82. Carmi C, Lodola A, Rivara S et al (2011) Epidermal growth factor receptor irreversible
inhibitors: chemical exploration of the cysteine-trap portion. Mini Rev Med Chem
11:1019–1030. https://doi.org/10.2174/138955711797247725
83. Weinstein IB, Joe AK (2006) Mechanisms of disease: oncogene addiction – a rationale for
molecular targeting in cancer therapy. Nat Clin Pract Oncol 3:448–457. https://doi.org/10.
1038/ncponc0558
84. Li D, Ambrogio L, Shimamura T et al (2008) BIBW2992, an irreversible EGFR/HER2
inhibitor highly effective in preclinical lung cancer models. Oncogene 27:4702–4711.
https://doi.org/10.1038/onc.2008.109
85. Eskens FALM, Mom CH, Planting AST et al (2008) A phase I dose escalation study of BIBW
2992, an irreversible dual inhibitor of epidermal growth factor receptor 1 (EGFR) and
2 (HER2) tyrosine kinase in a 2-week on, 2-week off schedule in patients with advanced
solid tumours. Br J Cancer 98:80–85. https://doi.org/10.1038/sj.bjc.6604108
86. Fiala O, Pesek M, Finek J et al (2013) Skin rash as useful marker of erlotinib efficacy in
NSCLC and its impact on clinical practice. Neoplasma 60:26–32. https://doi.org/10.4149/neo_
2013_004
87. Giordano P, Manzo A, Montanino A et al (2016) Afatinib: an overview of its clinical
development in non-small-cell lung cancer and other tumours. Crit Rev Oncol Hematol
97:143–151
88. Solca F, Dahl G, Zoephel A et al (2012) Target binding properties and cellular activity of
afatinib (BIBW 2992), an irreversible ErbB family blocker. J Pharmacol Exp Ther
343:342–350. https://doi.org/10.1124/jpet.112.197756
89. Miller VA, Hirsh V, Cadranel J et al (2012) Afatinib versus placebo for patients with
advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both,
and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet
Oncol 13:528–538. https://doi.org/10.1016/S1470-2045(12)70087-6
90. Sanderson K (2013) Irreversible kinase inhibitors gain traction. Nat Rev Drug Discov
12:649–651. https://doi.org/10.1038/nrd4103
91. Cross DAE, Ashton SE, Ghiorghiu S et al (2014) AZD9291, an irreversible EGFR TKI,
overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov
4:1046–1061. https://doi.org/10.1158/2159-8290.CD-14-0337
92. Smit EF, Baas P (2015) Lung cancer in 2015: bypassing checkpoints, overcoming resistance,
and honing in on new targets. Nat Rev Clin Oncol 13:75–76. https://doi.org/10.1038/
nrclinonc.2015.223
93. Thress KS, Paweletz CP, Felip E et al (2015) Acquired EGFR C797S mutation mediates
resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat Med
21:560–562. https://doi.org/10.1038/nm.3854
94. Hanan EJ, Eigenbrot C, Bryan MC et al (2014) Discovery of selective and non-covalent
diaminopyrimidine based inhibitors of EGFR containing the T790M resistance mutation.
J Med Chem 57:10176. https://doi.org/10.1021/jm501578n
95. Heald R, Bowman KK, Bryan MC et al (2015) Noncovalent mutant selective epidermal
growth factor receptor inhibitors: a lead optimization case study. J Med Chem
58:8877–8895. https://doi.org/10.1021/acs.jmedchem.5b01412
96. Jia Y, Yun C-H, Park E et al (2016) Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors. Nature 534:129–132. https://doi.org/10.1038/
nature17960
97. Holmes K, Roberts OL, Thomas AM, Cross MJ (2007) Vascular endothelial growth factor
receptor-2: structure, function, intracellular signalling and therapeutic inhibition. Cell Signal
19:2003–2012. https://doi.org/10.1016/j.cellsig.2007.05.013
98. Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med
9:669–676. https://doi.org/10.1038/nm0603-669
Case Study on Receptor Tyrosine Kinases EGFR, VEGFR, and PDGFR
197
inhibitors: chemical exploration of the cysteine-trap portion. Mini Rev Med Chem
11:1019–1030. https://doi.org/10.2174/138955711797247725
83. Weinstein IB, Joe AK (2006) Mechanisms of disease: oncogene addiction – a rationale for
molecular targeting in cancer therapy. Nat Clin Pract Oncol 3:448–457. https://doi.org/10.
1038/ncponc0558
84. Li D, Ambrogio L, Shimamura T et al (2008) BIBW2992, an irreversible EGFR/HER2
inhibitor highly effective in preclinical lung cancer models. Oncogene 27:4702–4711.
https://doi.org/10.1038/onc.2008.109
85. Eskens FALM, Mom CH, Planting AST et al (2008) A phase I dose escalation study of BIBW
2992, an irreversible dual inhibitor of epidermal growth factor receptor 1 (EGFR) and
2 (HER2) tyrosine kinase in a 2-week on, 2-week off schedule in patients with advanced
solid tumours. Br J Cancer 98:80–85. https://doi.org/10.1038/sj.bjc.6604108
86. Fiala O, Pesek M, Finek J et al (2013) Skin rash as useful marker of erlotinib efficacy in
NSCLC and its impact on clinical practice. Neoplasma 60:26–32. https://doi.org/10.4149/neo_
2013_004
87. Giordano P, Manzo A, Montanino A et al (2016) Afatinib: an overview of its clinical
development in non-small-cell lung cancer and other tumours. Crit Rev Oncol Hematol
97:143–151
88. Solca F, Dahl G, Zoephel A et al (2012) Target binding properties and cellular activity of
afatinib (BIBW 2992), an irreversible ErbB family blocker. J Pharmacol Exp Ther
343:342–350. https://doi.org/10.1124/jpet.112.197756
89. Miller VA, Hirsh V, Cadranel J et al (2012) Afatinib versus placebo for patients with
advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both,
and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet
Oncol 13:528–538. https://doi.org/10.1016/S1470-2045(12)70087-6
90. Sanderson K (2013) Irreversible kinase inhibitors gain traction. Nat Rev Drug Discov
12:649–651. https://doi.org/10.1038/nrd4103
91. Cross DAE, Ashton SE, Ghiorghiu S et al (2014) AZD9291, an irreversible EGFR TKI,
overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov
4:1046–1061. https://doi.org/10.1158/2159-8290.CD-14-0337
92. Smit EF, Baas P (2015) Lung cancer in 2015: bypassing checkpoints, overcoming resistance,
and honing in on new targets. Nat Rev Clin Oncol 13:75–76. https://doi.org/10.1038/
nrclinonc.2015.223
93. Thress KS, Paweletz CP, Felip E et al (2015) Acquired EGFR C797S mutation mediates
resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat Med
21:560–562. https://doi.org/10.1038/nm.3854
94. Hanan EJ, Eigenbrot C, Bryan MC et al (2014) Discovery of selective and non-covalent
diaminopyrimidine based inhibitors of EGFR containing the T790M resistance mutation.
J Med Chem 57:10176. https://doi.org/10.1021/jm501578n
95. Heald R, Bowman KK, Bryan MC et al (2015) Noncovalent mutant selective epidermal
growth factor receptor inhibitors: a lead optimization case study. J Med Chem
58:8877–8895. https://doi.org/10.1021/acs.jmedchem.5b01412
96. Jia Y, Yun C-H, Park E et al (2016) Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors. Nature 534:129–132. https://doi.org/10.1038/
nature17960
97. Holmes K, Roberts OL, Thomas AM, Cross MJ (2007) Vascular endothelial growth factor
receptor-2: structure, function, intracellular signalling and therapeutic inhibition. Cell Signal
19:2003–2012. https://doi.org/10.1016/j.cellsig.2007.05.013
98. Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med
9:669–676. https://doi.org/10.1038/nm0603-669
Case Study on Receptor Tyrosine Kinases EGFR, VEGFR, and PDGFR
197