Akt Pathway Inhibitors
| Autor: | Osman F. Güner, Nne E. Uko, J. Phillip Bowen, Diane F. Matesic |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Benzylamines
Protein Conformation Antineoplastic Agents Thiophenes Diamines Ipatasertib Piperazines Phosphatidylinositol 3-Kinases Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Cell Line Tumor Quinoxalines Thiadiazoles Drug Discovery Solenopsin Humans Pyrroles Protein Kinase Inhibitors Protein kinase B Phospholipids PI3K/AKT/mTOR pathway 030304 developmental biology Sulfonamides 0303 health sciences Kinase General Medicine Afuresertib Perifosine Molecular Docking Simulation Pyrimidines chemistry Drug Design 030220 oncology & carcinogenesis Cancer research Pyrazoles Phosphorylation Heterocyclic Compounds 3-Ring Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | Current Topics in Medicinal Chemistry. 20:883-900 |
| ISSN: | 1568-0266 |
| DOI: | 10.2174/1568026620666200224101808 |
| Popis: | Cancer is a devastating disease that has plagued humans from ancient times to this day. After decades of slow research progress, promising drug development, and the identification of new targets, the war on cancer was launched, in 1972. The P13K/Akt pathway is a growth-regulating cellular signaling pathway, which in many human cancers is over-activated. Studies have demonstrated that a decrease in Akt activity by Akt inhibitors is associated with a reduction in tumor cell proliferation. There have been several promising drug candidates that have been studied, including but not limited to ipatasertib (RG7440), 1; afuresertib (GSK2110183), 2; uprosertib (GSK2141795), 3; capivasertib (AZD5363), 4; which reportedly bind to the ATP active site and inhibit Akt activity, thus exerting cytotoxic and antiproliferative activities against human cancer cells. For most of the compounds discussed in this review, data from preclinical studies in various cancers suggest a mechanistic basis involving hyperactivated Akt signaling. Allosteric inhibitors are also known to alter the activity of kinases. Perifosine (KRX- 0401), 5, an alkylphospholipid, is known as the first allosteric Akt inhibitor to enter clinical development and is mechanistically characterized as a PH-domain dependent inhibitor, non-competitive with ATP. This results in a reduction in Akt enzymatic and cellular activities. Other small molecule (MK- 2206, 6, PHT-427, Akti-1/2) inhibitors with a similar mechanism of action, alter Akt activity through the suppression of cell growth mediated by the inhibition of Akt membrane localization and subsequent activation. The natural product solenopsin has been identified as an inhibitor of Akt. A few promising solenopsin derivatives have emerged through pharmacophore modeling, energy-based calculations, and property predictions. |
| Databáze: | OpenAIRE |
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