20. Humphries PS, Lafontaine JA, Agree CS, Alexander D, Chen P, Do QQT, Li LLY, Lunney EA,
Rajapakse RJ, Siegel K, Timofeevski SL, Wang TL, Wilhite DM (2009) Synthesis and SAR of
4-substituted-2-aminopyrimidines as novel c-Jun N-terminal kinase (JNK) inhibitors. Bioorg
Med Chem Lett 19:2099–2102. https://doi.org/10.1016/j.bmcl.2009.03.023
21. Song XY, Chen WM, Lin L, Ruiz CH, Cameron MD, Duckett DR, Kamenecka TM (2011)
Synthesis and SAR of 2-phenoxypyridines as novel c-Jun N-terminal kinase inhibitors. Bioorg
Med Chem Lett 21:7072–7075. https://doi.org/10.1016/j.bmcl.2011.09.090
22. Song X, He Y, Koenig M, Shin Y, Noël R, Chen W, Ling YY, Feurstein D, Lin L,
Ruiz CH, Cameron MD, Duckett DR, Kamenecka TM (2012) Synthesis and SAR of
2,4-diaminopyrimidines as potent c-Jun N-terminal kinase inhibitors. Med Chem Commun
3:238–243. https://doi.org/10.1039/C1MD00219H
23. Palmer WS, Alam M, Arzeno HB, Chang KC, Dunn JP, Goldstein DM, Gong LY, Goyal B,
Hermann JC, Hogg JH, Hsieh G, Jahangir A, Janson C, Jin S, Kammlott RU, Kuglstatter A,
Lukacs C, Michoud C, Niu LH, Reuter DC, Shao A, Silva T, Trejo-Martin TA, Stein K,
Tan YC, Tivitmahaisoon P, Tran P, Wagner P, Weller P, Wu SY (2013) Development
of amino-pyrimidine inhibitors of c-Jun N-terminal kinase (JNK): kinase profiling guided
optimization of a 1,2,3-benzotriazole lead. Bioorg Med Chem Lett 23:1486–1492. https://doi.
org/10.1016/j.bmcl.2012.12.047
24. Kamenecka T, Jiang R, Song XY, Duckett D, Chen WM, Ling YY, Habel J, Laughlin JD,
Chambers J, Figuera-Losada M, Cameron MD, Lin L, Ruiz CH, LoGrasso PV (2010)
Synthesis, biological evaluation, X-ray structure, and pharmacokinetics of aminopyrimidine
c-Jun-N-terminal kinase (JNK) inhibitors. J Med Chem 53:419–431. https://doi.org/10.1021/
jm901351f
25. Chambers JW, Pachori A, Howard S, Ganno M, Hansen D, Kamenecka T, Song XY,
Duckett D, Chen WM, Ling YY, Cherry L, Cameron MD, Lin L, Ruiz CH, LoGrasso P
(2011) Small molecule c-Jun-N-terminal kinase inhibitors protect dopaminergic neurons
in a model of Parkinson’s disease. ACS Chem Neurosci 2:198–206. https://doi.org/10.1021/
cn100109k
26. Scapin G, Patel SB, Lisnock J, Becker JW, LoGrasso PV (2003) The structure of JNK3 in
complex with small molecule inhibitors: structural basis for potency and selectivity. Chem Biol
10:705–712. https://doi.org/10.1016/S1074-5521(03)00159-5
27. Crocker CE, Khan S, Cameron MD, Robertson HA, Robertson GS, LoGrasso P (2011)
JNK inhibition protects dopamine neurons and provides behavioral improvement in a rat
6-hydroxydopamine model of Parkinson’s disease. ACS Chem Neurosci 2:207–212. https://
doi.org/10.1021/cn1001107
28. Chambers JW, Pachori A, Howard S, Iqbal S, LoGrasso PV (2013) Inhibition of JNK
mitochondrial localization and signaling is protective against ischemia/reperfusion injury in
rats. J Biol Chem 288:4000–4011. https://doi.org/10.1074/jbc.M112.406777
29. Griswold DE, Marshall PJ, Webb EF, Godfrey R, Newton J, DiMartino MJ, Sarau HM,
Gleason JG, Poste G, Hanna N (1987) SK&F 86002: a structurally novel anti-inflammatory
agent that inhibits lipoxygenase- and cyclooxygenase-mediated metabolism of arachidonic
acid. Biochem Pharmacol 36:3463–3470. https://doi.org/10.1016/0006-2952(87)90327-3
30. Günther M, Juchum M, Kelter G, Fiebig H, Laufer S (2016) Lung cancer: EGFR inhibitors
with low nanomolar activity against a therapy-resistant L858R/T790M/C797S mutant.
Angew Chem Int Ed 55:10890–10894. https://doi.org/10.1002/anie.201603736
31. Günther M, Lategahn J, Juchum M, Döring E, Keul M, Engel J, Tumbrink HL, Rauh D,
Laufer S (2017) Trisubstituted pyridinylimidazoles as potent inhibitors of the clinically resistant
L858R/T790M/C797S EGFR mutant: targeting of both hydrophobic regions and the phosphate
binding site. J Med Chem 60:5613–5637. https://doi.org/10.1021/acs.jmedchem.7b00316
32. Halekotte J, Witt L, Ianes C, Krüger M, Bührmann M, Rauh D, Pichlo C, Brunstein C,
Luxenburger A, Baumann U, Knippschild U, Bischof J, Peifer C (2017) Optimized
Inhibitors of c-Jun N-Terminal Kinase 3
223
Rajapakse RJ, Siegel K, Timofeevski SL, Wang TL, Wilhite DM (2009) Synthesis and SAR of
4-substituted-2-aminopyrimidines as novel c-Jun N-terminal kinase (JNK) inhibitors. Bioorg
Med Chem Lett 19:2099–2102. https://doi.org/10.1016/j.bmcl.2009.03.023
21. Song XY, Chen WM, Lin L, Ruiz CH, Cameron MD, Duckett DR, Kamenecka TM (2011)
Synthesis and SAR of 2-phenoxypyridines as novel c-Jun N-terminal kinase inhibitors. Bioorg
Med Chem Lett 21:7072–7075. https://doi.org/10.1016/j.bmcl.2011.09.090
22. Song X, He Y, Koenig M, Shin Y, Noël R, Chen W, Ling YY, Feurstein D, Lin L,
Ruiz CH, Cameron MD, Duckett DR, Kamenecka TM (2012) Synthesis and SAR of
2,4-diaminopyrimidines as potent c-Jun N-terminal kinase inhibitors. Med Chem Commun
3:238–243. https://doi.org/10.1039/C1MD00219H
23. Palmer WS, Alam M, Arzeno HB, Chang KC, Dunn JP, Goldstein DM, Gong LY, Goyal B,
Hermann JC, Hogg JH, Hsieh G, Jahangir A, Janson C, Jin S, Kammlott RU, Kuglstatter A,
Lukacs C, Michoud C, Niu LH, Reuter DC, Shao A, Silva T, Trejo-Martin TA, Stein K,
Tan YC, Tivitmahaisoon P, Tran P, Wagner P, Weller P, Wu SY (2013) Development
of amino-pyrimidine inhibitors of c-Jun N-terminal kinase (JNK): kinase profiling guided
optimization of a 1,2,3-benzotriazole lead. Bioorg Med Chem Lett 23:1486–1492. https://doi.
org/10.1016/j.bmcl.2012.12.047
24. Kamenecka T, Jiang R, Song XY, Duckett D, Chen WM, Ling YY, Habel J, Laughlin JD,
Chambers J, Figuera-Losada M, Cameron MD, Lin L, Ruiz CH, LoGrasso PV (2010)
Synthesis, biological evaluation, X-ray structure, and pharmacokinetics of aminopyrimidine
c-Jun-N-terminal kinase (JNK) inhibitors. J Med Chem 53:419–431. https://doi.org/10.1021/
jm901351f
25. Chambers JW, Pachori A, Howard S, Ganno M, Hansen D, Kamenecka T, Song XY,
Duckett D, Chen WM, Ling YY, Cherry L, Cameron MD, Lin L, Ruiz CH, LoGrasso P
(2011) Small molecule c-Jun-N-terminal kinase inhibitors protect dopaminergic neurons
in a model of Parkinson’s disease. ACS Chem Neurosci 2:198–206. https://doi.org/10.1021/
cn100109k
26. Scapin G, Patel SB, Lisnock J, Becker JW, LoGrasso PV (2003) The structure of JNK3 in
complex with small molecule inhibitors: structural basis for potency and selectivity. Chem Biol
10:705–712. https://doi.org/10.1016/S1074-5521(03)00159-5
27. Crocker CE, Khan S, Cameron MD, Robertson HA, Robertson GS, LoGrasso P (2011)
JNK inhibition protects dopamine neurons and provides behavioral improvement in a rat
6-hydroxydopamine model of Parkinson’s disease. ACS Chem Neurosci 2:207–212. https://
doi.org/10.1021/cn1001107
28. Chambers JW, Pachori A, Howard S, Iqbal S, LoGrasso PV (2013) Inhibition of JNK
mitochondrial localization and signaling is protective against ischemia/reperfusion injury in
rats. J Biol Chem 288:4000–4011. https://doi.org/10.1074/jbc.M112.406777
29. Griswold DE, Marshall PJ, Webb EF, Godfrey R, Newton J, DiMartino MJ, Sarau HM,
Gleason JG, Poste G, Hanna N (1987) SK&F 86002: a structurally novel anti-inflammatory
agent that inhibits lipoxygenase- and cyclooxygenase-mediated metabolism of arachidonic
acid. Biochem Pharmacol 36:3463–3470. https://doi.org/10.1016/0006-2952(87)90327-3
30. Günther M, Juchum M, Kelter G, Fiebig H, Laufer S (2016) Lung cancer: EGFR inhibitors
with low nanomolar activity against a therapy-resistant L858R/T790M/C797S mutant.
Angew Chem Int Ed 55:10890–10894. https://doi.org/10.1002/anie.201603736
31. Günther M, Lategahn J, Juchum M, Döring E, Keul M, Engel J, Tumbrink HL, Rauh D,
Laufer S (2017) Trisubstituted pyridinylimidazoles as potent inhibitors of the clinically resistant
L858R/T790M/C797S EGFR mutant: targeting of both hydrophobic regions and the phosphate
binding site. J Med Chem 60:5613–5637. https://doi.org/10.1021/acs.jmedchem.7b00316
32. Halekotte J, Witt L, Ianes C, Krüger M, Bührmann M, Rauh D, Pichlo C, Brunstein C,
Luxenburger A, Baumann U, Knippschild U, Bischof J, Peifer C (2017) Optimized
Inhibitors of c-Jun N-Terminal Kinase 3
223