ERK5 (MAPK7) Kinase Targeted Library

For two decades, scientists have been interested in demonstrating the role of extracellular signal-regulated kinase 5 (ERK5) and its upstream activator, mitogen-activated protein kinase 5 (MAPK5) in the field of cancer research. 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, where it plays a key role in mediating multiple parts in the cell cycle. Under normal physiological conditions, MAPK5 and ERK5 are activated by growth factors and cellular stress, and by embryonic knockout using MEK5 or MAPK7. In addition, various clinical evidence suggests that dysregulated MEK5/ERK5 signaling is a crucial driver of tumorigenesis in several cancers. Compared to mitogen activated protein kinases (MAPKs), ERK5 has unique structural and functional properties which can offer a critical opportunity for therapeutic development. Small molecule inhibitors of ERK5 are being evaluated in preclinical studies to examine the potential of blocking ERK5 kinase activity for cancer therapy.

BOC Sciences has developed a ERK5 (MAPK7) kinase targeted library containing about 900 ERK5 compounds.

Figure 1. Impact of ERK5 on the cancer. (Stecca, B.; Rovida, E. 2019)

Library Design

1. Firstly, we apply the X-ray structure of the protein recorded in the PDB entry to establish the docking model of ERK5 binding site
2. Then, a glide docking procedure is used for the virtual screening procedure:
• The following features and constraints are well defined from the ligand and binding sites
  1) Purine moiety from the ligand is identified as a hydrophobic (aromatic) feature
  2) A set of residues are responsible for hydrogen bonding:
  Met140, Asp200, Glu102, Gln146, Asp143, Arg98, Ala65, Lys84, Arg125, Asp138, Ser71
• Generation of electrostatic maps of binding pockets within default parameters including hydrophobicity and active residues
• A sequential screening is transformed from high throughput (HTS) to standard docking procedure (SP)
3. Docking results will be evaluated by employing the scoring function in the Gaussian software
4. In this step, the two docking models are optimized and validated
5. 36 known ERK5 inhibitors with IC₅₀<1 μM) reported in the literature are used as reference molecules for the docking procedure for optimization and validation
6. Finally, the entire BOC Sciences compound collections are processed using our in-house filters to detect and remove PAINS compounds

ERK5 (MAPK7) Kinase Targeted Library Characteristics

• The 4IC7 structure has proved to have better reproducibility for the co-crystalline ligand conformation
• the RMSD value between the crystallographic conformation of ligand (ANP) and the best docking pose is 0.6 Å
• Screening results closely correlate with the biological data from a reference set of compounds with known ERK5 inhibitory activity
• Favorable physicochemical parameters and solubility requirements
• 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
• 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 ERK5 (MAPK7) Kinase Targeted Library design at competitive prices for global customers. Personalized and customized services of ERK5 (MAPK7) Kinase 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!