PI3K/Akt/mTOR Focused Library

Signal transduction and other biological processes, including cell proliferation, apoptosis, metabolism, and angiogenesis, are regulated by the PI3K/AKT/mTOR pathway. Components of the PI3K/AKT/mTOR signalling pathway are more complex than those of other signalling pathways. The PI3K/AKT/mTOR signaling pathway plays a critical role in a number of diseases, including ischemic brain injury, neurodegenerative disorders, and cancer. This signalling pathway can be inhibited by both single-component and dual inhibitors. Small molecule inhibitors of phosphatidylinositol-3-kinase (PI3K) include PI3K/mTOR inhibitors, pan-PI3K inhibitors, and isoform-selective PI3K inhibitors. Preclinical trials have shown that several PI3K inhibitors are very effective, and some have also been clinically tested in solid tumors and hematological malignancies.

The PI3K/Akt/mTOR pathway is a good example of redundancy in biological systems, particularly in cancer cells. Indeed, cancer responds to chronic treatment with drugs targeting a single pathway readjusting its signaling circuitry, taking advantage of pathway redundancy and routes of feedback and crosstalk to maintain their function and, thus, escape from drug-induced growth inhibition and death. Due to this, tumors ultimately evade inhibition of this pathway despite recent successes in cancer treatment. With new agents targeting PI3K/Akt/mTOR we will be able to further advance the results achieved so far, as they are more potent, selective, and can be combined with other therapies. In order to take another step forward, we need translational research that addresses this highly integrated and varied network of signaling pathways, as well as mechanisms that are resistant to their inhibition.

At Life Chemicals, we have successfully created a PI3K/Akt/mTOR Focused Library of around 4,400 drug-like screening compounds selected by a ligand-based approach and intended for anti-cancer drug discovery projects.

At the first step of its design, a reference set of over 35,000 molecules with reported inhibitory activity against the PI3K/Akt/mTOR pathway component extracted from the ChEMBL database was prepared (IC50, Ki, etc., less than 10 μM, Inhibition > 50 %). Then, the Life Chemicals HTS Compound Collection was analyzed using a 2D fingerprint similarity search approach (Tanimoto > 0.80) against the above-mentioned reference set of PI3K/Akt/mTOR pathway inhibitors (Fig. 1). Finally, the resulting small-molecule screening compounds were filtered by in-house MedChem filters to remove PAINS, toxicophore and reactive moieties.

Cherry-picking is available. Custom compound selection based on specific parameters can be performed on request.

Please, contact us at orders@lifechemicals.com for any details and quotations.

Reference compounds and their analogs from the PI3K/Akt/mTOR focused library

Figure 1. Reference compounds and their analogs from the PI3K/Akt/mTOR focused library

The predicted activity in this PI3K-Targeted Library is distributed across the following molecular targets (Fig. 2):

  • 3-phosphoinositide dependent protein kinase-1
  • AMP-activated protein kinase (AMPK) alpha-1/beta-1/gamma-1
  • AMP-activated protein kinase, alpha-1, alpha-2 subunits
  • AMP-activated protein kinase, AMPK
  • AMPK alpha2/beta1/gamma1
  • DEPTOR/mTOR
  • DNA-dependent protein kinase
  • Glycogen synthase kinase-3
  • Glycogen synthase kinase-3 alpha & beta
  • MAP kinase p38
  • MAP kinase p38 alpha/beta/gamma/delta
  • Maternal embryonic leucine zipper kinase
  • mTORC1
  • NUAK family SNF1-like kinase 1
  • Phosphatidylinositol 3-kinase catalytic subunit type 3
  • Phosphatidylinositol-4-phosphate 3-kinase C2 domain-containing beta polypeptide
  • Phosphatidylinositol-4-phosphate 3-kinase C2 domain-containing subunit gamma
  • PI3-kinase p110-alpha subunit
  • PI3-kinase p110-alpha/p85-alpha
  • PI3-kinase p110-beta subunit
  • PI3-kinase p110-delta subunit
  • PI3-kinase p110-delta/p85-alpha
  • PI3-kinase p110-gamma subunit
  • PI3-kinase p85-alpha subunit
  • PI4-kinase alpha subunit
  • PI4-kinase beta subunit
  • Protein kinase C (PKC)
  • Protein kinase C alpha
  • Protein kinase C beta
  • Protein kinase C eta
  • Protein kinase C gamma
  • Protein kinase C iota
  • Protein kinase C zeta
  • Ribosomal protein S6 kinase
  • Ribosomal protein S6 kinase 1
  • Ribosomal protein S6 kinase 2
  • Ribosomal protein S6 kinase alpha 1
  • Ribosomal protein S6 kinase alpha 2
  • Ribosomal protein S6 kinase alpha 3
  • Ribosomal protein S6 kinase alpha 4
  • Ribosomal protein S6 kinase alpha 5
  • Ribosomal protein S6 kinase alpha 6
  • Serine/threonine-protein kinase AKT
  • Serine/threonine-protein kinase AKT2
  • Serine/threonine-protein kinase AKT3
  • Serine/threonine-protein kinase mTOR
  • Serine/threonine-protein kinase PLK1
  • Serine/threonine-protein kinase PLK2
  • Serine/threonine-protein kinase PLK3
  • Serine/threonine-protein kinase PLK4
  • Serine-protein kinase AT

Overview of the PI3K/AKT/mTOR pathway and drug targets.

Figure 2. Overview of the PI3K/AKT/mTOR pathway and drug targets. Picture source: Dienstmann R. at al. Mol Cancer Ther May 1 2014 (13) (5) 1021-1031; DOI: 10.1158/1535-7163.MCT-13-0639 

 

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