Ex-Rad (recilisib) / Traws Pharma - LARVOL DELTA

Berberine-cinnamic acid co-crystal effect in ameliorating hyperlipidemia might be regulated through the PI3K/AKT/mTOR/SREBP-1 signaling pathway. (PubMed, FEBS Open Bio) - "Furthermore, the phosphorylation of phosphatidylinositol 3-kinase (PI3K), AKT and mammalian target of rapamycin (mTOR) was inhibited by BBR-CA, contributing to decreased active SREBP-1 in the nucleus, and was reversed and enhanced by the PI3K agonist recilisib and inhibitor LY294002, respectively. Taken together, our results suggest that BBR-CA could function by modulating the PI3K/AKT/mTOR signaling pathway, resulting in decreased nuclear expression of SREBP-1, as well as reduced expression of stearoyl-CoA desaturase 1 and acetyl-CoA carboxylase, thus alleviating hyperlipidemia. Further experimental validation is required to confirm these results."

Journal • Dyslipidemia • Hepatocellular Cancer • Oncology • Solid Tumor • SCD

Dendrobin A inhibits gastric cancer: Mechanistic insights supported by integrated evidence. (PubMed, Phytomedicine) - "Dendrobin A exerts potent anti-GC effects by inhibiting HSP90AB1/CDK2/PARP1 expression and modulating P53/PI3K-Akt signaling, supporting its therapeutic potential."

Journal • Gastric Cancer • Oncology • Solid Tumor • CDC37 • CDKN1A • HSP90AB1

Sappanone A, a potential natural inhibitor of PI3K, alleviates metabolic dysfunction-associated steatohepatitis in experimental models. (PubMed, Biochem Pharmacol) - "Network pharmacology results indicated that SA might alleviate MASH through the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/(Mechanistic target of rapamycin) mTOR signaling pathway. Notably, the PI3K activator Recilisib weakened the inhibitory effect of SA on PA-induced p-AKT and COL1a1 in LX-2 cells, further confirming the dependence of SA on PI3K activity. In conclusion, we identified SA as a potential natural PI3K inhibitor and promising compound for the treatment of MASH."

Journal • Fibrosis • Hepatocellular Cancer • Hepatology • Immunology • Liver Failure • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Oncology • Solid Tumor • COL1A1

Mechanistic Insights into AKT1/GSK3β/CD36 Axis Regulation in ZLY06-Induced Hepatic Lipid Metabolism Dysfunction and Protective Intervention via AKT Activation Strategies. (PubMed, Food Chem Toxicol) - "Experimental evidence demonstrated that AKT activators (such as SC79 and Recilisib) mitigated ZLY06-induced lipid accumulation by restoring AKT1 phosphorylation, reducing CD36 expression, and normalizing lipid metabolism. These findings provided critical mechanistic insights into ZLY06-induced hepatotoxicity and suggested a potential therapeutic strategy to alleviate hepatic lipid accumulation through AKT pathway activation. This work advances our understanding of drug-induced hepatic lipid metabolism disorders and lays a foundation for the development of safer therapeutic agents."

Journal • Dyslipidemia • Metabolic Disorders • CD36 • GSK3B • SCARB1

PI3K-Mediated Regulation of Glycogen Metabolism To Facilitate Tomato chlorosis Virus Transmission by Bemisia tabaci MED. (PubMed, J Agric Food Chem) - "Similarly, feeding whiteflies with the PI3K inhibitor PI3K-IN-1 decreased ToCV transmission, while the PI3K activator Recilisib enhanced it...Conversely, the inhibition of PI3K disrupts glycogen metabolism, consequently impairing viral transmission. These findings highlight that PI3K is crucial for facilitating ToCV transmission by whiteflies and offer a potential target for controlling vector-borne plant viruses."

Journal

Discovery of a novel quinoxaline derivative modulator via a dual P53/TLR2 targeting strategy for the alleviation of radiation damage. (PubMed, Eur J Med Chem) - "In this study, a series of novel quinoxaline molecules were designed and synthesized with Ex-RAD and TLR2 agonist as the lead, showing anti-radiation effects and compound Z9 was the best one of them...Notably, Z9 showed excellent stability and affinity for the TLR2 protein conjugate in molecular docking and molecular dynamics simulations. These findings suggested that Z9 was worth further research being a potential candidate for anti-radiation drugs, as the dual modulator of P53/TLR2."

Journal • BAX • MYD88 • TLR2

Curcumol attenuates hyperproliferation and inflammatory response in a psoriatic HaCaT keratinocyte model by inhibiting the PI3K-Akt pathway and ameliorates skin lesions and inflammatory status in psoriasis-like mice. (PubMed, Inflammopharmacology) - "Additionally, in vivo, curcumol ameliorates psoriasis-like skin lesions and inflammatory status in imiquimod-induced mice. Further investigation shows that curcumol partially counteracts the activation of PI3K-Akt by recilisib in keratinocytes. These results suggest that curcumol may be a promising therapeutic option for psoriasis."

Journal • Preclinical • Dermatology • Immunology • Inflammation • Psoriasis

Asperosaponin VI alleviates TNBS-induced Crohn's disease-like colitis in mice by reducing intestinal epithelial cell apoptosis via inhibiting the PI3K/AKT/NF-κB signaling pathway (PubMed, Nan Fang Yi Ke Da Xue Xue Bao) - "AVI can improve TNBS-induced CD-like colitis in mice by reducing intestinal epithelial cell apoptosis and intestinal barrier damage via inhibiting the PI3K/AKT/NF-κB signaling pathway."

Journal • Preclinical • Crohn's disease • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease

Design, synthesis and biological evaluation of (E)-kojyl-styryl-sulfones: Novel recilisib hybrids as promising radioprotectors. (PubMed, Arch Pharm (Weinheim)) - "Moreover, the antioxidant evaluation of these selected hybrids on the IR-induced reactive oxygen species (ROS) generation and lipid peroxidation in the HFF-1 cells revealed that they could significantly downregulate IR-induced oxidative stress in the HFF-1 cells, while mechanistically recilisib is not a well-established ROS scavenger. The obtained results suggest that these privileged (E)-kojyl-styryl-sulfones can serve as promising radioprotectors for further studies and development."

Journal

HYPOCRELLIN A, A NATURAL SMALL COMPOUND, EXERTS ANTI-TUMOR EFFECTS VIA MULTI-TARGET INHIBITION OF THE PI3K-AKT-MTOR, MAPK, AND STAT3 SIGNALING PATHWAYS IN INTRAHEPATIC CHOLANGIOCARCINOMA (AASLD 2024) - "This inhibitory effect can be rescued by recilisib, an activator of PI3K-AKT-mTOR... HA demonstrated promising therapeutic efficacy against ICC through its multi-target inhibition effects on the PI3K-AKT-mTOR, MAPK, and STAT3 signaling pathways. Moreover, it exhibited notable therapeutic benefits in primary ICC model (KRAS/P19/SB), positioning it as a novel therapeutic agent for treating ICC."

Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • KRAS

Hypocrellin A against intrahepatic Cholangiocarcinoma via multi-target inhibition of the PI3K-AKT-mTOR, MAPK, and STAT3 signaling pathways. (PubMed, Phytomedicine) - "HA, a novel natural small molecule, demonstrated promising therapeutic efficacy against ICC through its multi-target inhibitory effects on the PI3K-AKT-mTOR, MAPK, and STAT3 signaling pathways. Moreover, it exhibited notable therapeutic benefits in a primary ICC model (KRAS/P19/SB), positioning it as a novel therapeutic agent for ICC."

Journal • Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • KRAS

MG-132 activates sodium palmitate-induced autophagy in human vascular smooth muscle cells and inhibits senescence via the PI3K/AKT/mTOR axis. (PubMed, Lipids Health Dis) - "MG-132 activates autophagy by inhibiting the PI3K/AKT/mTOR pathway, thereby inhibiting palmitate-induced proliferation, migration, and oxidative stress in vascular smooth muscle cells and suppressing their senescence."

Journal • Atherosclerosis • Cardiovascular • Dyslipidemia • BECN1

New mechanistic understanding of osteoclast differentiation and bone resorption mediated by P2X7 receptors and PI3K-Akt-GSK3β signaling. (PubMed, Cell Mol Biol Lett) - "P2X7 receptors positively regulate osteoclast formation and bone resorption by activating the PI3K-Akt-GSK3β signaling pathway."

Journal • Metabolic Disorders • Musculoskeletal Diseases • Orthopedics • Osteoporosis • Rheumatology • CSF1 • GSK3B • MMP9 • NFATC1 • TNFRSF11A • TRAP

FNDC5 inhibits malignant growth of human cervical cancer cells via restraining PI3K/AKT pathway. (PubMed, J Cell Physiol) - "The effects of FNDC5 were prevented by inhibiting integrin with cilengitide, activating PI3K with recilisib or activating Akt with SC79...PI3K inhibitor LY294002 showed similar effects to FNDC5 in HeLa and SiHa cells...These results indicate that FNDC5 inhibits the malignant phenotype of CxCa cells through restraining PI3K/Akt signaling. Upregulation of FNDC5 may play a beneficial role in retarding the tumor growth of CxCa."

Journal • Cervical Cancer • Oncology • Solid Tumor

Serum microRNA profile of rhesus macaques following ionizing radiation exposure and treatment with a medical countermeasure, Ex-Rad. (PubMed, Sci Rep) - "Finally, Ex-Rad treatment restored the level of several miRNAs whose expression was significantly changed after radiation exposure, including miR-16-2, an miRNA previously associated with radiation survival. Taken together, our findings support the use of miRNA expression as an indicator of radiation exposure and the use of Ex-Rad as a potential radioprotectant."

Journal • Inflammation • ACACA • MIR16 • miR-185 • MIR27B • MIR30A • MIR375 • MIR423

Effects of the PI3K/Akt/HO-1 pathway on autophagy in a sepsis-induced acute lung injury mouse model. (PubMed, Int Immunopharmacol) - "Furthermore, when PI3K inhibitors LY294002, PI3K activators Recilisib and hemin were administered before the surgery, Akt, p-Akt, HO-1, and LC3-II levels were measured 24 h post-surgery. LY294002 inhibited p-Akt/Akt, HO-1, and LC3B-II protein expression; and hemin reversed the inhibitory effect of LY294002. The protective effect of HO-1 was involved in the mediation of autophagy, which may be regulated by the PI3K/Akt signaling pathway during sepsis-induced lung injury in mice."

Journal • Preclinical • Acute Lung Injury • Infectious Disease • Inflammation • Respiratory Diseases • Septic Shock • BECN1 • IL10 • IL1B • LAMP2 • TNFA

BDNF alleviates Parkinson's disease by promoting STAT3 phosphorylation and regulating neuronal autophagy. (PubMed, Cell Tissue Res) - "The PI3K agonist Recilisib activated the PI3K/AKT/mTOR pathway, promoted autophagy, and alleviated neuronal cell damage. BDNF alleviates PD pathology by promoting STAT3 phosphorylation and regulating neuronal autophagy in SH-SY5Y cells and cultured primary neurons. Finally, BDNF has neuroprotective effects on PD model mice."

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease • BDNF • NTRK2

Inhibiting PI3K/Akt-Signaling Pathway Improves Neurobehavior Changes in Anti-NMDAR Encephalitis Mice by Ameliorating Blood-Brain Barrier Disruption and Neuronal Damage. (PubMed, Cell Mol Neurobiol) - "To study its potential mechanism, LY294002 (PI3K inhibitor, 8 mg/kg) and Recilisib (PI3K agonist, 10 mg/kg) were treated by intraperitoneal injection, respectively. Our results showed that the activation of PI3K/Akt, along with the changes in TJ-related proteins ZO-1 and Claudin-5, may be closely related to BBB damage and neurobehavior changes in anti-NMDAR encephalitis mice. PI3K inhibition attenuates BBB disruption and neuronal damage in mice, thereby improving neurobehavior."

Journal • Preclinical • CNS Disorders • CLDN5 • TJP1

Analysis of the Proteomic Profile in Serum of Irradiated Nonhuman Primates Treated with Ex-Rad, a Radiation Medical Countermeasure. (PubMed, J Proteome Res) - "We observed that administration of Ex-Rad post-irradiation is capable of mitigating radiation-induced perturbations in protein abundance, particularly in restoring protein homeostasis, immune response, and mitigating hematopoietic damage, at least in part after acute exposure. Taken together, restoration of functionally significant pathway perturbations may serve to protect damage to vital organs and provide long-term survival benefits to the afflicted population."

Journal

Effect of miR‑29a‑3p in exosomes on glioma cells by regulating the PI3K/AKT/HIF‑1α pathway. (PubMed, Mol Med Rep) - "Similarly, Recilisib slowed the inhibitory effect of miR‑29a‑3p on glycolysis and glycolysis‑related molecules. The results of this study tentatively confirm that miR‑29a‑3p carried by exosomes can be used as a novel diagnostic marker and a potential inhibitory molecule for glioma cells, providing a new theoretical and experimental basis for the precise clinical treatment of glioma."

Journal • Brain Cancer • CNS Tumor • Glioma • Oncology • Solid Tumor • BCL2 • HIF1A • MIR29A • PDK1

Inhibiting specificity protein 1 attenuated sevoflurane-induced mitochondrial stress and promoted autophagy in hippocampal neurons through PI3K/Akt/mTOR and α7-nAChR signaling. (PubMed, Neurosci Lett) - "Meanwhile, recilisib was utilized for PI3K/Akt/mTOR signaling activation, GTS-21 and MLA (methylycaconitine citrate) were used to activate or inactivate alpha 7 nicotinic acetylcholine receptor (α7-nAChR), respectively. In conclusions, our research indicated that SP1 regulated sevoflurane-induced oxidative stress dysregulation, mitochondrial function and cell autophagy in hippocampus via mediating the PI3K/Akt/mTOR and α7-nAChR pathways. Therefore, it might provide a novel sight for sevoflurane-induced hippocampus injury and POCD therapy."

Journal • Anesthesia • CNS Disorders • Cognitive Disorders • Metabolic Disorders

Autophagy participates in germline cyst breakdown and follicular formation by modulating glycolysis switch via Akt signaling in newly-hatched chicken ovaries. (PubMed, Dev Biol) - "Furthermore, the glycolysis level was downregulated in ovaries treated with 3-MA, while Recilisib (a specific activator of Akt) reversed this inhibiting effect of 3-MA on primordial folliculogenesis. Collectively, these data indicate that autophagy functions to maintain germ cell cyst breakdown and primordial follicle assembly by regulating ovarian glycolysis involving Akt signaling in the ovaries of newly-hatched chickens."

Journal

Recent applications of vinyl sulfone motif in drug design and discovery. (PubMed, Eur J Med Chem) - "It can be found in the chemical structure of many leads and drug candidates such as Rigosertib, Recilisib, K11777, WRR-483 and BAY 11-7085. The vinyl sulfone motif has been especially used in the design of chemotherapeutics and neuroprotective as well as radioprotective agents. In this review, we have described design, chemical structures, biological properties and related mechanism of actions, and structure activity relationship (SAR) study of vinyl sulfone-based compounds."

Journal • Review

Analysis of the metabolomic profile in serum of irradiated nonhuman primates treated with Ex-Rad, a radiation countermeasure. (PubMed, Sci Rep) - "We observed alterations in biochemical pathways relating to inflammation and oxidative stress after radiation exposure that were alleviated in animals that received Ex-Rad I or Ex-Rad II. The results from this study lend credence to the possible radiomitigative effects of this drug possibly via a dampening of metabolism-based tissue injury, thus aiding in recovery of vital, radiation-injured organ systems."

Journal • Immunology • Inflammation

miR-15b, a diagnostic biomarker and therapeutic target, inhibits oesophageal cancer progression by regulating the PI3K/AKT signalling pathway. (PubMed, Exp Ther Med) - "Treatment of EC cells with the PI3K/AKT pathway agonist recilisib displayed the opposite effects, blocking the inhibitory function of miR-15b mimic on EC cell viability, migration and invasion. In summary, the results indicated that miR-15b suppressed EC cell viability, migration and invasion, and promoted EC cell apoptosis by inhibiting the PI3K/AKT signalling pathway."

Biomarker • Journal • Colorectal Cancer • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma