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Molecules 2018, 23(4), 908; https://doi.org/10.3390/molecules23040908

PKIDB: A Curated, Annotated and Updated Database of Protein Kinase Inhibitors in Clinical Trials

1
Institut de Chimie Organique et Analytique (ICOA), UMR CNRS-Université d’Orléans 7311, Université d’Orléans BP 6759, 45067 Orléans CEDEX 2, France
2
Janssen-Cilag, Centre de Recherche Pharma, CS10615-Chaussée du Vexin, 27106 Val-de-Reuil, France
*
Author to whom correspondence should be addressed.
Academic Editors: Pierre Koch and Stefan Laufer
Received: 14 February 2018 / Revised: 5 April 2018 / Accepted: 12 April 2018 / Published: 15 April 2018
(This article belongs to the Special Issue Kinase Inhibitors)
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Abstract

The number of protein kinase inhibitors (PKIs) approved worldwide continues to grow steadily, with 39 drugs approved in the period between 2001 and January 2018. PKIs on the market have been the subject of many reviews, and structure-property relationships specific to this class of drugs have been inferred. However, the large number of PKIs under development is often overlooked. In this paper, we present PKIDB (Protein Kinase Inhibitor Database), a monthly-updated database gathering approved PKIs as well as PKIs currently in clinical trials. The database compiles currently 180 inhibitors ranging from phase 0 to 4 clinical trials along with annotations extracted from seven public resources. The distribution and property ranges of standard physicochemical properties are presented. They can be used as filters to better prioritize compound selection for future screening campaigns. Interestingly, more than one-third of the kinase inhibitors violate at least one Lipinski’s rule. A Principal Component Analysis (PCA) reveals that Type-II inhibitors are mapped to a distinct chemical space as compared to orally administrated drugs as well as to other types of kinase inhibitors. Using a Principal Moment of Inertia (PMI) analysis, we show that PKIs under development tend to explore new shape territories as compared to approved PKIs. In order to facilitate the analysis of the protein space, the kinome tree has been annotated with all protein kinases being targeted by PKIs. Finally, we analyzed the pipeline of the pharmaceutical companies having PKIs on the market or still under development. We hope that this work will assist researchers in the kinase field in identifying and designing the next generation of kinase inhibitors for still untargeted kinases. The PKIDB database is freely accessible from a website at http://www.icoa.fr/pkidb and can be easily browsed through a user-friendly spreadsheet-like interface. View Full-Text
Keywords: protein kinase inhibitors; clinical trials; approved drugs; database; chemometrics analysis; kinome protein kinase inhibitors; clinical trials; approved drugs; database; chemometrics analysis; kinome
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Carles, F.; Bourg, S.; Meyer, C.; Bonnet, P. PKIDB: A Curated, Annotated and Updated Database of Protein Kinase Inhibitors in Clinical Trials. Molecules 2018, 23, 908.

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