72. Dillon LM, Miller TW (2014) Therapeutic targeting of cancers with loss of PTEN function.
Curr Drug Targets 15(1):65–79
73. Greenwell IB, Ip A, Cohen JB (2017) PI3K inhibitors: understanding toxicity mechanisms and
management. Oncology (Williston Park) 31(11):821–828
74. Williams RL (2011) Structure of lipid kinase p110b/p85b elucidates an unusual SH2-domainmediated inhibitory mechanism. Mol Cell 41:567–578
75. Metz A, Ciglia E, Gohlke H (2012) Modulating protein-protein interactions: from structural
determinants of binding to Druggability prediction to application. Curr Pharm Des
18:4630–4647
76. Vlahos CJ, Matter WF, Hui KY, Brown RF (1994) A specific inhibitor of phosphatidylinositol
3 kinase, 2-(4-Morpholinyl)-8-phenyl-4H-l-benzopyran-4-one (LY294002). J Biol Chem 269
(7):5241–5248
77. Certal V, Halley F, Virone-Oddos A et al (2012) Discovery and optimization of new benzimidazole- and benzoxazole-pyrimidone selective PI3Kβ inhibitors for the treatment of phosphatase and TENsin homologue (PTEN)-deficient cancers. J Med Chem 55:4788–4805
78. Knight ZA, Williams RL, Shokat KM (2006) A pharmacological map of the PI3-K family
defines a role for p110α in insulin signaling. Cell 125(4):733–747
79. Certal V, Carry JC, Frank Halley F et al (2014) Discovery and optimization of pyrimidone
indoline amide PI3Kβ inhibitors for the treatment of phosphatase and Tensin homologue
(PTEN)-deficient cancers. J Med Chem 57:903–992
80. Somoza JR et al (2015) Structural, biochemical, and biophysical characterization of Idelalisib
binding to Phosphoinositide 3-kinase δ. JBC 290(13):8439–8446
81. Robinson DD. WaterMap – theory and practical applications. http://content.schrodinger.com/
Training+Material/WM/Hsp90/WaterMap-orig.pdf
82. Wang L, Berne BJ, Friesner RA (2011) Ligand binding to protein-binding pockets with wet and
dry regions. PNAS 108(4):1326–1330
83. Robinson D, Bertrand T, Carry JC et al (2016) Differential water thermodynamics determine
PI3K-Beta/Delta selectivity for solvent-exposed ligand modifications. J Chem Inf Model
56:886–894
84. Demers B et al (2018) First-in-human trial of the PI3Kβ-selective inhibitor SAR260301 in
patients with advanced solid tumors. Cancer 124(2):315–324
85. Wu P, Clausen MH, Nielsen TE (2015) Allosteric small-molecule kinase inhibitors. Pharmacol
Ther 156:59–68
86. Cowan-Jacob SW, Jahnke W, Knapp S (2014) Novel approaches for targeting kinases: allosteric inhibition, allosteric activation and pseudokinases. Future Med Chem 6(5):541–561
87. Cheng Y et al (2012) MK-2206, a novel allosteric inhibitor of Akt, synergizes with gefitinib
against malignant glioma via modulating both autophagy and apoptosis. Mol Cancer Ther 11
(1):154–164
88. Simard JR, Rauh R (2014) FLiK: a direct-binding assay for the identification and kinetic
characterization of stabilizers of inactive kinase conformations. Methods Enzymol
548:147–171
89. Leis S, Schneider S, Zacharias M (2010) In Silico prediction of binding sites on proteins. Curr
Med Chem 17:1550–1562
Achieving High Levels of Selectivity for Kinase Inhibitors
123
Curr Drug Targets 15(1):65–79
73. Greenwell IB, Ip A, Cohen JB (2017) PI3K inhibitors: understanding toxicity mechanisms and
management. Oncology (Williston Park) 31(11):821–828
74. Williams RL (2011) Structure of lipid kinase p110b/p85b elucidates an unusual SH2-domainmediated inhibitory mechanism. Mol Cell 41:567–578
75. Metz A, Ciglia E, Gohlke H (2012) Modulating protein-protein interactions: from structural
determinants of binding to Druggability prediction to application. Curr Pharm Des
18:4630–4647
76. Vlahos CJ, Matter WF, Hui KY, Brown RF (1994) A specific inhibitor of phosphatidylinositol
3 kinase, 2-(4-Morpholinyl)-8-phenyl-4H-l-benzopyran-4-one (LY294002). J Biol Chem 269
(7):5241–5248
77. Certal V, Halley F, Virone-Oddos A et al (2012) Discovery and optimization of new benzimidazole- and benzoxazole-pyrimidone selective PI3Kβ inhibitors for the treatment of phosphatase and TENsin homologue (PTEN)-deficient cancers. J Med Chem 55:4788–4805
78. Knight ZA, Williams RL, Shokat KM (2006) A pharmacological map of the PI3-K family
defines a role for p110α in insulin signaling. Cell 125(4):733–747
79. Certal V, Carry JC, Frank Halley F et al (2014) Discovery and optimization of pyrimidone
indoline amide PI3Kβ inhibitors for the treatment of phosphatase and Tensin homologue
(PTEN)-deficient cancers. J Med Chem 57:903–992
80. Somoza JR et al (2015) Structural, biochemical, and biophysical characterization of Idelalisib
binding to Phosphoinositide 3-kinase δ. JBC 290(13):8439–8446
81. Robinson DD. WaterMap – theory and practical applications. http://content.schrodinger.com/
Training+Material/WM/Hsp90/WaterMap-orig.pdf
82. Wang L, Berne BJ, Friesner RA (2011) Ligand binding to protein-binding pockets with wet and
dry regions. PNAS 108(4):1326–1330
83. Robinson D, Bertrand T, Carry JC et al (2016) Differential water thermodynamics determine
PI3K-Beta/Delta selectivity for solvent-exposed ligand modifications. J Chem Inf Model
56:886–894
84. Demers B et al (2018) First-in-human trial of the PI3Kβ-selective inhibitor SAR260301 in
patients with advanced solid tumors. Cancer 124(2):315–324
85. Wu P, Clausen MH, Nielsen TE (2015) Allosteric small-molecule kinase inhibitors. Pharmacol
Ther 156:59–68
86. Cowan-Jacob SW, Jahnke W, Knapp S (2014) Novel approaches for targeting kinases: allosteric inhibition, allosteric activation and pseudokinases. Future Med Chem 6(5):541–561
87. Cheng Y et al (2012) MK-2206, a novel allosteric inhibitor of Akt, synergizes with gefitinib
against malignant glioma via modulating both autophagy and apoptosis. Mol Cancer Ther 11
(1):154–164
88. Simard JR, Rauh R (2014) FLiK: a direct-binding assay for the identification and kinetic
characterization of stabilizers of inactive kinase conformations. Methods Enzymol
548:147–171
89. Leis S, Schneider S, Zacharias M (2010) In Silico prediction of binding sites on proteins. Curr
Med Chem 17:1550–1562
Achieving High Levels of Selectivity for Kinase Inhibitors
123