62. Oxnard GR, Arcila ME, Chmielecki J et al (2011) New strategies in overcoming acquired
resistance to epidermal growth factor receptor tyrosine kinase inhibitors in lung cancer. Clin
Cancer Res 17:5530–5537. https://doi.org/10.1158/1078-0432.CCR-10-2571
63. Bikker JA, Brooijmans N, Wissner A, Mansour TS (2009) Kinase domain mutations in cancer:
implications for small molecule drug design strategies. J Med Chem 52:1493–1509
64. Holohan C, Van Schaeybroeck S, Longley DB, Johnston PG (2013) Cancer drug resistance: an
evolving paradigm. Nat Rev Cancer 13:714–726. https://doi.org/10.1038/nrc3599
65. Godin-Heymann N, Ulkus L, Brannigan BW et al (2008) The T790M “gatekeeper” mutation
in EGFR mediates resistance to low concentrations of an irreversible EGFR inhibitor. Mol
Cancer Ther 7:874–879. https://doi.org/10.1158/1535-7163.MCT-07-2387
66. Gajiwala KS, Feng J, Ferre R et al (2013) Insights into the aberrant activity of mutant EGFR
kinase domain and drug recognition. Structure 21:209–219. https://doi.org/10.1016/j.str.2012.
11.014
67. Doebele RC, Oton AB, Peled N et al (2010) New strategies to overcome limitations of
reversible EGFR tyrosine kinase inhibitor therapy in non-small cell lung cancer. Lung Cancer
69:1–12. https://doi.org/10.1016/j.lungcan.2009.12.009
68. Zhou W, Ercan D, Chen L et al (2009) Novel mutant-selective EGFR kinase inhibitors against
EGFR T790M. Nature 462:1070–1074. https://doi.org/10.1038/nature08622
69. Kwak EL, Sordella R, Bell DW et al (2005) Irreversible inhibitors of the EGF receptor may
circumvent acquired resistance to gefitinib. Proc Natl Acad Sci U S A 102:7665–7670. https://
doi.org/10.1073/pnas.0502860102
70. Liu Q, Sabnis Y, Zhao Z et al (2013) Developing irreversible inhibitors of the protein kinase
cysteinome. Chem Biol 20:146–159. https://doi.org/10.1016/j.chembiol.2012.12.006
71. Mah R, Thomas JR, Shafer CM (2014) Drug discovery considerations in the development of
covalent inhibitors. Bioorg Med Chem Lett 24:33–39
72. Singh J, Petter RC, Baillie TA, Whitty A (2011) The resurgence of covalent drugs. Nat Rev
Drug Discov 10:307–317. https://doi.org/10.1038/nrd3410
73. Barf T, Kaptein A (2012) Irreversible protein kinase inhibitors: balancing the benefits and
risks. J Med Chem 55:6243–6262. https://doi.org/10.1021/jm3003203
74. Kalgutkar AS, Dalvie DK (2012) Drug discovery for a new generation of covalent drugs.
Expert Opin Drug Discovery 7:561–581. https://doi.org/10.1517/17460441.2012.688744
75. Levitzki A (2013) Tyrosine kinase inhibitors: views of selectivity, sensitivity, and clinical
performance. Annu Rev Pharmacol Toxicol 53:161–185. https://doi.org/10.1146/annurevpharmtox-011112-140341
76. Singh J, Dobrusin EM, Fry DW et al (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
77. Fry DW, Bridges AJ, Denny WA et al (1998) Specific, irreversible inactivation of the
epidermal growth factor receptor and erbB2, by a new class of tyrosine kinase inhibitor.
Proc Natl Acad Sci U S A 95:12022–12027. https://doi.org/10.1073/pnas.95.20.12022
78. Smaill JB, Palmer BD, Rewcastle GW et al (1999) 4-(Phenylamino)pyrido[d]pyrimidine
acrylamides as irreversible inhibitors of the ATP binding site of the epidermal growth factor
receptor. J Med Chem 42:1803–1815
79. Smaill JB, Rewcastle GW, Loo JA et al (2000) Tyrosine kinase inhibitors. 17. Irreversible
inhibitors of the epidermal growth factor receptor: 4-(phenylamino)quinazoline- and 4(phenylamino)pyrido[3,2-d]pyrimidine-6-acrylamides bearing additional solubilizing functions. J Med Chem 43:1380–1397. https://doi.org/10.1021/jm990482t
80. Williams R (2008) Discontinued drugs in 2006: oncology drugs. Expert Opin Investig Drugs
17:269–283. https://doi.org/10.1517/13543784.17.3.269
81. Tsou HR, Mamuya N, Johnson BD et al (2001) 6-Substituted-4-(3-bromophenylamino)
quinazolines as putative irreversible inhibitors of the epidermal growth factor receptor
(EGFR) and human epidermal growth factor receptor (HER-2) tyrosine kinases with enhanced
antitumour activity. J Med Chem 44:2719–2734. https://doi.org/10.1021/jm0005555
196
L. M. Lima et al.
resistance to epidermal growth factor receptor tyrosine kinase inhibitors in lung cancer. Clin
Cancer Res 17:5530–5537. https://doi.org/10.1158/1078-0432.CCR-10-2571
63. Bikker JA, Brooijmans N, Wissner A, Mansour TS (2009) Kinase domain mutations in cancer:
implications for small molecule drug design strategies. J Med Chem 52:1493–1509
64. Holohan C, Van Schaeybroeck S, Longley DB, Johnston PG (2013) Cancer drug resistance: an
evolving paradigm. Nat Rev Cancer 13:714–726. https://doi.org/10.1038/nrc3599
65. Godin-Heymann N, Ulkus L, Brannigan BW et al (2008) The T790M “gatekeeper” mutation
in EGFR mediates resistance to low concentrations of an irreversible EGFR inhibitor. Mol
Cancer Ther 7:874–879. https://doi.org/10.1158/1535-7163.MCT-07-2387
66. Gajiwala KS, Feng J, Ferre R et al (2013) Insights into the aberrant activity of mutant EGFR
kinase domain and drug recognition. Structure 21:209–219. https://doi.org/10.1016/j.str.2012.
11.014
67. Doebele RC, Oton AB, Peled N et al (2010) New strategies to overcome limitations of
reversible EGFR tyrosine kinase inhibitor therapy in non-small cell lung cancer. Lung Cancer
69:1–12. https://doi.org/10.1016/j.lungcan.2009.12.009
68. Zhou W, Ercan D, Chen L et al (2009) Novel mutant-selective EGFR kinase inhibitors against
EGFR T790M. Nature 462:1070–1074. https://doi.org/10.1038/nature08622
69. Kwak EL, Sordella R, Bell DW et al (2005) Irreversible inhibitors of the EGF receptor may
circumvent acquired resistance to gefitinib. Proc Natl Acad Sci U S A 102:7665–7670. https://
doi.org/10.1073/pnas.0502860102
70. Liu Q, Sabnis Y, Zhao Z et al (2013) Developing irreversible inhibitors of the protein kinase
cysteinome. Chem Biol 20:146–159. https://doi.org/10.1016/j.chembiol.2012.12.006
71. Mah R, Thomas JR, Shafer CM (2014) Drug discovery considerations in the development of
covalent inhibitors. Bioorg Med Chem Lett 24:33–39
72. Singh J, Petter RC, Baillie TA, Whitty A (2011) The resurgence of covalent drugs. Nat Rev
Drug Discov 10:307–317. https://doi.org/10.1038/nrd3410
73. Barf T, Kaptein A (2012) Irreversible protein kinase inhibitors: balancing the benefits and
risks. J Med Chem 55:6243–6262. https://doi.org/10.1021/jm3003203
74. Kalgutkar AS, Dalvie DK (2012) Drug discovery for a new generation of covalent drugs.
Expert Opin Drug Discovery 7:561–581. https://doi.org/10.1517/17460441.2012.688744
75. Levitzki A (2013) Tyrosine kinase inhibitors: views of selectivity, sensitivity, and clinical
performance. Annu Rev Pharmacol Toxicol 53:161–185. https://doi.org/10.1146/annurevpharmtox-011112-140341
76. Singh J, Dobrusin EM, Fry DW et al (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
77. Fry DW, Bridges AJ, Denny WA et al (1998) Specific, irreversible inactivation of the
epidermal growth factor receptor and erbB2, by a new class of tyrosine kinase inhibitor.
Proc Natl Acad Sci U S A 95:12022–12027. https://doi.org/10.1073/pnas.95.20.12022
78. Smaill JB, Palmer BD, Rewcastle GW et al (1999) 4-(Phenylamino)pyrido[d]pyrimidine
acrylamides as irreversible inhibitors of the ATP binding site of the epidermal growth factor
receptor. J Med Chem 42:1803–1815
79. Smaill JB, Rewcastle GW, Loo JA et al (2000) Tyrosine kinase inhibitors. 17. Irreversible
inhibitors of the epidermal growth factor receptor: 4-(phenylamino)quinazoline- and 4(phenylamino)pyrido[3,2-d]pyrimidine-6-acrylamides bearing additional solubilizing functions. J Med Chem 43:1380–1397. https://doi.org/10.1021/jm990482t
80. Williams R (2008) Discontinued drugs in 2006: oncology drugs. Expert Opin Investig Drugs
17:269–283. https://doi.org/10.1517/13543784.17.3.269
81. Tsou HR, Mamuya N, Johnson BD et al (2001) 6-Substituted-4-(3-bromophenylamino)
quinazolines as putative irreversible inhibitors of the epidermal growth factor receptor
(EGFR) and human epidermal growth factor receptor (HER-2) tyrosine kinases with enhanced
antitumour activity. J Med Chem 44:2719–2734. https://doi.org/10.1021/jm0005555
196
L. M. Lima et al.