AKT inhibitors(Hendrix College)

Prostate cancer (PCa) is among the most common malignancies and remains a leading cause of cancer-related mortality in men worldwide. One of the main drivers is the dysregulation of the downstream signalling machinery. The PI3K, AKT, and mTOR signalling pathways play a pivotal role in cellular sustenance, growth, metabolism, and proliferation. In prostate cancer this pathway is generally altered due to the mutation or deletion of the PTEN (phosphatase and tensin homolog) gene and unnecessary activities of some components of PI3K, AKT, or mTOR. Extracellular communication of the androgen receptor (AR) with a wide array of oncogenic signatures is a primary evasion mechanism of cancer therapy and metastasis. This review focuses on the structure and function of the PI3K/AKT/mTOR pathway to better understand its role in prostate tumor biology. Furthermore, current therapeutic strategies that combinatorically target individual components of this pathway, such as allosteric and ATP-competitive AKT inhibitors, isoform-selective PI3K inhibitors, first- and second-generation mTOR inhibitors, are under consideration. The study particularly focuses on the combined use of immunotherapy (checkpoint inhibitors), chemotherapy (docetaxel), and androgen deprivation therapy (ADT), which are designed to break through the resistance-generating mechanisms and increase clinical efficacy. Overall, the findings support the need to conduct comprehensive preclinical and clinical studies on these alternative treatment regimens, and the eventual goal is to develop new treatment options for prostate cancer. The evidence of the pathway-specific therapy approach for the treatment of prostate cancer in recent clinical trials still failed to give a conclusive result. The current discussion also investigates the emerging areas of focus and perfection of combination regimens. The combination of all these developments makes it clear that the PI3K/AKT/mTOR signalling pathway is a key strategic point for developing therapeutics.

Hepatic fibrosis is a progressive disorder marked by abnormal extracellular matrix buildup, with no effective antifibrotic drugs currently available. Recent evidence indicates that inhibiting phosphodiesterase 5 (PDE5) can have significant benefits for fibrotic diseases, suggesting PDE5 inhibitors may be effective antifibrotic agents. This study aimed to develop a new PDE5 inhibitor, potassium salt crystal form B (CPD1), which has much greater aqueous solubility than sildenafil. We assessed CPD1's efficacy in inhibiting hepatic stellate cells (HSCs) activation and investigated its mechanism of action. The therapeutic effect of CPD1 was studied in a carbon tetrachloride-induced liver fibrosis model, exploring its antifibrotic mechanisms via cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG1) or Akt inhibitors and PKG1 overexpression in LX-2 cells. As anticipated, the expression of PDE5A was significantly elevated in both human and mouse fibrotic liver tissues, as well as in LX-2 cells induced by transforming growth factor-beta 1 (TGFβ1). In vivo, CPD1 reduced serum transaminases in a dose-dependent manner, mitigated liver damage, decreased collagen deposition, and suppressed the activation of HSCs. Additionally, CPD1 is more effective than sildenafil at a lower dosage. In vitro, CPD1 inhibited TGFβ1-induced activation of LX-2 and reduced the expression of fibrotic marker proteins and genes. Notably, the anti-fibrotic effects of CPD1 were completely negated following the administration of a PKG1 inhibitor. Mechanistically, the CPD1 intervention effectively countered the TGFβ1-induced increase in p-IκBα and p-P65. This study demonstrated that CPD1 mitigates liver fibrosis by activating the cGMP/PKG pathway, which in turn inhibits the AKT/NF-κB pathway. Therefore, it may be considered a potential therapeutic agent that warrants further investigation for the treatment of liver fibrosis.