Top Med Chem (2021) 36: 95–124
https://doi.org/10.1007/7355_2020_99
© Springer Nature Switzerland AG 2020
Published online: 26 June 2020
Achieving High Levels of Selectivity
for Kinase Inhibitors
Laurent Schio and Herve Minoux
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
2 Discovery of an Exquisite Selective Aurora Inhibitor as Neo-Cytotoxic Agent . . . . . . . . . . . 99
3 Development of a Selective MET Kinase Inhibitor Active Against Oncogenic
Mutants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
4 Design of Specific VPS34 Inhibitors for Autophagy Blockade in Tumors . . . . . . . . . . . . . . . . 109
5 PI3Kβ Inhibitor: Leveraging Water Molecules in the Active Site for Selectivity
Enhancement . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . .. . . . . . . . . . . 111
6 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
Abstract Kinase inhibitors have emerged over the last two decades as one of the
most prolific therapeutic classes of agents to reach clinical trials and to obtain
marketing approval, mainly for oncology. We describe here the methodologies
that we performed for hit and lead finding in the context of four internal projects
to identify selective inhibitors for development or preclinical pharmacological
evaluation.
Keywords Kinase inhibitors, Ligands, Oncology, Protein conformations,
Selectivity, Targeted therapy
L. Schio (*) and H. Minoux
Integrated Drug Discovery, Sanofi, Vitry-sur-Seine, France
e-mail: Laurent.Schio@sanofi.com
https://doi.org/10.1007/7355_2020_99
© Springer Nature Switzerland AG 2020
Published online: 26 June 2020
Achieving High Levels of Selectivity
for Kinase Inhibitors
Laurent Schio and Herve Minoux
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
2 Discovery of an Exquisite Selective Aurora Inhibitor as Neo-Cytotoxic Agent . . . . . . . . . . . 99
3 Development of a Selective MET Kinase Inhibitor Active Against Oncogenic
Mutants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
4 Design of Specific VPS34 Inhibitors for Autophagy Blockade in Tumors . . . . . . . . . . . . . . . . 109
5 PI3Kβ Inhibitor: Leveraging Water Molecules in the Active Site for Selectivity
Enhancement . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . .. . . . . . . . . . . 111
6 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
Abstract Kinase inhibitors have emerged over the last two decades as one of the
most prolific therapeutic classes of agents to reach clinical trials and to obtain
marketing approval, mainly for oncology. We describe here the methodologies
that we performed for hit and lead finding in the context of four internal projects
to identify selective inhibitors for development or preclinical pharmacological
evaluation.
Keywords Kinase inhibitors, Ligands, Oncology, Protein conformations,
Selectivity, Targeted therapy
L. Schio (*) and H. Minoux
Integrated Drug Discovery, Sanofi, Vitry-sur-Seine, France
e-mail: Laurent.Schio@sanofi.com