Tyrosine Kinase Screening Library

Protein kinases belong to a complex group of enzymes that arose in the early stages of evolution and, along with protein phosphatases, are involved in phosphorylation and dephosphorylation of proteins. Separate groups of proteins: serine/threonine specific-, Mg2+/Mn2+dependent-, tyrosine and dual specific kinases are unique in structure and functions and typical for representatives of individual kingdoms [1].

Numerous studies have shown that tyrosine kinases (TKs) are important mediators of signaling cascades, determining key scenarios in diverse biological processes, such as growth, differentiation, metabolism, and apoptosis in response to external and internal stimuli [2]. Tyrosine kinases are attractive biological targets for cancer therapy, as their abnormal signaling has often been linked with tumor development and growth. They are a group of around 90 enzymes capable of phosphorylating the amino acid tyrosine on another protein that leads to conformational changes and, typically, to activation of that protein (Fig. 1) [3].

Life Chemicals has designed a new Tyrosine Kinase Screening Library of about 5,700 drug-like screening compounds offered for high throughput screening (HTS).

Initially, about 150,000 reference compounds with known TKs blocking activity were obtained from ChEMBL, CHEBI, and DrugBank databases. The compounds have been filtered to retain only those possessing moderate and high activity against TKs that has narrowed down the reference set to 48,064 compounds. At the next step, a similarity search of the Life Chemicals HTS Compound Collection has been done against the reference set employing 2D molecular fingerprints with similarity metrics (Tanimoto > 0.85). Compounds obtained by this search were filtered by the Lipinski's Rule of Five to include only drug-like ones. In addition, PAINS compounds, as well as those with "bad" and reactive groups, have been removed from the Library (Ro5 compliance is indicated).

The selected potential tyrosine kinase inhibitors are predicted to possess activity against the following targets:

ALK tyrosine kinase receptor
Discoidin domain-containing receptor 2 (Tissues remodeling TK)
Dual specificity protein kinase TTK
Dual specificity tyrosine-phosphorylation-regulated kinase 1A
Dual-specificity tyrosine-phosphorylation regulated kinase 1A
Dual-specificity tyrosine-phosphorylation regulated kinase 3
Ephrin type-A receptor 2 (Receptor TK)
Ephrin type-A receptor 4 (Receptor TK)
Ephrin type-B receptor 3 (Receptor TK)
Ephrin type-B receptor 4 (Receptor TK)
Epidermal growth factor receptor erbB1 (Receptor TK)
Epithelial discoidin domain-containing receptor 1 (Receptor TK)
Fibroblast growth factor receptor 1 (Receptor TK)
Hepatocyte growth factor receptor (Receptor TK)
Vascular endothelial growth factor receptor 1 (Receptor TK)
Macrophage-stimulating protein receptor (Receptor TK)
Maternal embryonic leucine zipper kinase (non-membrane TK activity)
Nerve growth factor receptor Trk-A (Receptor TK)
Neurotrophic tyrosine kinase receptor type 2
NT-3 growth factor receptor (Receptor TK) (Receptor TK)
Vascular endothelial growth factor receptor 2
Proto-oncogene tyrosine-protein kinase MER
Receptor protein-tyrosine kinase erbB-2
Stem cell growth factor receptor (Receptor TK)
Interferon-induced, double-stranded RNA-activated protein kinase
(non-membrane spanning protein tyrosine kinase activity)

Tyrosine-protein kinase ITK/TSK
Tyrosine-protein kinase JAK1
Tyrosine-protein kinase JAK2
Tyrosine-protein kinase JAK3
Tyrosine-protein kinase LCK
Tyrosine-protein kinase Lyn
Tyrosine-protein kinase receptor FLT3
Tyrosine-protein kinase receptor RET
Tyrosine-protein kinase receptor TYRO3
Tyrosine-protein kinase receptor UFO
Tyrosine-protein kinase SRC
Tyrosine-protein kinase SYK
Tyrosine-protein kinase TIE-2
Tyrosine-protein kinase TXK
Tyrosine-protein kinase YES
Tyrosine-protein kinase ZAP-70
Leukocyte tyrosine kinase receptor
Protein tyrosine kinase 2 beta
Tyrosine kinase non-receptor protein 2
Tyrosine-protein kinase ABL
Tyrosine-protein kinase BTK
Tyrosine-protein kinase CSK
Tyrosine-protein kinase FER
Tyrosine-protein kinase FES
Tyrosine-protein kinase FYN
Tyrosine-protein kinase TYK2

 

Histogram of tyrosine kinase family: receptor tyrosine kinases are in red, non-receptor tyrosine kinases are in blue. Image source: Cell Signaling Technology website.

Figure 1. Histogram of tyrosine kinase family: receptor tyrosine kinases are in red, non-receptor tyrosine kinases are in blue. Image source: Cell Signaling Technology website.

 

 References:

  1. Roskoski R Jr. A historical overview of protein kinases and their targeted small molecule inhibitors // Pharmacol Res. 2015; 100:1-23.
  2. Yamaoka T, Kusumoto S, Ando K, Ohba M, Ohmori T. Receptor Tyrosine Kinase-Targeted Cancer Therapy // Int J Mol Sci. 2018;19(11).
  3. Roskoski R Jr. Src protein-tyrosine kinase structure, mechanism, and small molecule inhibitors // Pharmacol Res. 2015;94:9-25.