Human Kinases Annotated Library

Description

The Human Kinases Annotated Library is a comprehensive collection of small molecule compounds specifically designed to target kinase proteins. Kinases are enzymatic proteins that play a crucial role in cellular functions by phosphorylating other functional proteins, thereby regulating various physiological processes. Kinase enzymatic activity can be modulated through two primary mechanisms: binding at the catalytic ATP site or through allosteric binders that induce conformational changes within the catalytic site.

This library is particularly valuable as kinases are well-recognized therapeutic targets for several critical medical conditions. In oncology, kinase inhibitors are extensively used in cancer immunotherapy. For inflammatory diseases, such as fibrosis and rheumatoid arthritis, modulating kinase activity can significantly impact disease progression and symptoms. Additionally, kinases play a vital role in the cardiovascular system, where their inhibition can be beneficial in treating conditions like cerebral vasospasm and pulmonary arterial hypertension.

The Human Kinases Annotated Library includes a unique collection of small molecule compounds with annotated activities against 249 kinase targets. For research and drug development needs, the library is available in two versions:

●      An express delivery set containing 640 compounds

●      A complete version with 2,585 compounds, providing a robust resource for discovering and optimizing kinase-targeted therapies.

The Human Kinases Annotated Library is a powerful resource for drug discovery and development, providing researchers with a comprehensive collection of small molecule compounds specifically targeting kinase proteins. By leveraging the detailed annotations and high-quality data from multiple reputable sources, researchers can rapidly identify and validate potential drug candidates with established activities against critical kinase targets. This enables the acceleration of preclinical research by focusing on compounds with proven efficacy, reducing the time and cost associated with initial screening phases. Moreover, the library's emphasis on compounds with activities below 5 µM ensures that only highly potent candidates are considered, enhancing the likelihood of successful therapeutic development. This targeted approach is particularly valuable for addressing complex diseases such as cancer, inflammatory conditions, and cardiovascular disorders, where kinases play a pivotal role in disease progression and treatment.

The Human Kinases Annotated Library is meticulously curated using data from multiple reputable sources to ensure comprehensive and accurate annotations. These sources include Pharos, ChEMBL 25, PubChem, PubMed, and the current patent literature (CAS, Integrity). Each compound in the library is annotated with detailed information to facilitate targeted research and drug discovery:

IDNUMBER: This is the unique identifier for each compound in the ChemDiv catalog. Note that some ID numbers may have multiple annotation entries, either due to data from multiple sources or because the compound exhibits activity against multiple similar targets.

UNIPROT: This column includes SwissProt and ChEMBL target accession IDs, providing a link to the specific protein targets associated with each compound.

Type: This describes the nature of the measured activity, indicating whether the compound acts as an inhibitor, activator, or through another mechanism.

Value: Only compounds with reported activities of less than 5 µM are included in the library, ensuring that the selection criteria prioritize highly active compounds.

pubmed_id: This entry refers to the PubMed record for the publication that reported the activity of the compound, providing a link to the primary scientific literature.

doi, patent_id: These fields contain the Digital Object Identifier (DOI) or patent reference, linking to the original publication or patent documentation of the compound’s data.

assay_description: For data extracted from PubChem, this column details the names of the assays (entry names as PUBCHEM_BIOASSAY) used to determine the bioactivity of the compounds.

This detailed composition ensures that researchers have access to robust and reliable data, enabling precise and efficient drug discovery efforts targeting kinase proteins.

The Human Kinases Annotated Library is an invaluable tool for a diverse group of professionals involved in drug discovery and development studies. Academic researchers can utilize this library to deepen their understanding of kinase biology, investigate disease mechanisms, and identify new therapeutic targets. Pharmaceutical companies and biotech firms can leverage the library for high-throughput screening, enabling the identification and optimization of lead compounds with proven efficacy against kinase targets. This resource accelerates the drug development pipeline by providing access to compounds with established safety profiles, reducing the time and cost associated with early-stage drug discovery. Clinical researchers can use the library to facilitate the translation of laboratory findings into clinical applications, bridging the gap between bench and bedside. Additionally, regulatory scientists can rely on the comprehensive data provided to assess the safety and efficacy of kinase-targeting compounds during the drug approval process.

The main therapeutic areas where the Human Kinases Annotated Library proves particularly useful include oncology, inflammatory diseases, and cardiovascular diseases. In oncology, kinase inhibitors are essential for developing targeted therapies and cancer immunotherapy, disrupting cancer cell signaling and proliferation. For inflammatory diseases such as rheumatoid arthritis, psoriasis, and fibrosis, the library offers compounds that modulate kinase-driven signaling pathways to reduce inflammation. Cardiovascular diseases, including cerebral vasospasm, pulmonary arterial hypertension, and heart failure, can benefit from kinase modulation to improve patient outcomes. Furthermore, the library's potential extends to neurodegenerative diseases and metabolic disorders, where kinases play critical roles in neuronal signaling and metabolic regulation. By providing a curated set of compounds with known kinase activities, the Human Kinases Annotated Library supports the development of innovative therapeutics across these critical areas, ultimately aiming to address unmet medical needs and enhance patient care.

Library Composition

Data sources of annotations : Pharos, ChEMBL 25, PubChem, PubMed, Current Patent Literature (CAS, Integrity)

IDNUMBER – ChemDiv Catalog ID (in some instances the same IDNUMBER might have multiple annotation entries due to multiple data sources or because having activity against multiple similar targets);

UNIPROT – SwissProt and ChEMBL Target accesion ID; 

Type – character of the measured activity;

Value – Active compounds selection criteria, included only compounds with reported activities < 5 µM;

pubmed_id – PubMed record entry; 

doi, patent_id – journal or patent reference to a publication of original data;  

For screening data extracted from PubChem, see column assay_description for entry names PUBCHEM_BIOASSAY

Example of Annotations - an Excel file structure

IDNUMBER	UNIPROT	Target Name	Type	Relation	Value	Units	pubmed_id	doi	patent_id	Target Description	assay_description
8008-7025	Q7L7X3	Serine/threonine-protein kinase TAO1	IC50	<	50	nM			US-20070208166-A1	Serine/threonine-protein kinase TAO1	Inhibition of human KIAA1361 kinase domain
5122-1774	P43250	G protein-coupled receptor kinase 6	IC50	=	1030	nM			US-20140309185-A1	G protein-coupled receptor kinase 6	Inhibition of human recombinant full-length GST-tagged human GRK6
0073-0059	O75460	Serine/threonine-protein kinase/endoribonuclease IRE1	IC50	=	170	nM			US-8614253-B2	Serine/threonine-protein kinase/endoribonuclease IRE1	In Vitro Enzyme Assays: IRE-1 alpha T1 RNase and RNase A assays
S553-1690	Q00535	Cyclin-dependent kinase 5	Ki	=	50.12	nM				Cyclin-dependent-like kinase 5	PUBCHEM_BIOASSAY: Navigating the Kinome.
Y031-8414	P50613	Cyclin-dependent kinase 7/ cyclin H	IC50	=	400	nM	20627564	10.1016/j.bmcl.2010.05.039		Cyclin-dependent kinase 7	Inhibition of human CDK7/Cyclin H/MAT1
L785-0049	P49336	CDK8/Cyclin C	IC50	=	9	nM	28231524	10.1016/j.ejmech.2017.02.020		Cyclin-dependent kinase 8	Inhibition of Alexa647 tracer binding to full length recombinant human His-tagged CDK8/Cyclin C
H025-3231	Q2M2I8	Adaptor-associated kinase	Kd	=	1200	nM	22037378	10.1038/nbt.1990		AP2-associated protein kinase 1	Binding constant for AAK1 kinase domain
8012-7305	Q5S007	Leucine-rich repeat serine/threonine-protein kinase 2	IC50	=	100	nM	28774425	10.1016/j.bmcl.2017.07.052		Leucine-rich repeat serine/threonine-protein kinase 2	Inhibition of LRRK2 (unknown origin) by HTRF assay

Publications

1.J Med Chem 2017 60(14):6337-6352. Discovery of Potent and Selective Inhibitors of Cdc2-Like Kinase 1 (CLK1) as a New Class of Autophagy Inducers. Sun QZ Lin GF Li LL Jin XT Huang LY Zhang G Yang W Chen K Xiang R Chen C Wei YQ Lu GW Yang SY.

2.Bioorg Med Chem Lett 2017 27(11):2617-2621. Developing DYRK inhibitors derived from the meridianins as a means of increasing levels of NFAT in the nucleus. Shaw SJ Goff DA Lin N Singh R Li W McLaughlin J Baltgalvis KA Payan DG Kinsella TM.

3.J Med Chem 2017 60(16):7099-7107. Optimization of Allosteric With-No-Lysine (WNK) Kinase Inhibitors and Efficacy in Rodent Hypertension Models. Yamada K Levell J Yoon T Kohls D Yowe D Rigel DF Imase H Yuan J Yasoshima K DiPetrillo K Monovich L Xu L Zhu M Kato M Jain M Idamakanti N Taslimi P Kawanami T Argikar UA Kunjathoor V Xie X Yagi YI Iwaki Y Robinson Z Park HM.

4.J. Med. Chem. 2015 58(3):1563-1568. A high-throughput screen reveals new small-molecule activators and inhibitors of pantothenate kinases. Sharma LK Leonardi R Lin W Boyd VA Goktug A Shelat AA Chen T Jackowski S Rock CO.

5.ACS Med. Chem. Lett. 2014 5(9):963-967. Hydroxybenzothiophene Ketones Are Efficient Pre-mRNA Splicing Modulators Due to Dual Inhibition of Dyrk1A and Clk1/4. Schmitt C Miralinaghi P Mariano M Hartmann RW Engel M.

6.J. Med. Chem. 2014 57(6):2755-2772. Protein kinase CK-1 inhibitors as new potential drugs for amyotrophic lateral sclerosis. Salado IG Redondo M Bello ML Perez C Liachko NF Kraemer BC Miguel L Lecourtois M Gil C Martinez A Perez DI.

7.Nat. Biotechnol. 2011 29(11):1046-1051. Comprehensive analysis of kinase inhibitor selectivity. Davis MI Hunt JP Herrgard S Ciceri P Wodicka LM Pallares G Hocker M Treiber DK Zarrinkar PP.

8.Bioorg. Med. Chem. Lett. 2011 21(13):4108-4114. Identification of new inhibitors of protein kinase R guided by statistical modeling. Bryk R Wu K Raimundo BC Boardman PE Chao P Conn GL Anderson E Cole JL Duffy NP Nathan C Griffin JH.

9.ACS Med. Chem. Lett. 2011 2(2):154-159. Synthesis and Structure-Activity Relationships of Benzothienothiazepinone Inhibitors of Protein Kinase D. Bravo-Altamirano K George KM Frantz MC Lavalle CR Tandon M Leimgruber S Sharlow ER Lazo JS Wang QJ Wipf P.