3-Phosphoinositide-Dependent Kinase-1 (PDK1) Targeted Library

Kinases are a class of master regulators of many downstream signaling protein kinase cascades, for example, PDK1 plays an important role in insulin and growth factor signaling cascades and many signal transduction of growth factors and oncogenes is mediated by PDK1. Since pathological upregulation of PDK1 signaling caused by constitutive growth factor receptor activation and/or mutations in PTEN (phosphatase and tensin homolog) can significantly trigger downstream signaling, such as PKB/Akt, which subsequently promote proliferative events such as tumor aggressiveness, angiogenesis and progression. From this prospective, PDK1 inhibitors may offer new opportunities for the development of effective therapeutic approaches. Currently, a lot of research data suggests that more than 50% of human cancers have significant overstimulation of the PDK1 signaling pathway, which indicates that may inhibition of this protein kinase by small molecules is expected to be effective in inhibiting cancer cell proliferation. Moreover, the effects of PDK1 inhibitors on cancer cell growth in vitro and in vivo suggest that PDK1 is an effective drug target. Thus, PDK1 is a promising therapeutic target and its inhibition has a huge potential in helping prevent cancer progression and abnormal tissue dissemination.

BOC Sciences is focused on designing a PDK1 targeted library to deliver a variety of PDK1 inhibitors.

Figure 1. Overview of PDK1 kinase domain in complex with ATP. (Barile, E.; et al. 2012)

Library Design

1. Since most of PDK1 inhibitors are ATP-competitive and capable of accurately targeting the ATP-binding site of the kinase. BOC Sciences comprehensively analyzes the PDB structure of various PDK1 inhibitor complexes
2. This structure is then used to perform a in silico search for potential inhibitors in the BOC Sciences HTS compound collection
3. Based on the characteristics of the residues responsible for protein-ligand interactions, we employ the following screening model of protein binding sites:
• Residues responsible for polar interactions: Ala162, Ser160, Thr222, Val143, Glu166
• hydrophobic region: Leu159, Leu212, Thr222, Val143, Tyr170

Among them, the query model of the binding sites are prepared rapidly in SYBYL-X, including the donor, acceptor and 2 hydrophobic sites with surface volume constraints

4. Then, our teams perform a virtual screening of the prepared set of molecules
5. Finally, the hit compounds can be selected successfully using BOC Sciences’ well-designed scoring function

3-Phosphoinositide-Dependent Kinase-1 (PDK1) Targeted Library Characteristics

• 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

Figure 2. Overview of PDK1 kinase domain (residues 71–232) in complex with ATP. (Barile, E.; et al. 2012)

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 3-Phosphoinositide-Dependent Kinase-1 (PDK1) Targeted Library design at competitive prices for global customers. Personalized and customized services of 3-Phosphoinositide-Dependent Kinase-1 (PDK1) 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!