes long-term allograft
survival and spares the recipient from multiple toxicities. J Immunol 175:4236–4246. https://
doi.org/10.4049/jimmunol.175.7.4236
254
M. Gehringer and M. Forster
diseases. J Med Chem 58:7195–7216. https://doi.org/10.1021/acs.jmedchem.5b00301
26. Soth M, Hermann JC, Yee C, Alam M, Barnett JW, Berry P, Browner MF, Frank K,
Frauchiger S, Harris S, He Y, Hekmat-Nejad M, Hendricks T, Henningsen R, Hilgenkamp R,
Ho H, Hoffman A, Hsu P-Y, Hu D-Q, Itano A, Jaime-Figueroa S, Jahangir A, Jin S,
Kuglstatter A, Kutach AK, Liao C, Lynch S, Menke J, Niu L, Patel V, Railkar A, Roy D,
Shao A, Shaw D, Steiner S, Sun Y, Tan S-L, Wang S, Vu MD (2013) 3-Amido pyrrolopyrazine
JAK kinase inhibitors: development of a JAK3 vs JAK1 selective inhibitor and evaluation in
cellular and in vivo models. J Med Chem 56:345–356. https://doi.org/10.1021/jm301646k
27. Gehringer M, Pfaffenrot E, Bauer S, Laufer SA (2014) Design and synthesis of tricyclic JAK3
inhibitors with picomolar affinities as novel molecular probes. ChemMedChem 9:277–281.
https://doi.org/10.1002/cmdc.201300520
28. Nakajima Y, Aoyama N, Takahashi F, Sasaki H, Hatanaka K, Moritomo A, Inami M, Ito M,
Nakamura K, Nakamori F, Inoue T, Shirakami S (2016) Design, synthesis, and evaluation of
4,6-diaminonicotinamide derivatives as novel and potent immunomodulators targeting JAK3.
Bioorg Med Chem 24:4711–4722. https://doi.org/10.1016/j.bmc.2016.08.007
29. Haan C, Rolvering C, Raulf F, Kapp M, Drückes P, Thoma G, Behrmann I, Zerwes H-G (2011)
Jak1 has a dominant role over Jak3 in signal transduction through γc-containing cytokine
receptors. Chem Biol 18:314–323. https://doi.org/10.1016/j.chembiol.2011.01.012
30. Thorarensen A, Banker ME, Fensome A, Telliez J-B, Juba B, Vincent F, Czerwinski RM,
Casimiro-Garcia A (2014) ATP-mediated Kinome selectivity: the missing link in understanding
the contribution of individual JAK kinase isoforms to cellular signaling. ACS Chem Biol
9:1552. https://doi.org/10.1021/cb5002125
31. Yoshida T, Kakizuka A, Imamura H (2016) BTeam, a novel BRET-based biosensor for the
accurate quantification of ATP concentration within living cells. Sci Rep 6:39618. https://doi.
org/10.1038/srep39618
32. Leonard WJ, Mitra S, Lin J-X (2016) Immunology: JAK3 inhibition—is it sufficient? Nat Chem
Biol 12:308–310. https://doi.org/10.1038/nchembio.2066
33. Chaikuad A, Koch P, Laufer SA, Knapp S (2018) The cysteinome of protein kinases as a target
in drug development. Angew Chem Int Ed 57:4372–4385. https://doi.org/10.1002/anie.
201707875
34. Fry DW, Bridges AJ, Denny WA, Doherty A, Greis KD, Hicks JL, Hook KE,
Keller PR, Leopold WR, Loo JA, McNamara DJ, Nelson JM, Sherwood V, Smaill JB,
Trumpp-Kallmeyer S, Dobrusin EM (1998) Specific, irreversible inactivation of the
epidermal growth factor receptor and erbB2, by a new class of tyrosine kinase inhibitor.
PNAS 95:12022–12027. https://doi.org/10.1073/pnas.95.20.12022
35. Thorarensen A, Dowty ME, Banker ME, Juba B, Jussif J, Lin T, Vincent F, Czerwinski RM,
Casimiro-Garcia A, Unwalla R, Trujillo JI, Liang S, Balbo P, Che Y, Gilbert AM,
Brown MF, Hayward M, Montgomery J, Leung L, Yang X, Soucy S, Hegen M, Coe J,
Langille J, Vajdos F, Chrencik J, Telliez J-B (2017) Design of a Janus Kinase 3 (JAK3)
specific inhibitor 1-((2S,5R)-5-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin1-yl)prop-2-en-1-one (PF-06651600) allowing for the interrogation of JAK3 signaling in
humans. J Med Chem 60:1971–1993. https://doi.org/10.1021/acs.jmedchem.6b01694
36. Hanks SK, Hunter T (1995) Protein kinases 6. The eukaryotic protein kinase superfamily:
kinase (catalytic) domain structure and classification. FASEB J 9:576–596
37. Brown GR, Bamford AM, Bowyer J, James DS, Rankine N, Tang E, Torr V, Culbert EJ (2000)
Naphthyl ketones: a new class of Janus kinase 3 inhibitors. Bioorg Med Chem Lett 10:575–579.
https://doi.org/10.1016/S0960-894X(00)00051-2
38. Stepkowski SM, Kao J, Wang M-E, Tejpal N, Podder H, Furian L, Dimmock J, Jha A, Das U,
Kahan BD, Kirken RA (2005) The Mannich base NC1153 promotes long-term allograft
survival and spares the recipient from multiple toxicities. J Immunol 175:4236–4246. https://
doi.org/10.4049/jimmunol.175.7.4236
254
M. Gehringer and M. Forster