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. 2016 Jul 20;5:Chem Inf Sci-1366. Originally published 2016 Jun 14. [Version 2] doi: 10.12688/f1000research.8950.2

High quality, small molecule-activity datasets for kinase research

Rajan Sharma 1, Stephan C Schürer 2, Steven M Muskal 1,a
PMCID: PMC4943296  PMID: 27429748

Version Changes

Revised. Amendments from Version 1

We have addressed the reviewer’s comments by updating the titles of Figures 1 and 2 and the data presented in Fig 2 is now reported with fractional percents. We also corrected the column names in Table 2, fixed some general typos throughout the article and updated some terminology.

Abstract

Kinases regulate cell growth, movement, and death. Deregulated kinase activity is a frequent cause of disease. The therapeutic potential of kinase inhibitors has led to large amounts of published structure activity relationship (SAR) data. Bioactivity databases such as the Kinase Knowledgebase (KKB), WOMBAT, GOSTAR, and ChEMBL provide researchers with quantitative data characterizing the activity of compounds across many biological assays. The KKB, for example, contains over 1.8M kinase structure-activity data points reported in peer-reviewed journals and patents. In the spirit of fostering methods development and validation worldwide, we have extracted and have made available from the KKB 258K structure activity data points and 76K associated unique chemical structures across eight kinase targets. These data are freely available for download within this data note.

Keywords: Kinase, SAR, Bioactivity Database, Dataset, Drug Discovery, Bioactive Molecules, Kinase Knowledgebase, KKB

Introduction

Since their discovery in 1975 by Cohen et al. 1, kinases are now one of the most established drug target families, second only to G-protein-coupled receptors (GPCRs). Most progress in kinase research has occurred in the last 25 years including the discovery of many new kinases 2, 3, identification of new isoforms of pre-existing kinases 4, 5, elucidation of new biological pathways, and identification of many new kinase-disease associations 6, 7. While kinases are well-validated anti-cancer targets 8– 11, kinase inhibitors also have been pursued in cardiovascular 12, autoimmune 13, inflammatory skin and bowel 14, neurodegenerative 15, and renal disease programs 16. Most small-molecule kinase inhibitors target the ATP binding site of the kinase catalytic domain 11. The ATP binding region of the catalytic domain is highly conserved among protein kinases, which has important consequences for drug development. Achieving selectivity of a small molecule inhibitor against kinase off-targets to avoid adverse reactions can be a major hurdle. However, the cross reactivity of many chemotypes can also open opportunities to focus on other closely related kinases. Despite the high degree of conservation in the ATP binding site, reasonably selective inhibitors with favorable pharmacological properties can be developed 17. It is now common in discovery programs to profile inhibitors against an extensive set of kinase targets 18. These kinase-profiling efforts have generated valuable data, providing insight into selectivity and promiscuity of clinical inhibitors 19– 21.

Medicinal chemists can benefit significantly from well-curated databases documenting chemical structure(s) with an experimentally measured biological activity. These structure and activity databases or SAR databases help to better understand drug-target interaction, which can assist in the design of potent and selective chemical inhibitors 22– 25. A well populated, editable, easy to search and flexible SAR database is an integral part of the modern drug design process 26. SAR databases provide elementary insights to researchers, including:

  • (a)

    Target druggability: known small molecule binders are required to categorize a protein as druggable. High-affinity and non-promiscuous inhibitors are particularly valuable to establish druggability; and can be further validated using structure biology information. In many cases druggability can be inferred for new targets using homology models 27 where similarities can be mapped via sequences, pathways or functions. Examples include the Target Informatics Platform ( TIP) 28 and Modbase 29.

  • (b)

    Scaffold selectivity: the golden principle that applies is “less selective scaffolds have more undesirable side effects.” A prior knowledge of selectivity profiles can help in making informed decisions on which chemotypes to pursue at the start of discovery programs 30. Organizing data by scaffold enables classic SAR analysis in which side-chain moieties can be evaluated and considered or avoided in lead optimization 31.

  • (c)

    Clinical molecules: it can be very helpful to see scaffold(s) or derivatives under the study of launched drugs. This enables medicinal chemists to associate therapeutic classes with active scaffolds.

  • (d)

    Development and validation of computational methods: well-curated datasets are very helpful in the development and refinement of computational methodologies. With a common set of data, computational researchers can also compare and contrast methods, providing additional validation 32.

  • (e)

    Virtual screening: high-quality, well-curated, standardized and annotated datasets are required to build predictive models for virtual screening as we have shown previously specifically for the Kinase Knowledgebase ( KKB) data 33.

Materials and Methods

The KKB is a database of biological activity data, structure-activity relationships, and chemical synthesis data focused on protein kinases. Since its inception in 2001, the KKB has grown steadily with quarterly updates each year. With more than two decades of high quality SAR data, the KKB represents one of the first kinase target specific databases of biological activity and chemical synthesis data from curated scientific literature and patents. The KKB contains a large number of kinase structure-activity data points (>1.8M) reported in peer-reviewed literature covering journals and patents. The data have been curated from over 150 different journals reporting kinase inhibitors with activity data, with leading contributions from J Med Chem, Bioorg Med Chem, Bioorg Med ChemLett and Euro J Med Chem. In addition, the KKB contains data curated from patents/applications from WO, EP and US. The scientific information is curated from the published text using a combination of automatic and manual efforts.

A summary of the first quarter release for year 2016 (Q1-2016) is reported in Table 1. With the Q1-2016 KKB release, there are total of 506 unique kinase targets with over 682K unique small molecules. A listing of few “hot” kinase targets with their inhibitors (data points) is reported in Table 2.

Table 1. Eidogen-Sertanty Kinase Knowledgebase.

Summary Statistics – Q1 2016 Release.

Articles covered: 2,780
Patents and patent applications covered: 6,346
Total Number of Bio-activity data points: 1,775,368
Total Number of unique molecules: 682,289
Total Number of unique molecules w/ assay data: 337,491
Total Number of assay protocols: 32,462
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Table 2. Eidogen-Sertanty Kinase Knowledgebase.

Data Points for Selected Targets– Q1 2016 Release.

Kinase
Classification		 Enzyme Assay Cell-Based Assay
Family Target Name All
SAR
Data
Points		 All
IC50
Data
Points		 Unique
Assay
Molecules		 All
SAR
Data
Points		 All
IC50
Data
Points		 Unique
Assay
Molecules
Non-Receptor
Tyrosine Kinases 		Abl ABL1 14750 4843 2177 4237 1836 1098
Csk CSK 3792 1448 450 548 266 146
Fak FAK/PTK2 10311 4067 3863 2880 1306 1300
JakA JAK3 29550 8778 11456 1327 605 440
Src SRC 21936 8289 4480 3425 1473 747
LCK 23819 10514 6090 784 381 214
FYN 3125 873 151 28 11 7
Syk SYK 39426 17549 16774 1037 484 268
ZAP70 5951 2998 1013 5 2 2
Tec ITK 10131 3690 2197 219 83 113
Receptor
Tyrosine Kinases 		EGFR EGFR 34293 14684 6593 19731 9068 3321
ERBB2 11182 5199 1756 7988 4115 1803
Eph EPHA2 2935 765 223 12 0 1
FGFR FGFR1 19582 8394 4149 8781 3345 1622
InsR INSR 4607 1293 1032 920 422 395
Met MET 27032 10406 9308 5147 2526 1983
PDGFR PDGFRB 14058 5889 2388 5426 2653 983
FLT3/FLK2 13082 3974 2830 10224 4386 2268
KIT 14991 5153 2527 7040 3339 2747
Tie TEK 9142 4306 2300 3122 1561 1360
Trk NTRK1/TRKA 8199 3207 2925 1743 814 563
VEGFR KDR/FLK1 55991 24821 13899 20317 9119 6541
FLT1 9963 4251 1116 864 432 197
CMGC Kinases CDK CDK2 33878 12695 10411 5344 1119 667
CDK5 8227 3048 1714 18 3 3
GSK GSK3B 22950 7766 6992 2013 519 832
MAPK MAPK14 36067 16077 14270 6541 2373 2787
MAPK1 11286 3073 3081 2725 1064 1085
MAPK10 5725 1615 1610 96 48 23
MAPK8 6225 1803 1523 880 285 393
MAPK11 1162 196 100 0 0 0
AGC Kinases AKT AKT1 14601 6333 5794 6970 3064 2831
DMPK ROCK1 9135 2052 3105 189 40 65
PKB PDPK1 9569 3765 2642 148 68 44
PKC PRKCA 10670 3528 2588 5477 669 510
PRKCE 3759 1494 1032 2 1 1
CAMK Kinases CAMKL CHEK1 13724 5192 5202 3140 220 1130
MAPKAPK MAPKAPK2 11041 4073 3747 1311 649 637
MAPKAPK3 2138 518 299 0 0 0
Other Protein
Kinases 		AUR AURKA 22646 7904 7034 1128 474 382
IKK IKBKB 7628 2978 3146 367 83 144
CHUK/IKBKA 2938 999 764 296 148 147
PLK PLK1 9181 3223 3480 2986 1364 888
STE MAP2K1 6340 2551 2045 1651 573 655
TKL ILK 360 180 172 581 253 80
RAF1 11302 5058 3378 1956 885 581
BRAF 26349 12169 8983 6726 2442 2106
Other Non-
Protein Kinases 		Lipid Kinases PIK3/PIK3CG 29925 13438 10899 3525 1758 1217
PIK3CA 36168 16418 12448 3392 1310 1219
Nucleotide
Kinases		 TK1 1106 301 339 2416 533 193
ADK 1924 931 723 669 252 240
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Kinase inhibitors are biologically active small molecules and their activity refers to experimentally measured data on a given kinase target (in enzyme or in cell based assays), using predefined experimental protocols. After curation and standardization, these measured values together with related information are indexed in the KKB. Each inhibitor entered in the KKB carries unique identifiers such as:

  • (a)

    Chemical information and biological information: unique structure IDs (MR_ID) are assigned based on unique canonical SMILES. In addition hand-drawn Cartesian coordinates are captured. Chemical compounds are associated with calculated chemical and physical properties.

  • (b)

    Biological target and assay protocol: biological targets are annotated by EntrezGeneID, UniProt ID, and HUGO approved names. An assay protocol includes detailed information pertaining to the experiments performed to measure the biological activity for the compound. Each protocol has a descriptive title and a unique set of keywords. Assays are categorized by assay format (biochemical, cell-based, etc.) following standards set forth by BioAssay Ontology (BAO) 34, 35. Kinase targets are classified by protein and non-protein kinases and protein kinases by the typical domain-based classification into group, family, etc. We are in the process of mapping KKB targets to the Drug Target Ontology ( DTO), which is in development.

  • (c)

    Experimental bioactivity screening results. A bioactivity data point is a defined result/endpoint of a specified small molecule compound tested in a biological assay. The assay is defined in b); result type/endpoint captured include IC 50, K i, K d; the vast majority for biochemical and cell-based assays correspond to BAO definitions.

  • (d)

    Source reference: bibliographic information and unique identifiers for journal article and patents from which information related to the molecules was extracted include PubMedID, DOI, and standardized patent numbers. For journals, the KKB provides title, authors name, journal-name, volume, issues, and page numbers. For patents their titles, patent or patent application number (along with family members), inventor’s names, assignee names, publication data and priority numbers are provided.

It is observed that a disease type can be related to multiple kinase groups, and several diseases can arise from a common set of kinase group ( Table 3) 6. In the KKB, kinases are classified by protein and non-protein kinases with several sub-categories such as carbohydrate and lipid kinase and the typical protein kinase groups (such CMGC, CAMK, TK, TKL, RGC, AGC) and further sub-groups such as families. DTO provides a functional and phylogenetic classification of kinase domains to facilitate navigation of kinase drug targets. DTO is developed as part of the Illuminating the Druggable Genome (IDG) project. Here we make datasets freely available for the research community including to support efforts such as IDG. We also offer to run our predictive models built using KKB data to support prioritization of drug targets.

Table 3. Kinase-disease association in top therapeutic segments.

Disease Class Kinase Group
Cancer AGC;atypical;CAMK;CK1;
CMGC;RGC;STE;TK;TKL
Diabetes AGC;CMGC;TK
Cardiovascular AGC;CAMK;CMGC;TKL
Hypertension AGC;CAMK;RGC
Neurodegeneration AGC;CAMK;CMGC;CK1
Inflammation CMGC;STE;TKL
Immunity AGC;TK
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Kinase inhibitor datasets

The wealth of kinase inhibitor data presents opportunities for analysis as a whole or by integrating such data into various computational platforms to support development and validation of hypotheses of kinase inhibition. Several years ago, Eidogen-Sertanty made available 3880 pIC 50 data points across three kinase targets (ABL1, SRC, and AURKA – validation sets) to foster algorithm development and validation worldwide. With this data note, eight additional targets comprising inhibitors for therapeutically important classes: EGFR, CDK2, ROCK2, MAPK14 and PI3K (class I catalytic) ( Table 4) totaling ~258K data points (structure with standard results/endpoints such as IC 50, K i or K d) and ~76K unique chemical structures now have been made available to further foster worldwide development, validation, and collaborative interaction (see KB_SAR_DATA_F1000.txt and KB_SAR_DATA_F1000.sdf files). These datapoints have been exported from the KKB and survey 1044 articles and 942 patents.

Table 4. Important aspects about the selected targets.

Kinase Approved Name Class Diseases Associated Entrez
GeneID		 Uniprot
ID
EGFR* Epidermal Growth Factor
Receptor		 Receptor Tyrosine
Kinase		 NSCLC, Medullary Thyroid
Cancer, Breast Cancer,
Neonatal Inflammatory Skin
and Bowel Disease		 1956 P00533
CDK2 Cyclin-Dependent Kinase 2 Serine/Threonine
Kinase		 Angiomyoma, Carbuncle 1017 P24941
ROCK2 Rho-Associated, Coiled-Coil
Containing Protein Kinase 2		 Serine/Threonine
Kinase		 Colorectal Cancer, Penile
Disease, Hepatocellular
Carcinoma		 9475 O75116
MAPK14 Mitogen-Activated Protein
Kinase 14		 Serine/Threonine
Kinase		 Acquired Hyperkeratosis,
Prostate Transitional Cell
Carcinoma, Immunity-related
Diseases		 1432 Q16539
PIK3CA Phosphatidylinositol-4,5-
Bisphosphate 3-Kinase,
Catalytic Subunit Alpha		 Lipid Kinase Colorectal Cancer, Actinic
Keratosis		 5290 P42336
PIK3CB Phosphatidylinositol-4,5-
Bisphosphate 3-Kinase,
Catalytic Subunit Beta		 Lipid Kinase - 5291 P42338
PIK3CD Phosphatidylinositol-4,5-
Bisphosphate 3-Kinase,
Catalytic Subunit Delta		 Lipid Kinase Immunodeficiency 14,
Activated PIK3-Delta
Syndrome		 5293 O00329
PIK3CG Phosphatidylinositol-4,5-
Bisphosphate 3-Kinase,
Catalytic Subunit Gamma		 Lipid Kinase Lichen Nitidus 5294 P48736
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*Afatinib, Erlotinib, Gefitinib, Lapatinib, Osimertinib, Vandetanib are US-FDA approved kinase inhibitors with EGFR as one of the valid targets.

The datasets cover a broad range of biochemical and cell based studies investigating kinase inhibition; and they represent a diverse collection of pharmaceutically active scaffolds. These scaffolds can be easily examined for selectivity and specificity for the given eight kinase targets. Additionally, they can be used to infer novel target-inhibitor relationships for kinases and compounds not included in these subsets.

Bibliographic information is reported in the files ArticleInfo_F1000.txt and PatentInfo_F1000.txt. Experimental procedure along with metadata information for targets including EntrezGeneIDs, assay format/type (biochemical/enzyme, cell based, etc), keywords, species, and cell lines used in cell-based data are stored in AssayProtocols_F1000 (txt and xml attached).

The KKB validation sets have a maximum contribution from EGFR with nearly ~54K inhibitor molecules. This is followed by ~43K inhibitors for MAPK14; CDK2 and PIK3CA each have ~39K inhibitors. Figure 1 depicts data point distributions for each kinase in the attached subset. Moreover, 84% of the data are from biochemical enzyme based assay experiments, and 16% of the data from cell-based assays (in Figure 2). The datapoint measures include IC 50, K i and K d ( Figure 3).

Figure 1. Data point distributions for each kinase.

Figure 1.

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Figure 2. Data points share for each assay type.

Figure 2.

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Figure 3. Data points in various assay measures.

Figure 3.

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Analysis of ~76K unique molecules for selectivity against targets reveals that ~64K inhibit only one kinase of the eight kinases extracted ( Figure 4). Approximately 5K molecules show activity against two kinase targets, and ~3K molecules show activity against three kinases. A total of 79 molecules in the subset have some activity against all the eight kinase targets.

Figure 4. Selectivity profile for data points.

Figure 4.

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High quality, small molecule-activity for kinase research. Raw data behind the analyses described in the Data Note are included

The file 'Datasets legends' contains descriptions for each dataset.

Copyright: © 2016 Sharma R et al.

Data associated with the article are available under the terms of the Creative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication).

Click here for additional data file. (20.9MB, tgz)

Conclusions

The KKB is available in various formats such as SQL, SDF and IJC format ( Instant JChem) as quarterly updates. Two mobile apps, iKinase and iKinasePro 25, are also available for download which enable basic search access into KKB content, including kinase inhibitor structures, biological data and references/patents. Simple substructure and exact structure search access into the KKB is also available. We have extracted from the KKB ~258K structure activity data points and ~76K associated unique chemical structures across eight kinase targets and made these data freely available for download within this data note to foster algorithms development and validation worldwide.

Data availability

The data referenced by this article are under copyright with the following copyright statement: Copyright: © 2016 Sharma R et al.

Data associated with the article are available under the terms of the Creative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication). http://creativecommons.org/publicdomain/zero/1.0/

F1000Research: Dataset 1. High quality, small molecule-activity for kinase research, 10.5256/f1000research.8950.d124591 36

Funding Statement

The work of SCS was supported by grant U54CA189205 (Illuminating the Druggable Genome Knowledge Management Center, IDG-KMC). The IDG-KMC is a component of the Illuminating the Druggable Genome (IDG) project and NIH Common Fund project, awarded by the NCI.

[version 2; referees: 2 approved]

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F1000Res. 2016 Jul 21. doi: 10.5256/f1000research.9948.r15123

Referee response for version 2

Sorin Avram 1

I have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

F1000Res. 2016 Jul 8. doi: 10.5256/f1000research.9629.r14358

Referee response for version 1

Sorin Avram 1

The paper describes Kinase Knowledgebase (KKB), i.e., a database containing structure-activity data on kinases. The current data note briefly presents the KKB Q1 2016 Release and the appended eight kinase data sets, which are made hereby publicly available. 

Kinases are valuable targets for many diseases, especially cancers. The subject is of real scientific. In general, the amount of bioactivity data, coming from various sources (scientific literature, high-throughput screening results, patents etc), is heterogeneous and a proper curation and standardization of the data can provide reliable activity points. These data may be employed in many ways as described by the authors. In my opinion, the main applications for a database such as KKB would be to build predictors to search the chemical space for new kinase inhibitors, and further to optimize the selectivity of kinase inhibitors. Currently, ChEMBL’s 1 publicly available Kinase SARfari ( https://www.ebi.ac.uk/chembl/sarfari/kinasesarfari), provides a standard source for these tasks, covering about 532155 bioactivity data points i.e., version: 6.00- accessed June 20, 2016. This is less than one third of the 1.8 million KKB activity data point reported by the authors. In these circumstances, KKB might add valuable information for kinase research. Finally, the future analysis and employment of the eight data sets made freely available in the current note will provide a clearer view of the potential and versatility of KKB. 

There would be two minor observations:

  1. The methodology used to generate the data is described in the first paragraph in the section entitled “Kinase Knowledgebase (KKB)”. In order to be more accessible for the reader, this paragraph should be encompassed in a separate section named “Materials and methods”.

  2. In Table 2 there are three columns with repeated headers. In order to remove any doubts, I would recommend the authors to clarify this issue.  

Otherwise, the data note is well written, kinases are indexed using the widely adopted Uniprot IDs and the references are updated.

I recommend this data note for indexation and would like the authors to address the minor observations.

I have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

References

  • 1. Bento AP, Gaulton A, Hersey A, Bellis LJ, Chambers J, Davies M, Krüger FA, Light Y, Mak L, McGlinchey S, Nowotka M, Papadatos G, Santos R, Overington JP: The ChEMBL bioactivity database: an update. Nucleic Acids Res.2014;42(Database issue) : 10.1093/nar/gkt1031 D1083-90 10.1093/nar/gkt1031 [DOI] [PMC free article] [PubMed] [Google Scholar]
F1000Res. 2016 Jul 8. doi: 10.5256/f1000research.9629.r14833

Referee response for version 1

George Nicola 1

This article describes an overview of current kinase-related databases of significance, with particular focus on the contents of the Kinase Knowledgebase (KKB). The KKB has the largest repository of high-quality kinase activity data. Providing access to over ¼ million data points on several of the most important kinases allows for an exciting insight into the relevance of these validated drug targets and the diversity of compounds affecting them.  It is a promising trend that private companies are unlocking their proprietary data troves for the advancement of academic research. This is a nice Data Note that merits indexing in F1000Research.

A few minor typographical corrections:

  • Table 2: Three of the column names seem to be duplicated.

  • Table 2: It is unclear what the grey vs white rows represent in ‘Kinase Classification’ and ‘Family’ columns. If only for readability, perhaps these should alternate.

  • Section ‘Kinase inhibitor datasets’ at the end of the first paragraph: The word ‘respectively’ is not needed.

  • Section ‘Kinase inhibitor datasets’ 4 th paragraph, ‘~54K inhibitors molecules’: ‘inhibitors’ does not need to be plural.

  • Figures 1 & 2:I would use the word ‘Breakdown’ instead of ‘Breakup’.

  • Figure 2: Are ‘Cell-Free’ and ‘Animal Model’ truly zero percent? If so, they should be excluded; if not, the fractional percent should be listed.

  • ‘Conclusions’: ‘datanote’ should be two words, to be consistent with the F1000 article type.

I have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Data Citations

    1. Muskal S, Sharma R: Dataset 1 in: High Quality, Small Molecule-Activity Datasets for Kinase Research. F1000Research. 2016. Data Source [DOI] [PMC free article] [PubMed]

    Supplementary Materials

    High quality, small molecule-activity for kinase research. Raw data behind the analyses described in the Data Note are included

    The file 'Datasets legends' contains descriptions for each dataset.

    Copyright: © 2016 Sharma R et al.

    Data associated with the article are available under the terms of the Creative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication).

    Click here for additional data file. (20.9MB, tgz)

    Data Availability Statement

    The data referenced by this article are under copyright with the following copyright statement: Copyright: © 2016 Sharma R et al.

    Data associated with the article are available under the terms of the Creative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication). http://creativecommons.org/publicdomain/zero/1.0/

    F1000Research: Dataset 1. High quality, small molecule-activity for kinase research, 10.5256/f1000research.8950.d124591 36

    Articles from F1000Research are provided here courtesy of F1000 Research Ltd

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