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AKT Serine/threonine Kinase Targeted Library

AKT1 and AKT2 are serine-threonine AKT protein kinases that are integral components of many processes in the cell, such as growth factor-induced signal transduction, phosphorylation of serine and threonine amino acid residues in proteins, cellular glucose uptake, proliferation, cell survival, growth, and angiogenesis [1].

More than 100 substrates are known for AKT1 and AKT2, suggesting the importance of AKT kinases in many metabolic processes and pathways, such as the PI3K/AKT/mTOR pathway, skeletal muscle regulation or brown adipose tissue development [2-5]. These facts suggest that AKT1 and AKT2 kinases have the potential to be involved in many pathological processes, in particular hepatocarcinogenesis, breast cancer, osteocarceopenia, diabetes, and the development of inflammation and fibrosis associated with alcoholic liver disease [6-10]. The importance of AKT kinases in all of the above processes makes it necessary to find new selective inhibitors for the development of the next generation of drugs.

Using the proprietary HTS Compound Collection, the Life Chemicals team has recently developed its AKT Serine/threonine Kinase Targeted Library, which contains about 1,800 drug-like screening compounds targeting AKT1 and AKT2 kinases.

Additionally, a pathway-based PI3K/Akt/mTOR Focused Library of around 4,600 structurally diverse molecules selected by the ligand-based approach is offered for anti-cancer drug discovery projects.

The compound selection can be customized based on your requirements, cherry picking is available.

Please, contact us at orders@lifechemicals.com for any additional information and price quotations.

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 Illustration of the PI3K/AKT/mTOR signaling pathway

Figure 1. Illustration of the PI3K/AKT/mTOR signaling pathway. Black arrows indicate the activation of enzymes, substrates, or metabolic processes, and red arrows indicate inhibition. Legend:

  • GF RTK - growth factor receptor tyrosine kinase
  • PI3K- phosphatidyl-inositol-3-kinase
  • PIP2 - phosphatidylinositol-3,4,5-bisphosphate
  • PIP3 - phosphatidylinositol-3,4,5-triphosphate
  • AKT - serine/threonine-protein kinase AKT
  • PDK1and PDK2 - protein serine/threonine kinase-3’
  • ATM and ATR - protein kinases
  • DNA-PK - nuclear serine/threonine kinase
  • TSC1 and TSC2 - tuberous sclerosis protein 1/2
  • mTORC1, mTORC2 - ser/thr-protein kinase 1/2
  • Rheb - GTP-binding protein
  • YAP - pro-apoptotic molecules
  • Casp9 - procaspase 9
  • 4E-BP1 - eukaryotic translation initiation factor 4E-binding protein 1
  • p70S6K - ribosomal protein S6 kinase
  • PTEN - phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase
  • BAD - Bcl2-associated agonist of cell death
  • FoxO1 - forkhead box protein O1
  • GLUT4 - glucose transporter 4, can autoinhibit itself
  • GSK-3β - glycogen synthase kinase 3 beta

Potassium channel, Sodium channel, NMDA, and GABA B receptor are examples of targets that are also available in other Life Chemicals libraries.

Compound selection

Life Chemicals has developed this new Screening Library by using HTVS ligand-receptor docking based on the HTS Compound Collection. The resulting 1,800 screening compounds were filtered by physicochemical parameters and bioactivity and then sorted according to the score values associated with the results of the docking validation experiments.

RAC-alpha serine/threonine-protein kinase (AKT1)

Key features:

  • Method: high-throughput virtual screening (docking), molecular fitting
  • X-Ray data used: 7NH5
  • Constraints: H-bond (Gly85)
  • Filters used: QikProp properties and descriptors
  • Number of compounds selected: 661

Spatial structure binding site of the complex of AKT1 with lead docking molecule F1060-0006 (docking score = -9.804)

Figure 2. Spatial structure binding site of the complex of AKT1 with lead docking molecule F1060-0006 (docking score = -9.804)

RAC-alpha serine/threonine-protein kinase (AKT2)

Key features:

  • Method: high-throughput virtual screening (docking), molecular fitting
  • X-Ray data used: 1O6L
  • Constraints: H-bond (Gly230)
  • Filters used: QikProp properties and descriptors
  • Number of compounds selected: 1211

Spatial structure binding site of the complex of AKT2 with the lead docking molecule F6414-3786 (docking score = -10.457)

Figure 3. Spatial structure binding site of the complex of AKT2 with the lead docking molecule F6414-3786 (docking score = -10.457)

References

  1. Heron-Milhavet L, Khouya N, Fernandez A, Lamb NJ. Akt1 and Akt2: differentiating the aktion. Histol Histopathol. 2011;26(5):651-662.
  2. Hers I, Vincent EE, Tavaré JM. Akt signalling in health and disease. Cell Signal. 2011;23(10):1515-1527.
  3. Peng Y, Wang Y, Zhou C, Mei W, Zeng C. PI3K/Akt/mTOR Pathway and Its Role in Cancer Therapeutics: Are We Making Headway?. Front Oncol. 2022;12:819128.
  4. Matheny RW Jr, Geddis AV, Abdalla MN, et al. AKT2 is the predominant AKT isoform expressed in human skeletal muscle. Physiol Rep. 2018;6(6):e13652.
  5. Sanchez-Gurmaches J, Martinez Calejman C, Jung SM, Li H, Guertin DA. Brown fat organogenesis and maintenance requires AKT1 and AKT2. Mol Metab. 2019;23:60-74.
  6. Xu Z, Xu M, Liu P, et al. The mTORC2-Akt1 Cascade Is Crucial for c-Myc to Promote Hepatocarcinogenesis in Mice and Humans. Hepatology. 2019;70(5):1600-1613.
  7. Hinz N, Jücker M. Distinct functions of AKT isoforms in breast cancer: a comprehensive review. Cell Commun Signal. 2019;17(1):154.
  8. Sasako T, Umehara T, Soeda K, et al. Deletion of skeletal muscle Akt1/2 causes osteosarcopenia and reduces lifespan in mice. Nat Commun. 2022;13(1):5655.
  9. Liu H, Stepicheva NA, Ghosh S, et al. Reducing Akt2 in retinal pigment epithelial cells causes a compensatory increase in Akt1 and attenuates diabetic retinopathy. Nat Commun. 2022;13(1):6045.
  10. Reyes-Gordillo K, Shah R, Arellanes-Robledo J, Cheng Y, Ibrahim J, Tuma PL. Akt1 and Akt2 Isoforms Play Distinct Roles in Regulating the Development of Inflammation and Fibrosis Associated with Alcoholic Liver Disease. Cells. 2019;8(11):1337.
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