91. Fischer S et al (2013) Dibenzosuberones as p38 mitogen-activated protein kinase
inhibitors with low ATP competitiveness and outstanding whole blood activity. J Med
Chem 56(1):241–253
92. Martz KE et al (2012) Targeting the hinge glycine flip and the activation loop: novel
approach to potent p38alpha inhibitors. J Med Chem 55(17):7862–7874
93. Schindler T et al (2000) Structural mechanism for STI-571 inhibition of abelson tyrosine
kinase. Science 289(5486):1938–1942
94. Mol CD et al (2004) Structural basis for the autoinhibition and STI-571 inhibition of c-Kit
tyrosine kinase. J Biol Chem 279(30):31655–31663
95. Karaman MW et al (2008) A quantitative analysis of kinase inhibitor selectivity.
Nat Biotechnol 26(1):127–132
96. Goldstein DM, Gray NS, Zarrinkar PP (2008) High-throughput kinase profiling as a platform
for drug discovery. Nat Rev Drug Discov 7(5):391–397
97. Zhao Z et al (2014) Exploration of type II binding mode: a privileged approach for
kinase inhibitor focused drug discovery? ACS Chem Biol 9(6):1230–1241
98. Alexander LT et al (2015) Type II inhibitors targeting CDK2. ACS Chem Biol
10(9):2116–2125
99. Georgi V et al (2018) Binding kinetics survey of the drugged Kinome. J Am Chem Soc
140(46):15774–15782
100. Heroven C et al (2018) Halogen-aromatic pi interactions modulate inhibitor residence times.
Angew Chem Int Ed Engl 57(24):7220–7224
101. Liu Y, Gray NS (2006) Rational design of inhibitors that bind to inactive kinase
conformations. Nat Chem Biol 2(7):358–364
102. Zuccotto F et al (2010) Through the “gatekeeper door”: exploiting the active kinase
conformation. J Med Chem 53(7):2681–2694
103. Wentsch HK et al (2017) Optimized target residence time: type I1/2 inhibitors for p38alpha
MAP kinase with improved binding kinetics through direct interaction with the R-spine.
Angew Chem Int Ed Engl 56(19):5363–5367
104. Wood ER et al (2004) A unique structure for epidermal growth factor receptor bound
to GW572016 (Lapatinib): relationships among protein conformation, inhibitor off-rate,
and receptor activity in tumor cells. Cancer Res 64(18):6652–6659
105. Axten JM et al (2012) Discovery of 7-methyl-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}2,3-dihydro-1H-indol-5-yl)-7H-p yrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a potent
and selective first-in-class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum
kinase (PERK). J Med Chem 55(16):7193–7207
106. Wang H et al (2010) Structural determinants of PERK inhibitor potency and selectivity.
Chem Biol Drug Des 76(6):480–495
107. Guimaraes CR et al (2011) Understanding the impact of the P-loop conformation on
kinase selectivity. J Chem Inf Model 51(6):1199–1204
108. Chaikuad A et al (2014) A unique inhibitor binding site in ERK1/2 is associated with
slow binding kinetics. Nat Chem Biol 10(10):853–860
109. Buchanan SG et al (2009) SGX523 is an exquisitely selective, ATP-competitive inhibitor
of the MET receptor tyrosine kinase with antitumor activity in vivo. Mol Cancer Ther
8(12):3181–3190
110. Over B et al (2013) Natural-product-derived fragments for fragment-based ligand discovery.
Nat Chem 5(1):21–28
111. Tomita N et al (2013) Structure-based discovery of cellular-active allosteric inhibitors of FAK.
Bioorg Med Chem Lett 23(6):1779–1785
112. Heinrich T et al (2010) Allosteric IGF-1R inhibitors. ACS Med Chem Lett 1(5):199–203
113. Goodwin NC et al (2015) Discovery of a type III inhibitor of LIM kinase 2 that binds
in a DFG-out conformation. ACS Med Chem Lett 6(1):53–57
22
S. Röhm et al.
inhibitors with low ATP competitiveness and outstanding whole blood activity. J Med
Chem 56(1):241–253
92. Martz KE et al (2012) Targeting the hinge glycine flip and the activation loop: novel
approach to potent p38alpha inhibitors. J Med Chem 55(17):7862–7874
93. Schindler T et al (2000) Structural mechanism for STI-571 inhibition of abelson tyrosine
kinase. Science 289(5486):1938–1942
94. Mol CD et al (2004) Structural basis for the autoinhibition and STI-571 inhibition of c-Kit
tyrosine kinase. J Biol Chem 279(30):31655–31663
95. Karaman MW et al (2008) A quantitative analysis of kinase inhibitor selectivity.
Nat Biotechnol 26(1):127–132
96. Goldstein DM, Gray NS, Zarrinkar PP (2008) High-throughput kinase profiling as a platform
for drug discovery. Nat Rev Drug Discov 7(5):391–397
97. Zhao Z et al (2014) Exploration of type II binding mode: a privileged approach for
kinase inhibitor focused drug discovery? ACS Chem Biol 9(6):1230–1241
98. Alexander LT et al (2015) Type II inhibitors targeting CDK2. ACS Chem Biol
10(9):2116–2125
99. Georgi V et al (2018) Binding kinetics survey of the drugged Kinome. J Am Chem Soc
140(46):15774–15782
100. Heroven C et al (2018) Halogen-aromatic pi interactions modulate inhibitor residence times.
Angew Chem Int Ed Engl 57(24):7220–7224
101. Liu Y, Gray NS (2006) Rational design of inhibitors that bind to inactive kinase
conformations. Nat Chem Biol 2(7):358–364
102. Zuccotto F et al (2010) Through the “gatekeeper door”: exploiting the active kinase
conformation. J Med Chem 53(7):2681–2694
103. Wentsch HK et al (2017) Optimized target residence time: type I1/2 inhibitors for p38alpha
MAP kinase with improved binding kinetics through direct interaction with the R-spine.
Angew Chem Int Ed Engl 56(19):5363–5367
104. Wood ER et al (2004) A unique structure for epidermal growth factor receptor bound
to GW572016 (Lapatinib): relationships among protein conformation, inhibitor off-rate,
and receptor activity in tumor cells. Cancer Res 64(18):6652–6659
105. Axten JM et al (2012) Discovery of 7-methyl-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}2,3-dihydro-1H-indol-5-yl)-7H-p yrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a potent
and selective first-in-class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum
kinase (PERK). J Med Chem 55(16):7193–7207
106. Wang H et al (2010) Structural determinants of PERK inhibitor potency and selectivity.
Chem Biol Drug Des 76(6):480–495
107. Guimaraes CR et al (2011) Understanding the impact of the P-loop conformation on
kinase selectivity. J Chem Inf Model 51(6):1199–1204
108. Chaikuad A et al (2014) A unique inhibitor binding site in ERK1/2 is associated with
slow binding kinetics. Nat Chem Biol 10(10):853–860
109. Buchanan SG et al (2009) SGX523 is an exquisitely selective, ATP-competitive inhibitor
of the MET receptor tyrosine kinase with antitumor activity in vivo. Mol Cancer Ther
8(12):3181–3190
110. Over B et al (2013) Natural-product-derived fragments for fragment-based ligand discovery.
Nat Chem 5(1):21–28
111. Tomita N et al (2013) Structure-based discovery of cellular-active allosteric inhibitors of FAK.
Bioorg Med Chem Lett 23(6):1779–1785
112. Heinrich T et al (2010) Allosteric IGF-1R inhibitors. ACS Med Chem Lett 1(5):199–203
113. Goodwin NC et al (2015) Discovery of a type III inhibitor of LIM kinase 2 that binds
in a DFG-out conformation. ACS Med Chem Lett 6(1):53–57
22
S. Röhm et al.