59. Walker EH, Pacold ME, Perisic O, Stephens L, Hawkins PT, Wymann MP, Williams RL
(2000) Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin,
LY294002, quercetin, myricetin, and staurosporine. Mol Cell 6:909–919. https://doi.org/10.
1016/S1097-2765(05)00089-4
60. Norman BH, Shih C, Toth JE, Ray JE, Dodge JA, Johnson DW, Rutherford PG, Schultz RM,
Worzalla JF, Vlahos CJ (1996) Studies on the mechanism of phosphatidylinositol 3-kinase
inhibition by wortmannin and related analogs. J Med Chem 39:1106–1111. https://doi.org/10.
1021/jm950619p
61. Singh J, Dobrusin EM, Fry DW, Haske T, Whitty A, McNamara DJ (1997) Structure-based
design of a potent, selective, and irreversible inhibitor of the catalytic domain of the erbB
receptor subfamily of protein tyrosine kinases. J Med Chem 40:1130–1135. https://doi.org/10.
1021/jm960380s
62. 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, TrumppKallmeyer 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
63. Smaill JB, Gonzales AJ, Spicer JA, Lee H, Reed JE, Sexton K, Althaus IW, Zhu T, Black SL,
Blaser A, Denny WA, Ellis PA, Fakhoury S, Harvey PJ, Hook K, McCarthy FOJ, Palmer BD,
Rivault F, Schlosser K, Ellis T, Thompson AM, Trachet E, Winters RT, Tecle H, Bridges A
(2016) Tyrosine kinase inhibitors. 20. Optimization of substituted Quinazoline and Pyrido
[3,4-d]pyrimidine derivatives as orally active, irreversible inhibitors of the epidermal growth
factor receptor family. J Med Chem 59:8103–8124. https://doi.org/10.1021/acs.jmedchem.
6b00883
64. Tsou H-R, Overbeek-Klumpers EG, Hallett WA, Reich MF, Floyd MB, Johnson BD,
Michalak RS, Nilakantan R, Discafani C, Golas J, Rabindran SK, Shen R, Shi X, Wang
Y-F, Upeslacis J, Wissner A (2005) Optimization of 6,7-Disubstituted-4-(arylamino)quinoline-3-carbonitriles as orally active, irreversible inhibitors of human epidermal growth factor
Receptor-2 kinase activity. J Med Chem 48:1107–1131. https://doi.org/10.1021/jm040159c
65. Zhou W, Ercan D, Chen L, Yun C-H, Li D, Capelletti M, Cortot AB, Chirieac L, Iacob RE,
Padera R, Engen JR, Wong K-K, Eck MJ, Gray NS, Jänne PA (2009) Novel mutant-selective
EGFR kinase inhibitors against EGFR T790M. Nature 462:1070–1074. https://doi.org/10.
1038/nature08622
66. Wilcken R, Zimmermann MO, Lange A, Joerger AC, Boeckler FM (2013) Principles and
applications of halogen bonding in medicinal chemistry and chemical biology. J Med Chem
56:1363–1388. https://doi.org/10.1021/jm3012068
67. Boeckler FM, Zimmermann M. Personal communication
68. Van Der Steen N, Caparello C, Rolfo C, Pauwels P, Peters GJ, Giovannetti E (2016) New
developments in the management of non-small-cell lung cancer, focus on rociletinib: what
went wrong? Onco Targets Ther 9:6065–6074. https://doi.org/10.2147/OTT.S97644
69. Yver A (2016) Osimertinib (AZD9291) – a science-driven, collaborative approach to rapid
drug design and development. Ann Oncol 27:1165–1170. https://doi.org/10.1093/annonc/
mdw129
70. 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
71. 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
72. Pan Z, Scheerens H, Li S-J, Schultz BE, Sprengeler PA, Burrill LC, Mendonca RV, Sweeney
MD, Scott KCK, Grothaus PG, Jeffery DA, Spoerke JM, Honigberg LA, Young PR,
88
M. Gehringer
(2000) Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin,
LY294002, quercetin, myricetin, and staurosporine. Mol Cell 6:909–919. https://doi.org/10.
1016/S1097-2765(05)00089-4
60. Norman BH, Shih C, Toth JE, Ray JE, Dodge JA, Johnson DW, Rutherford PG, Schultz RM,
Worzalla JF, Vlahos CJ (1996) Studies on the mechanism of phosphatidylinositol 3-kinase
inhibition by wortmannin and related analogs. J Med Chem 39:1106–1111. https://doi.org/10.
1021/jm950619p
61. Singh J, Dobrusin EM, Fry DW, Haske T, Whitty A, McNamara DJ (1997) Structure-based
design of a potent, selective, and irreversible inhibitor of the catalytic domain of the erbB
receptor subfamily of protein tyrosine kinases. J Med Chem 40:1130–1135. https://doi.org/10.
1021/jm960380s
62. 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, TrumppKallmeyer 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
63. Smaill JB, Gonzales AJ, Spicer JA, Lee H, Reed JE, Sexton K, Althaus IW, Zhu T, Black SL,
Blaser A, Denny WA, Ellis PA, Fakhoury S, Harvey PJ, Hook K, McCarthy FOJ, Palmer BD,
Rivault F, Schlosser K, Ellis T, Thompson AM, Trachet E, Winters RT, Tecle H, Bridges A
(2016) Tyrosine kinase inhibitors. 20. Optimization of substituted Quinazoline and Pyrido
[3,4-d]pyrimidine derivatives as orally active, irreversible inhibitors of the epidermal growth
factor receptor family. J Med Chem 59:8103–8124. https://doi.org/10.1021/acs.jmedchem.
6b00883
64. Tsou H-R, Overbeek-Klumpers EG, Hallett WA, Reich MF, Floyd MB, Johnson BD,
Michalak RS, Nilakantan R, Discafani C, Golas J, Rabindran SK, Shen R, Shi X, Wang
Y-F, Upeslacis J, Wissner A (2005) Optimization of 6,7-Disubstituted-4-(arylamino)quinoline-3-carbonitriles as orally active, irreversible inhibitors of human epidermal growth factor
Receptor-2 kinase activity. J Med Chem 48:1107–1131. https://doi.org/10.1021/jm040159c
65. Zhou W, Ercan D, Chen L, Yun C-H, Li D, Capelletti M, Cortot AB, Chirieac L, Iacob RE,
Padera R, Engen JR, Wong K-K, Eck MJ, Gray NS, Jänne PA (2009) Novel mutant-selective
EGFR kinase inhibitors against EGFR T790M. Nature 462:1070–1074. https://doi.org/10.
1038/nature08622
66. Wilcken R, Zimmermann MO, Lange A, Joerger AC, Boeckler FM (2013) Principles and
applications of halogen bonding in medicinal chemistry and chemical biology. J Med Chem
56:1363–1388. https://doi.org/10.1021/jm3012068
67. Boeckler FM, Zimmermann M. Personal communication
68. Van Der Steen N, Caparello C, Rolfo C, Pauwels P, Peters GJ, Giovannetti E (2016) New
developments in the management of non-small-cell lung cancer, focus on rociletinib: what
went wrong? Onco Targets Ther 9:6065–6074. https://doi.org/10.2147/OTT.S97644
69. Yver A (2016) Osimertinib (AZD9291) – a science-driven, collaborative approach to rapid
drug design and development. Ann Oncol 27:1165–1170. https://doi.org/10.1093/annonc/
mdw129
70. 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
71. 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
72. Pan Z, Scheerens H, Li S-J, Schultz BE, Sprengeler PA, Burrill LC, Mendonca RV, Sweeney
MD, Scott KCK, Grothaus PG, Jeffery DA, Spoerke JM, Honigberg LA, Young PR,
88
M. Gehringer