Successive Statistical and Structure-Based Modeling to Identify Chemically Novel Kinase Inhibitors

Journal of Chemical Information and Modeling, vol. 60, pp. 4283–4295

Abstract

High Resolution Image Download MS PowerPoint Slide Kinases are frequently studied in the context of anticancer drugs. Their involvement in cell responses, such as proliferation, differentiation, and apoptosis, makes them interesting subjects in multitarget drug design. In this study, a workflow is presented that models the bioactivity spectra for two panels of kinases: (1) inhibition of RET, BRAF, SRC, and S6K, while avoiding inhibition of MKNK1, TTK, ERK8, PDK1, and PAK3, and (2) inhibition of AURKA, PAK1, FGFR1, and LKB1, while avoiding inhibition of PAK3, TAK1, and PIK3CA. Both statistical and structure-based models were included, which were thoroughly benchmarked and optimized. A virtual screening was performed to test the workflow for one of the main targets, RET kinase. This resulted in 5 novel and chemically dissimilar RET inhibitors with remaining RET activity of <60% (at a concentration of 10 μM) and similarities with known RET inhibitors from 0.18 to 0.29 (Tanimoto, ECFP6). The four more potent inhibitors were assessed in a concentration range and proved to be modestly active with a pIC 50 value of 5.1 for the most active compound. The experimental validation of inhibitors for RET strongly indicates that the multitarget workflow is able to detect novel inhibitors for kinases, and hence, this workflow can potentially be applied in polypharmacology modeling. We conclude that this approach can identify new chemical matter for existing targets. Moreover, this workflow can easily be applied to other targets as well.

Authors 11

1. Lindsey Burggraaff Aachen Division of Drug Discovery and Safety Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Division of Drug Discovery & Safety, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands

2. Eelke Bart Lenselink Aachen Division of Drug Discovery and Safety Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Division of Drug Discovery & Safety, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands

3. Willem Jespers Aachen Division of Drug Discovery and Safety Leiden Academic Centre for Drug Research

   Leiden University · Uppsala University

   Affiliation as printed

   Department of Cell and Molecular Biology, Uppsala University, Uppsala 75124, Sweden

   Division of Drug Discovery & Safety, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands

4. Jesper E. van Engelen Aachen Department of Computer Science Leiden Institute of Advanced Computer Science

   Leiden University

   Affiliation as printed

   Department of Computer Science, Leiden Institute of Advanced Computer Science, Leiden University, Niels Bohrweg 1, 2333 CA, Leiden, The Netherlands

5. Brandon J. Bongers Aachen Division of Drug Discovery and Safety Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Division of Drug Discovery & Safety, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands

6. Marina Gorostiola González Aachen Division of Drug Discovery and Safety Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Division of Drug Discovery & Safety, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands

7. Rongfang Liu Aachen Division of Drug Discovery and Safety Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Division of Drug Discovery & Safety, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands

8. Holger H. Hoos Aachen Department of Computer Science Leiden Institute of Advanced Computer Science

   Leiden University

   Affiliation as printed

   Department of Computer Science, Leiden Institute of Advanced Computer Science, Leiden University, Niels Bohrweg 1, 2333 CA, Leiden, The Netherlands

9. Herman van Vlijmen Aachen Division of Drug Discovery and Safety Leiden Academic Centre for Drug Research

   Leiden University · Janssen (Belgium)

   Affiliation as printed

   Division of Drug Discovery & Safety, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands

   Janssen Research & Development, Turnhoutseweg 30, 2340 Beerse, Belgium

10. Adriaan P. IJzerman Aachen Division of Drug Discovery and Safety Leiden Academic Centre for Drug Research

    Leiden University

    Affiliation as printed

    Division of Drug Discovery & Safety, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands

11. Gerard J. P. van Westen corresponding Aachen Division of Drug Discovery and Safety Leiden Academic Centre for Drug Research

    Leiden University

    Affiliation as printed

    Division of Drug Discovery & Safety, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands