This study suggested that GLP-2 ameliorated D-galactose induced muscle aging by IGF-1/Pi3k/Akt/FoxO3a pathway.

P2, N=20, Recruiting, Memorial Sloan Kettering Cancer Center

HGF induced GPX1 expression through the NF-[Formula: see text]B and Akt pathways, suggesting a central role in gastric cell proliferation and invasion. Hence, GPX1 emerges as a potential therapeutic target for gastric cancer.

P1/2, N=49, Active, not recruiting, National Jewish Health | Recruiting --> Active, not recruiting

Research and development on Nectin-4 antibody-drug conjugates (ADC) have been greatly accelerated since the approval of enfortumab vedotin to treat uroepithelial cancer...Importantly, inhibiting autophagy by LY294002 and chloroquine significantly enhances the cytotoxicity effects of Nectin-4-MMAE in bladder cancer cells...The combination group exhibited a notable rise in apoptosis and necrosis, as indicated by H&E staining and immunohistochemistry (cleaved caspase-3, ki67). These findings demonstrated the cytoprotective role of autophagy during Nectin-4-MMAE treatment and highlighted the potential of combining Nectin-4-MMAE with autophagy inhibitors for bladder cancer treatment.

Unexpectedly, LY294002, a PI3K inhibitor, increased melanogenesis without UV or α-MSH stimulation, suggesting that the PI3K/AKT signaling pathway may not be a major signaling pathway for melanogenesis...In addition, FOXO4-wt overexpression showed that FOXO4 enhance melanin synthesis. Overall, the RSK2-FOXO4 signaling pathway plays a key role in modulating melanogenesis.

Subsequently, after antagonizing the TLR4 pathway with antagonists (TAK242, PDTC, KG501, SR11302, LY294002), the expression of IL-6, TNF-α, iNOS, and IL-1β mRNA were detected by RT-qPCR. Furthermore, JXY inhibited M1-related molecules such as IL-6, TNF-α, iNOS, and IL-1β after antagonizing the TLR4 pathway. Obviously, JXY could exhibit inhibitory effects on the development of colon tumors in mice with CAC by promoting M1 polarization through TLR4-mediated signaling and impeding M2 polarization of macrophages.

Astaxanthin significantly suppresses NPC cell proliferation, cell cycle arrest, migration, invasion while promoting cell apoptosis by inactivating PI3K/AKT and NF-κB pathways. The study first reveals the anticancer role of astaxanthin in NPC, providing a potential candidate for NPC treatment.

However, rapamycin (RAPA, an autophagy activator) and LY294002 (a PI3K inhibitor) reversed the effects of SNHG1 overexpression on the viability and apoptosis of chondrocytes as well as on the proteins related to PI3K/Akt pathway and autophagy. In OA-modeled mice, SNHG1 overexpression prevented the loss of chondrocytes via the activation of PI3K/Akt pathway and the suppression of autophagy. SNHG1 overexpression might inhibit the apoptosis of chondrocytes by promoting PI3K/Akt pathway and inhibiting autophagy.

P2, N=33, Not yet recruiting, M.D. Anderson Cancer Center

Administration of the PI3K/AKT pathway inhibitor LY294002 inhibited the radioprotective effects in Cx43-overexpressing intestinal epithelial cells. Our study demonstrated that Cx43 expression is decreased by ionizing radiation, which facilitates the radioprotection of intestinal epithelial cells.

Collectively, this study enhanced our understanding of NENA NSLA by elucidating the proteogenomic landscape and proposed saracatinib as a potential treatment for this patient population that lacks effective targeted therapies. The proteogenomic landscape in never-smoker lung cancer without known driver mutations reveals prognostic proteins and enhanced estrogen signaling that can be targeted as a potential therapeutic strategy to improve patient outcomes.

Overexpression of KLF15 can inhibit the proliferation and invasion of Gastric cancer cells and promote cell apoptosis and autophagy, and its mechanism may be related to the regulation of the PI3K/Akt/mTOR signaling pathway.

When RCC cells were treated with a PI3K inhibitor (LY294002), TFE3 expression increased and phospho-Akt expression decreased. TFE3 is related to the PI3K/Akt pathway in RCC, and our results suggest that PI3K/Akt inhibitors may potentially aid in treatment of patients with RCC by affecting tumor microenvironment.

P2, N=35, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: May 2024 --> May 2025 | Trial primary completion date: May 2024 --> May 2025

OPN promoted tumor sphere formation and angiogenesis in TNBC by activating the PI3K/AKT/mTOR pathway to regulate GPX4-mediated anti-lipid peroxidation levels.

P1/2, N=49, Recruiting, National Jewish Health | Trial completion date: Jun 2024 --> Jun 2025 | Trial primary completion date: Dec 2023 --> Sep 2024

LY294002 and siFOXO3 rescued the inhibition of the PI3K/AKT/mTOR/FOXO3 signalling pathway and the promotion of autophagy by Har...Interestingly, pretreatment with chloroquine (CQ), erastin, rapamycin (Rap), or ferrostatin-1 (Fer-1) increased or reversed the ferroptosis and pyroptosis promoted by Har, respectively...In conclusion, Har exerts its anti-ovarian cancer effect not only by promoting autophagy by regulating the PI3K/AKT/mTOR/FOXO3 signalling pathway but also by promoting ferroptosis and pyroptosis. Additionally, there is complex crosstalk between autophagy, ferroptosis, and pyroptosis in ovarian cancer.

Triphala exerted significant inhibitory effects on cell metabolic activity, migration, invasion, and proliferation in OSCC cell lines, accompanied by the induction of apoptosis, which was mediated through the inactivation of the PI3K/Akt pathway.

Avutometinib, and to a larger extent its combination with FAK inhibitor VS-4718, demonstrated promising in vivo activity against a KRAS wild-type LGSOC-PDX. These data support the ongoing registration-directed study (RAMP201/NCT04625270).

Phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signalling pathway inhibitor LY294002 was used for rescue experiments... LncRNA SNHG11 is highly expressed in colorectal cancer. lncRNA SNHG11 can promote the malignant progression of colorectal cancer cells by regulating the PI3K/Akt/mTOR signaling pathway, and this finding provides a new theoretical basis for targeted therapy of colorectal cancer.

P2, N=225, Active, not recruiting, Verastem, Inc. | Recruiting --> Active, not recruiting

P2, N=35, Active, not recruiting, National Cancer Institute (NCI)

P1/2, N=62, Recruiting, Amplia Therapeutics Limited | Phase classification: P1b/2a --> P1/2

In summary, the combined results of our network pharmacology analysis and in vitro tests emphasized that Kirenol hinders the growth of ovarian cancer cells, causes cell cycle arrest, enhances apoptosis, and hampers migration, possibly by regulating the PI3K/AKT/CDK4 signaling pathway.

P1/2, N=33, Recruiting, University of Utah | Not yet recruiting --> Recruiting

LY294002 reduced PI3K and Akt phosphorylation levels and attenuated AAV-VEGFA-related improvements. In conclusion, sustained local AAV-mediated VEGFA overexpression in spinal cord can significantly promote angiogenesis and ameliorate locomotor impairment after SCI in a contusion mouse model through activation of the PI3K/Akt signaling pathway.

FABP5 promotes active fatty acid synthesis and excessive proliferation of GCs by activating PI3K-AKT signaling, suggesting that abnormally high expression of FABP5 in GCs may be a novel biomarker or a research target for PCOS treatment.

The most promising compounds 12b and 12d exhibited excellent antitumor activity against the leukemia SR cell line, which is the most sensitive cell line, with IC50 0.10 ± 0.01 and 0.09 ± 0.01 μM, respectively, along with significant effects on PI3Kα/PI3Kβ/PI3Kδ with IC50 values of 0.17 ± 0.01, 0.13 ± 0.01 and 0.76 ± 0.04 μM, respectively, for 12b and 1.27 ± 0.07, 3.20 ± 0.16 and 1.98 ± 0.11, respectively, for 12d compared to LY294002. Compared to Afinitor, these compounds inhibited mTOR with IC50 values of 0.83 ± 0.05 and 2.85 ± 0.17 μM, respectively...Compounds 12b and 12d also caused a G2/M cell cycle arrest in the leukaemia SR cell line. The findings of this study indicate that the highest effect was observed for 12b, which was supported by western blot and docking analysis.

This study unveils CBG's ability to enhance MME expression, deactivate FAK/STAT3 signaling, and inhibit TNBC metastasis by suppressing M2-skewed macrophages.

Administration of the PI3K/AKT pathway inhibitor LY294002 inhibited the radioprotective effects in Cx43-overexpressing intestinal epithelial cells. Our study demonstrated that Cx43 expression is decreased by ionizing radiation, which facilitates the radioprotection of intestinal epithelial cells.

P1/2, N=153, Recruiting, Verastem, Inc. | N=53 --> 153 | Trial completion date: Sep 2025 --> Apr 2027

P2, N=42, Recruiting, Washington University School of Medicine | Trial completion date: Jun 2026 --> Dec 2026 | Trial primary completion date: Jun 2026 --> Dec 2026

Fortunately, 7c exhibited a better safety profile on normal cells (WI-38) than doxorubicin by 2.2-fold...In addition to its remarkable inhibitory activity on all PI3K isoforms, specifically PI3K-δ with IC50 = 0.64 µM Compared with LY294002 IC50 = 7.6 µM...MD showed the interaction of 7c with the crucial amino acids of the active domain of both EGFR/PI3K which may explain its potent inhibitory activities. In vivo study disclosed a significant decrease in tumor weight and the number of nodules in the group of mice treated with 7c compared with the control group.

Compound 4c displayed cytotoxicity more than erlotinib in the MDA-MB-231 cells with IC50 8.5 µM. Moreover, compound 5 exhibited potent inhibitory activity on EFGR with IC50 0.1812 µM, as well as PI3Kβ inhibitory activity that was twofold higher than LY294002, suggesting that this compound has a dual EGFR and PI3Kβ inhibiting activity...Furthermore, compound 5 decreased AKT and m-TOR expression in PC-3 cells, showing that it specifically targets these cells via the EGFR/PI3K/Akt/m-TOR signalling pathway. Simultaneously, compound 5 caused cell cycle arrest at S phase and induced activation of both intrinsic and extrinsic apoptotic pathways.

In an imiquimod (IMQ)-induced psoriasis mouse model, saracatinib effectively blocked MLKL phosphorylation and inflammatory responses in vivo. Taken together, these findings indicate that saracatinib inhibits necroptosis by targeting MLKL, providing a potential therapeutic approach for skin inflammation-related diseases such as psoriasis.

Specifically, dexamethasone (Dex) decreased p-PI3K and p-AKT levels, which were reversed following Ech addition. Validation of the PI3K inhibitor (LY294002) and molecular docking of Ech and PI3K/AKT further indicated that Ech could directly enhance PI3K/AKT activity to alleviate Dex-induced inhibition...Our results provide robust evidence that PI3K/AKT/FOXO1 plays a crucial role in the development of SONFH. Moreover, Ech may be a promising candidate drug for the treatment of SONFH.

Focal adhesion kinase (FAK) inhibitor defactinib was used to further explore the molecular mechanism of ITGB4...In addition, ITGB4 could interact with FAK in lung adenocarcinoma cells. ITGB4 may promote cell migration of lung adenocarcinoma through FAK signaling pathway and has the potential to be a biomarker for lung adenocarcinoma.

A septic mouse model was established by cecal ligation and puncture (CLP), then administered with lentivirus encoding si-TLR9/LY294002...TLR9 expression was augmented in the cecal tissues, TLR9 and MyD88 interaction was enhanced, nuclear p65 protein level was increased, cytoplasmic p65 protein level was decreased, and the nuclear factor kappa B (NF-κB) pathway was activated in CLP-induced septic mice, while TLR9 knockout protected against CLP-induced sepsis via the MyD88/NF-κB pathway inactivation. Briefly, TLR9 inhibition-mediated protection against CLP-induced sepsis was associated with a reduction in pro-inflammatory cytokine release and a promotion of bacterial clearance via a mechanism involving the MyD88/NF-κB pathway inactivation.

This study demonstrated that myricetin effectively mitigates kidney injury in DN mice through the regulation of macrophage polarization via the PI3K/Akt signaling pathway.

Tan IIA suppresses SCLC proliferation and metastasis by inhibiting the PI3K/Akt signaling pathway, thereby highlighting the potential of Tan IIA as a new and relatively safe drug candidate to treat SCLC.

A certain concentration of leptin (25∼100 ng/mL) could promote proliferation of undifferentiated spermatogonia, which was mediated by PI3K/AKT/mTOR pathway.