The evolution of small-molecule Akt inhibitors from hit to clinical candidate.

Item request has been placed! ×
Item request cannot be made. ×
loading   Processing Request
Read More Add to Saved list
  • Additional Information
    • Source:
      Publisher: Editions Scientifiques Elsevier Country of Publication: France NLM ID: 0420510 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1768-3254 (Electronic) Linking ISSN: 02235234 NLM ISO Abbreviation: Eur J Med Chem Subsets: MEDLINE
    • Publication Information:
      Publication: Paris : Editions Scientifiques Elsevier
      Original Publication: Paris, S.E.C.T. [etc.]
    • Subject Terms:
      Protein Kinase Inhibitors*/pharmacology ; Protein Kinase Inhibitors*/chemistry ; Protein Kinase Inhibitors*/chemical synthesis ; Proto-Oncogene Proteins c-akt*/antagonists & inhibitors ; Proto-Oncogene Proteins c-akt*/metabolism ; Small Molecule Libraries*/chemistry ; Small Molecule Libraries*/pharmacology ; Small Molecule Libraries*/chemical synthesis; Humans ; Molecular Structure ; Animals ; Structure-Activity Relationship ; Neoplasms/drug therapy ; Neoplasms/pathology ; Drug Discovery ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/chemical synthesis
    • Abstract:
      Akt, a key regulator of cell survival, proliferation, and metabolism, has become a prominent target for treatment of cancer and inflammatory diseases. The journey of small-molecule Akt inhibitors from discovery to the clinic has faced numerous challenges, with a significant emphasis on optimization throughout the development process. Early discovery efforts identified various classes of inhibitors, including ATP-competitive and allosteric modulators. However, during preclinical and clinical development, several issues arose, including poor specificity, limited bioavailability, and toxicity. Optimization efforts have been central to overcoming these hurdles. Researchers focused on enhancing the selectivity of inhibitors to target Akt isoforms more precisely, reducing off-target effects, and improving pharmacokinetic properties to ensure better bioavailability and distribution. Structural modifications and the design of prodrugs have played a crucial role in refining the efficacy and safety profile of these inhibitors. Additionally, efforts have been made to optimize the therapeutic window, balancing effective dosing with minimal adverse effects. The review highlights how these optimization strategies have been key in advancing small-molecule Akt inhibitors toward clinical success and underscores the importance of continued refinement in their development.
      Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
      (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)
    • Contributed Indexing:
      Keywords: AKT inhibitors; Clinical trials; Drug development; Inflammation therapy
    • Accession Number:
      0 (Protein Kinase Inhibitors)
      EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
      0 (Small Molecule Libraries)
      0 (Antineoplastic Agents)
    • Publication Date:
      Date Created: 20241001 Date Completed: 20241027 Latest Revision: 20241104
    • Publication Date:
      20241104
    • Accession Number:
      10.1016/j.ejmech.2024.116906
    • Accession Number:
      39353238