Top Med Chem (2021) 36: 155–202
https://doi.org/10.1007/7355_2020_95
© Springer Nature Switzerland AG 2020
Published online: 23 June 2020
Case Study on Receptor Tyrosine Kinases
EGFR, VEGFR, and PDGFR
Lídia Moreira Lima, Maria Letícia de Castro Barbosa,
Daniel Nascimento do Amaral, and Eliezer J. Barreiro
Contents
1 Receptor Tyrosine Kinases and Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
2 Epidermal Growth Factor Receptor (EGFR) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
2.1 FDA-Approved EGFR Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
2.2 Development of 4-Anilinoquinazolines as EGFR Inhibitors . . . . .. . . . . . . . . . . . . . . . . . . . . . 159
2.3 EGFR Inhibitors for Non-small Cell Lung Cancer (NSCLC) Treatment . . . . . . . . . . . . . . 166
2.4 Second-Generation EGFRi and the Strategy to Circumvent Resistance Development
Mediated by EGFR T790M Mutation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
3 Vascular Endothelial Growth Factor Receptors (VEGFRs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
3.1 VEGF and Angiogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172
3.2 VEGFR-2 Structural Characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
3.3 VEGFR Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
3.4 Lenvatinib Story Case . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . 177
4 Platelet-Derived Growth Factor Receptor (PDGFR) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182
4.1 PDGFR and Tumorigenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
4.2 PDGFR Role in Several Tumor Types . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
4.3 PDGFR Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
5 Epilogue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192
Abstract Receptor tyrosine kinases (RTKs) are cell-surface proteins that trigger
key cellular responses, such as survival, proliferation, differentiation, migration, and
cell-cycle control. As increased activity, abundance, and/or cellular distribution of
wild-type and mutant forms of RTKs is often associated with tumor establishment,
growth, and progression, several drugs directed to clinically relevant RTKs have
entered the pharmaceutical market since the beginning of the twenty-first century,
representing innovative approaches for cancer treatment. The modulation strategies
include small-molecule tyrosine kinase inhibitors (TKIs), targeting the ATP-binding
L. M. Lima, M. L. de Castro Barbosa, D. N. do Amaral, and E. J. Barreiro (*)
Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos (INCT-INOFAR),
Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio®), Universidade
Federal do Rio de Janeiro, Rio de Janeiro, Brazil
e-mail: ejbarreiro@ccsdecania.ufrj.br
https://doi.org/10.1007/7355_2020_95
© Springer Nature Switzerland AG 2020
Published online: 23 June 2020
Case Study on Receptor Tyrosine Kinases
EGFR, VEGFR, and PDGFR
Lídia Moreira Lima, Maria Letícia de Castro Barbosa,
Daniel Nascimento do Amaral, and Eliezer J. Barreiro
Contents
1 Receptor Tyrosine Kinases and Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
2 Epidermal Growth Factor Receptor (EGFR) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
2.1 FDA-Approved EGFR Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
2.2 Development of 4-Anilinoquinazolines as EGFR Inhibitors . . . . .. . . . . . . . . . . . . . . . . . . . . . 159
2.3 EGFR Inhibitors for Non-small Cell Lung Cancer (NSCLC) Treatment . . . . . . . . . . . . . . 166
2.4 Second-Generation EGFRi and the Strategy to Circumvent Resistance Development
Mediated by EGFR T790M Mutation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
3 Vascular Endothelial Growth Factor Receptors (VEGFRs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
3.1 VEGF and Angiogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172
3.2 VEGFR-2 Structural Characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
3.3 VEGFR Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
3.4 Lenvatinib Story Case . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . 177
4 Platelet-Derived Growth Factor Receptor (PDGFR) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182
4.1 PDGFR and Tumorigenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
4.2 PDGFR Role in Several Tumor Types . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
4.3 PDGFR Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
5 Epilogue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192
Abstract Receptor tyrosine kinases (RTKs) are cell-surface proteins that trigger
key cellular responses, such as survival, proliferation, differentiation, migration, and
cell-cycle control. As increased activity, abundance, and/or cellular distribution of
wild-type and mutant forms of RTKs is often associated with tumor establishment,
growth, and progression, several drugs directed to clinically relevant RTKs have
entered the pharmaceutical market since the beginning of the twenty-first century,
representing innovative approaches for cancer treatment. The modulation strategies
include small-molecule tyrosine kinase inhibitors (TKIs), targeting the ATP-binding
L. M. Lima, M. L. de Castro Barbosa, D. N. do Amaral, and E. J. Barreiro (*)
Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos (INCT-INOFAR),
Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio®), Universidade
Federal do Rio de Janeiro, Rio de Janeiro, Brazil
e-mail: ejbarreiro@ccsdecania.ufrj.br