Protein kinases are enzymes that regulate the energy balance by catalyzing phosphorylation. Thus, kinases are critical in cell signaling, metabolism, protein regulation, cellular transport and many other cellular pathways. Over the past 15 years, protein kinases have become the most important class of drug targets for the pharmaceutical industry in the field of cancer. The development of novel specific kinase inhibitors may lead to the discovery of effective anti-cancer drugs.
BOC Sciences has designed a series of kinase libraries capable of performing rapid discovery and design of novel potent kinase inhibitors, providing additional opportunities to target new chemical spaces and achieve selectivity profiles.
Kinase Sharp-aimed Targeted Library Design
BOC Sciences is able to prepare a collection of drug-like screening compounds with potential kinase inhibitory activity to facilitate kinase-based drug discovery. Our teams have used multiple computer-assisted methods, particularly docking-based virtual screening of the HTS compound collection for the identification of kinase active sites.
PDK1 plays an important role in the insulin and growth factor signaling cascade, and it has been shown that PDK1 inhibitors may offer new opportunities for the development of effective therapeutic approaches, and we have used a in silico search method for the selection of potential inhibitors in the BOC Sciences compounds collection.
Figure 1. Proposed functional role of flotillin proteins in insulin and NGF signaling cascades. (Kurrle, N. 2012)
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase which mainly expressed in specific regions of the central and peripheral nervous systems. Aberrantly expressed ALK tyrosine kinase is involved in the pathogenesis of various malignancies and therefore ALK TK inhibitors are widely used as treatment for NSCLC patients with ALK rearrangement. BOC Sciences has designed its proprietary ALK tyrosine kinase focused library through a ligand-based approach designed to provide over 2,500 potential anaplastic lymphoma kinase inhibitors.
Aurora kinase (Aurora A) is an important member of the serine/threonine kinase family, and is a key regulator of mitosis. Many studies have shown that drugs inhibiting Aurora A can exert anticancer effects in many areas such as gynecology. In addition, Aurora A inhibitors can avoid Aurora B-mediated neutropenia in clinical settings. Our experts have developed a library containing various potential selective inhibitors of Aurora A kinase based on the specific conformation of the ATP binding site of Aurora A.
In human thyroid cancer, cell lines originating from different histotypes have showed an increase in Aurora B expression. Therefore, the development of Aurora B kinase inhibitors could help discover effective anti-cancer drugs, and we are able to produce structurally diverse Aurora B kinase inhibitors by employing a in silico screening of BOC Sciences compound collections.
PKA is usually applied as a diagnostic biomarker due to its overexpression in blood plasma in association with several cancers. Cyclic adenosine monophosphate (cAMP) can regulate cellular processes, which makes PKA an "anti-target". Therefore, our experienced team is building a c-AMP dependent protein kinase targeted library to investigate and develop potent and selective inhibitors of protein kinase A.
c-Met, also known as MET or hepatocyte growth factor receptor (HGFR), is a receptor tyrosine kinase. c-Met kinase shows an aberrant activation in the malignant phenotype of various tumors, and has therefore attract considerable interest as a drug target for cancer therapy. BOC Sciences has designed a c-Met kinase targeted library by comparing the crucial amino acids in the protein binding site with the features of known potent inhibitors.
CDKs controls the cell division cycle, where CDK2 plays a key role in the G1- to S-phase checkpoint of the cell cycle. We are able to use a unique strategy to generate our CDK2 focused library to provide cyclin-dependent kinases inhibitors with anti-cancer potential.
Figure 2. The ERBB family of receptor tyrosine kinases (RTKs) orchestrates biological processes via distinct ligands in normal cells. (Black, L. E.; et al. 2019)
Protein kinase ERK5, also known as mitogen-activated protein kinase 7 (MAPK7), is an emerging drug target for a variety of indications, particularly for cancer. BOC Sciences supports the glide docking program used in screening programs to design ERK5 (MAPK7) kinase targeted libraries.
Fibroblast growth factor receptors and subtypes are considered as important drug targets for anticancer therapy. BOC Sciences has used a receptor-based approach to create a library of potential FGFR1 kinase inhibitors based on a diverse set of drug-like compounds from the BOC Sciences screening compound collections.
JAK is a family of intracellular, non-receptor tyrosine kinases. A variety of clinical trial data suggests that JAK kinase inhibitors have therapeutic applications in the treatment of cancer and inflammatory diseases. Based on a reference set of known JAK1, JAK2 and JAK3 inhibitors in the database, we have designed a high quality JAK targeted library.
The p38 MAP kinase inhibitors are effective in several disease models such as inflammatory arthritis and other joint diseases. BOC Sciences’ MAP-focused library is aimed at type I inhibitors that bind to the ATP-binding site of proteins within the DFG-in conformation of the activation loop.
As a lipid kinase, PI3K is able to regulate several fundamental signaling of biological processes and thus is a promising therapeutic target for cancer. Our scientists have developed a receptor-based approach to design a sharp-focused library of potential PI3K inhibitors as promising anti-cancer agents.
Figure 3. Pathways affected by the combined selected kinase inhibitors in BRAF mutant melanoma cells. (Margue, C.; et al. 2019)
Rho-associated protein kinases (ROCK) are involved in numerous cell motility regulatory processes from cell migration to cell contraction and control of the amount of microfilament. Therefore, ROCK1 and ROCK2 isoforms have been used as targets for virtual screening of BOC Sciences HTS compound collection.
The VEGF family and their corresponding receptor tyrosine kinases (VEGFR-1, VEGFR-2 and VEGFR-3) play critical roles in regulating multiple aspects of the angiogenic and lymphangiogenic processes as well as in the induction of vascular permeability and inflammation. We have developed the VGFR-2 focused library containing potential VEGFR-2 type II inhibitors that bind to kinase in DFG-out conformation of the activation loop.
The VEGF family and their corresponding receptor tyrosine kinases (VEGFR-1, VEGFR-2 and VEGFR-3) play critical roles in regulating multiple aspects of the angiogenic and lymphangiogenic processes as well as in the induction of vascular permeability and inflammation. We have developed the VGFR-2 focused library containing potential VEGFR-2 type II inhibitors that bind to kinase in DFG-out conformation of the activation loop.
Serine or threonine residues preceding proline are the main regulatory phosphorylation motifs that play an important role in various cellular processes. Enzymes responsible for this phosphorylation belong to a large family of Pro-directed protein kinases, and these kinases and phosphatases play critical roles in various cellular processes such as the cell cycle, transcription and various signal transduction pathways, as well as in human diseases such as cancer and Alzheimer's disease.
Akt kinase, also known as protein kinase B (PKB), plays an important role in various cellular processes such as glucose metabolism, cell proliferation, apoptosis, transcription and cell migration. Akt is closely associated with the survival, proliferation and invasiveness of tumor cells, and activation of Akt has also been associated with human cancer and tumor cells. BOC Sciences is able to design and synthesize a reliable Akt-targeted library to generate 15,000 compounds.
The mammalian target of rapamycin (mTOR) plays an important role in cell growth, proliferation, metabolism and angiogenesis. The protein is now an attractive target for new development of anticancer drugs. BOC Sciences scientists have established a range of computational approaches to accelerate the discovery and development of mTOR inhibitors, including modeling the structure of mTOR, screening compound databases, discovering structure-activity relationships (SAR) and optimizing hits, and designing library-focused libraries.
In recent years, scientists have been focused on developing new ligands for GPCRs. Allosteric modulators bind to GPCRs at sites that are topologically different from the orthologous site, resulting in altered receptor conformation. These ligands can modulate receptor function by acting at the allosteric site, thereby strongly affecting the signaling pathway. We have applied both ligand- and structure-based methods to create allosteric GPCR libraries.
Kinase Sharp-aimed Targeted Library Characteristics
- No PAINS or toxic substances/unwanted functions: filtered by strict ‘Ro5-like’ physicochemical and most stringent in-house structural filters
- Bioactivity and safety confirmed by preclinical studies and clinical trials
- Structural diversity, medicinal activity, and cellular penetration
- Structural document, IC50, and other chemical and biological data are provided
- All compounds are continually updated
- All of these compounds with Tanimoto index ≥ 0.80
- Compound cherry-picking service is provided
What We Deliver
- Delivered within 2 weeks in any customer-preferred format
- Powders, dry films or DMSO solutions formatted in vials, 96 or 384-well plates
- All compounds have a minimum purity of 90% assessed by 1H NMR and HPLC
- Analytical data is provided
BOC Sciences provides professional, rapid and high-quality services of Kinase Sharp-aimed Targeted Library design at competitive prices for global customers. Personalized and customized services of Kinase Sharp-aimed Targeted Library design can satisfy any innovative scientific study demands. Our clients have direct access to our staff and prompt feedback to their inquiries. If you are interested in our services, please contact us immediately!
References
- Kurrle, N. Function of Flotillins in Receptor Tyrosine Kinase Signaling and Endocytosis: Role of Tyrosine Phosphorylation and Oligomerization. INTECH. 2012. 308-342.
- Black, L. E.; et al. Mechanisms of Receptor Tyrosine-Protein Kinase ErbB-3 (ERBB3) Action in Human Neoplasia. The American Journal of Pathology. 2019. 189(10): 1898-1912.
- Margue, C.; et al. Kinase inhibitor library screening identifies synergistic drug combinations effective in sensitive and resistant melanoma cells. Journal of Experimental & Clinical Cancer Research. 2019. 38(1).
