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Comparative Assessment of Protein Kinase Inhibitors in Public Databases and in PKIDB

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Comparative Assessment of Protein Kinase Inhibitors in Public Databases and in PKIDB molecules Article Comparative Assessment of Protein Kinase Inhibitors in Public Databases and in PKIDB Colin Bournez 1, Fabrice Carles 1, Gautier Peyrat 1, Samia Aci-Sèche 1 , Stéphane Bourg 1 , Christophe Meyer 2 and Pascal Bonnet 1,* 1 Institut de Chimie Organique et Analytique (ICOA), UMR CNRS-Université d’Orléans 7311, Université d’Orléans BP 6759, 45067 Orléans CEDEX 2, France; [email protected] (C.B.); [email protected] (F.C.); [email protected] (G.P.); [email protected] (S.A.-S.); [email protected] (S.B.) 2 Janssen-Cilag, Centre de Recherche Pharma, CS10615-Chaussée du Vexin, 27106 Val-de-Reuil, France; [email protected] * Correspondence: [email protected]; Tel.: +33-238-417-254 Academic Editor: Christian Peifer Received: 17 June 2020; Accepted: 10 July 2020; Published: 15 July 2020 Abstract: Since the first approval of a protein kinase inhibitor (PKI) by the Food and Drug Administration (FDA) in 2001, 55 new PKIs have reached the market, and many inhibitors are currently being evaluated in clinical trials. This is a clear indication that protein kinases still represent major drug targets for the pharmaceutical industry. In a previous work, we have introduced PKIDB, a publicly available database, gathering PKIs that have already been approved (Phase 4), as well as those currently in clinical trials (Phases 0 to 3). This database is updated frequently, and an analysis of the new data is presented here. In addition, we compared the set of PKIs present in PKIDB with the PKIs in early preclinical studies found in ChEMBL, the largest publicly available chemical database. For each dataset, the distribution of physicochemical descriptors related to drug-likeness is presented. From these results, updated guidelines to prioritize compounds for targeting protein kinases are proposed. The results of a principal component analysis (PCA) show that the PKIDB dataset is fully encompassed within all PKIs found in the public database. This observation is reinforced by a principal moments of inertia (PMI) analysis of all molecules. Interestingly, we notice that PKIs in clinical trials tend to explore new 3D chemical space. While a great majority of PKIs is located on the area of “flatland”, we find few compounds exploring the 3D structural space. Finally, a scaffold diversity analysis of the two datasets, based on frequency counts was performed. The results give insight into the chemical space of PKIs, and can guide researchers to reach out new unexplored areas. PKIDB is freely accessible from the following website: http://www.icoa.fr/pkidb. Keywords: protein kinase inhibitors; clinical trials; approved drugs; database; chemometrics analysis; kinome; molecular scaffolds; rings system 1. Introduction The reversible phosphorylation of proteins plays a preeminent role in cell cycle regulation. 2 This process, which consists in the transfer of a phosphoryl group PO3 − to the target substrate, is catalyzed by enzymes pertaining to the protein kinase family. Protein kinases constitute one of the largest protein families encoded by the human genome and counts 518 members (or 538 members when atypical kinases are included) [1–3]. Numerous studies have shown that deregulation or mutation of kinases is responsible for a variety of cancers [4], as well as for other diseases in the immune or neurological area [5,6]. The majority of protein kinases, however, have not yet been fully explored [7], and there is still a high potential for innovation in targeting the protein kinome for the treatment of cancer. Molecules 2020, 25, 3226; doi:10.3390/molecules25143226 www.mdpi.com/journal/molecules Molecules 2020, 25, x 2 of 17 Molecules 2020, 25, 3226 2 of 17 [7], and there is still a high potential for innovation in targeting the protein kinome for the treatment of cancer. The Food and Drug Administration (FDA) approved 55 small-molecule protein kinase inhibitorsThe Food and(PKIs) Drug by Administration end of 2019, whereas (FDA) approved the Chinese 55 small-molecule and European protein regulatory kinase authorities inhibitors (PKIs)have grantedby end ofmarket 2019, whereasaccess to the five Chinese more andcompounds, European namely regulatory anlotinib, authorities apatinib, have grantedicotinib, marketfasudil access, and tivozanibto five more (Figure compounds, 1). It is worth namely mentioni anlotinib,ng that apatinib, higher icotinib, molecular fasudil, weight and inhibitors tivozanib like (Figure macrocyclic1). It is lactonesworth mentioning, such as sirolimus that higher and molecular temsirolimus weight, or inhibitors kinase-targeted like macrocyclic antibodies lactones,, such as such cetuximab as sirolimus and trastuzumaband temsirolimus,, have orbeen kinase-targeted approved for antibodies,the treatment such of ascolorectal, cetuximab head/neck and trastuzumab,, and breast have cancers been, rapprovedespectively for [8 the–10] treatment. These large of colorectal, molecules head were/neck, excluded and breast from cancers, this study respectively, which [focuses8–10]. These on small large- moleculemolecules PKIs were targeting excluded the from kinase this domain. study, which The first focuses PKI onapproved small-molecule by the FDA PKIs was targeting imatinib the in kinase 2001. Imatinibdomain. Theis a firstsmall PKI-molecule approved type by the-II inhibitor FDA was containing imatinib in 2001.a phenylamino Imatinib is-pyrimidine a small-molecule scaffold. type-II It targetsinhibitor the containing inactive conformation a phenylamino-pyrimidine of ABL1 kinase sca andffold. is used It targets against the chronic inactive myelogenous conformation leukemia of ABL1 (CML)kinase and[11]. is Since used againstthen, at chronic least one myelogenous new PKI leukemiareaches the (CML) market [11]. every Since then,year, at with least a one significant new PKI accelerationreaches the marketsince 2011. every The year, exceptions with a significant to this rule acceleration are 2002, 2008, since 2010 2011., and The 2016 exceptions, with no to thiscompound rule are approved2002, 2008, in 2010, these and years. 2016, with no compound approved in these years. Figure 1. Progression of Food and Drug Administration (FDA)-approved protein kinase inhibitors Figure 1. Progression of Food and Drug Administration (FDA)-approved protein kinase inhibitors (2001–2019) and their type of inhibition [12]. As of 11th December 2019, 55 kinase inhibitors were (2001–2019) and their type of inhibition [12]. As of 11th December 2019, 55 kinase inhibitors were approved by the FDA. Not shown here: tivozanib, approved by European Medicines Agency (EMA) approved by the FDA. Not shown here: tivozanib, approved by European Medicines Agency (EMA) in 2017; anlotinib, apatinib, and icotinib, approved by the China Food and Drug Administration in 2017; anlotinib, apatinib, and icotinib, approved by the China Food and Drug Administration (CFDA) in 2018, 2014, and 2011, respectively; and fasudil, approved in China and in Japan in 1995. (CFDA) in 2018, 2014, and 2011, respectively; and fasudil, approved in China and in Japan in 1995. ND: not defined. ND: not defined. In addition to approved PKIs, many novel compounds are currently being evaluated in clinical trialsIn throughout addition to the approved pharmaceutical PKIs, many industry. novel Taken compounds collectively, are currently these compounds being evaluated show new in clinical trends trialsin terms throughout of structures, the physicochemicalpharmaceutical industry. properties, Taken and biological collectively, activities these that compounds foreshadows show changes new trendsin the PKIin terms landscape. of structures, To collect physicochemical and organize this properties data as well, and as biological keep up toactivities date with that their foreshadows evolution, changeswe developed in the PKIDBPKI landscape. [12], a curated, To collect annotated and organize and updated this data database as well of as PKIs keep in clinicalup to date trials. with In ordertheir evolution,to enter the we PKIDB, developed compounds PKIDB [1 should2], a curated, be currently annotated in one and development updated database phase of (from PKIs Phasein clinical 0 to trials.Phase In 4), order have to a enter disclosed the PKIDB, chemical compounds structure, should as well be ascurrently an International in one development Nonproprietary phase Name(from Phase(INN) 0 [13 to]. Phase Each compound4), have a disclosed is provided chemical with comprehensive structure, as well descriptive as an International data, as well Nonpropri as with linksetary to Nameexternal (INN) databases [13]. Each such compound as ChEMBL is provided [14], PDB with [15], comprehensive PubChem [16], descriptive and others. data The, typeas well of bindingas with linksmode to specified external indatabases PKIDB has such been as ChEMBL manually [1 entered4], PDB and [15 comply], PubChem with [1 Roskoski’s6], and others. classification The type [12 of]. bindingThe database mode is specified freely accessible in PKID onB ahas dedicated been manually website ( http:entered//www.icoa.fr and comply/pkidb with). As Roskoski’s of 11th of classificationDecember 2019, [1 it2 contains]. The 218 database inhibitors: 60is approvedfreely andaccessible 158 in various on stagesa dedicated of clinical trialswebsite (from (http://www.icoa.fr/pkidb). As of 11th of December 2019, it contains 218 inhibitors: 60 approved and Phase 0 to Phase 3). 158 inIn various this study, stages we of comparedclinical trials PKIDB
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