perifosine (D21266) / COSCIENS Biopharma, Akebia Therap - LARVOL DELTA

MPP+ induces α-synuclein oligomerization and neurite impairment by disrupting mitochondrial function and Akt signaling, with apigenin emerging as a potential neuroprotective agent. (PubMed, Food Chem Toxicol) - "By using a specific Akt inhibitor, perifosine, the effects of apigenin on preventing MPP+-triggered PD pathologies were eliminated. Together, this work demonstrated that apigenin exerted neuroprotection by mitigating α-synuclein oligomers, neurite damage, mitochondrial dysfunction and neuronal apoptosis via Akt-dependent mechanism."

IO biomarker • Journal • CNS Disorders • Metabolic Disorders • Movement Disorders • Parkinson's Disease • BCL2 • CASP3

The combination of temozolomide and perifosine synergistically inhibits glioblastoma growth (EANO 2025) - "Our preclinical study provides optimism for future clinical trials exploring the combination of perifosine with TMZ for glioma treatment, especially in patients with poor prognosis of glioblastoma and recurrence. In Conclusion, our study suggests that the combination of TMZ and perifosine holds promise as a strategy for glioblastoma treatment."

Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor • AKT1 • BRCA1

miR-129-1-3p down-regulation promotes BAG cochaperone 3 (BAG3)-driven pro-fibrotic processes in primary fibroblasts from patients with recessive dystrophic epidermolysis bullosa. (PubMed, Noncoding RNA Res) - "Treatment of patients' fibroblasts with the AKT inhibitor perifosine (KRX-0401) recapitulated the effects observed with the mimic molecule of miR-129-1-3p and BAG3 silencing. Our results highlight the role of the miR-129-1-3p/BAG3/AKT axis in RDEB pathogenesis, complementing and expanding the knowledge on non-coding RNAs involved in fibrosis-related processes. Taken together, these findings may contribute to enlarge the toolkit of molecules and pathways that can be exploited as therapeutic targets in skin fibrosis."

Journal • Fibrosis • Immunology • Inflammation • BAG3 • COL7A1 • MIR129 • MIR129-1

AKT inhibitors in gynecologic oncology: past, present and future. (PubMed, Front Oncol) - "Currently, multiple classes of AKT inhibitors-PH domain competitors (perifosine), allosteric inhibitors (MK-2206), and ATP-competitive agents (AZD5363, GSK2110183, GSK2141795, and GDC-0068) are under development, with several agents in phase II/III trials. This study systematically reviews recent AKTi research in gynecological cancers, aiming to provide a theoretical foundation for identifying potential biomarkers, overcoming drug resistance, and developing prognostic models. These insights may further facilitate the clinical translation of key therapeutic agents."

Journal • Review • Gynecologic Cancers • Oncology

Hypertension-related genes STOM, MEF2C promote proliferation and migration of clear cell renal cell carcinoma. (PubMed, Exp Cell Res) - "Ultimately, through the utilisation of both Mendelian randomisation analysis and molecular docking, that Perifosine, 7-Hydroxystaurosporine, and Mitoxantrone could represent efficacious treatment options for ccRCC patients by targeting PRAME. The findings provide novel evidence that hypertension influences the progression of ccRCC and offer new insights into the disease's pathophysiology."

Journal • Cardiovascular • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Hypertension • Oncology • Renal Cell Carcinoma • Solid Tumor • MEF2C • PRAME

Headgroup-driven binding selectivity of alkylphospholipids to anionic lipid bilayers. (PubMed, Colloids Surf B Biointerfaces) - "Herein, we investigated how three representative APLs - miltefosine (MIL), edelfosine (EDE), and perifosine (PER) - interact with supported lipid bilayer (SLB) platforms mimicking the high phosphatidylserine (PS) lipid content of cancer cell membranes and related compositions, and elucidated key interaction principles in terms of headgroup sterics, chain length, binding strength and selectivity, and colloidal aggregation state...These findings shed light on the functional importance of APL headgroup chemistry that goes beyond the traditional focus on pharmacological optimization and identify key mechanistic factors that enable selective PS lipid binding relevant to cancer cell targeting. In turn, these insights provide a molecular-level framework for rational APL design and colloidal delivery strategies."

Journal • Oncology

Alkylphospholipids act through stabilization of planar membranes and inhibition of membrane budding and fusion. (PubMed, J Colloid Interface Sci) - "This geometric compensation mechanism profoundly impacts membrane dynamics, where miltefosine and edelfosine exhibit greater activity compared to perifosine. These findings provide significant insights into how APLs disrupt lipid homeostasis in cellular environments."

Journal • Metabolic Disorders • Oncology

Novel targeting API@API nanomedicines for synergistic molecular signaling modulation in head and neck cancer and the microenvironment (AACR 2025) - "The API@API nanoformulation leverages natural nanoparticles derived from Cordyceps sinensis, incorporating key drugs such as FTY720 and Perifosine...In conclusion, the API@API nanoformulation platform has shown potential as an effective therapeutic strategy for HNC, offering significant advantages in efficacy, reduced side effects, and TME modulation. This platform supports broader biopharmaceutical applications, aligning with the global need for advanced cancer treatments."

Head and Neck Cancer • Oncology • Solid Tumor

Identification of Endoplasmic Reticulum Stress-related Genes for Predicting Prognosis, Immunotherapy Response, and Drug Sensitivity in Thyroid Cancer. (PubMed, J Immunother) - "Immunotherapy, as well as Palbociclib and Perifosine, were predicted to be more effective for low-risk patients. Conversely, high-risk patients were more likely to benefit from Axitinib, Imatinib, Nilotinib, and Temsirolimus. This study identified 5 signature genes as potential biomarkers and therapeutic targets for THCA. These findings provide novel insights into the prognosis and targeted therapy of THCA, offering a foundation for furture clinical applications."

IO biomarker • Journal • Endocrine Cancer • Oncology • Solid Tumor • Thyroid Gland Carcinoma • ANK1 • APOE • ERP27 • FPR2 • NOS1

Effects of c-Kit Receptor, AKT, and NF-κB Inhibitors on Immune Evasion in Multiple Myeloma Cells. (PubMed, Iran J Allergy Asthma Immunol) - "Regarding PVR, combined treatment of U266B1 cells with Masitinib, Perifosine, and Bortezomib decreased the expression level of PVR. We showed that c-Kit receptor, AKT, and NF-κB pathway inhibitors not only serve as cytotoxic drugs but also inhibit the immune escape mechanisms of malignant plasma cells by disrupting signaling pathways."

IO biomarker • Journal • Hematological Malignancies • Multiple Myeloma • Oncology • IL6 • KIT • PD-L1 • PVR

Low-Dose Perifosine, a Phase II Phospholipid Akt Inhibitor, Selectively Sensitizes Drug-Resistant ABCB1-Overexpressing Cancer Cells. (PubMed, Biomol Ther (Seoul)) - "KBV20C cancer cells (P-gp overexpression, vincristine [VIC] resistance, and GSK690693-resistance), 3...Compared with other Akt inhibitors (AZD5363, BKM120, and GSK690693), low-dose perifosine specifically sensitized P-gp-overexpressing resistant MCF-7/ADR cancer cells...Considering that perifosine has both an alkyl-phospholipid structure and is an allosteric inhibitor for membrane-localizing Akt-targeting, we examined structurally and functionally similar Akt inhibitors (miltefosine and MK-2206)...These findings could contribute to its clinical use as a first-line treatment, explicitly targeting P-gp-overexpressing resistant cancer populations in heterogeneous tumor populations. Therefore, perifosine may be valuable in delaying or reducing cancer recurrence by targeting P-gp-overexpressing drug-resistant cancer cells."

Journal • P2 data • Oncology • ABCB1

Advances in Understanding How RhoB Regulates Akt Inhibition Efficacy in NSCLC. (PubMed, Curr Cancer Drug Targets) - "Both proliferation and apoptosis tests determined that the RhoB molecule is a negative regulator of the anti-tumor activity of Akt inhibition in non-small cell lung cancer. This study suggests that RhoB expression may play a critical role in the regulation of Akt inhibition in NSCLC, potentially opening new avenues for treatment strategies."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BCL2L11

Unraveling Cholesterol-Dependent Interactions of Alkylphospholipids with Supported Lipid Bilayers. (PubMed, Langmuir) - "Herein, we employed the quartz crystal microbalance-dissipation (QCM-D) technique to characterize the real-time membrane interactions of three alkylphospholipids-edelfosine, miltefosine, and perifosine-on supported lipid bilayers with varying cholesterol fractions...These results provide biophysical evidence that different alkylphospholipids have distinct membrane-interaction behaviors that align well with reported biological activities. Our supported lipid bilayer approach offers a valuable platform for designing and assessing alkylphospholipids with tailored membrane-interaction profiles."

Journal

Signaling Transduction Network Elucidation of ACE 2 Regulating Apostichopus japonicus Autolysis by Using Integrative TMT Proteomics and Transcriptomics. (PubMed, J Agric Food Chem) - "The ACE 2 inhibitor (captopril, Capt) accelerated the autolysis...Compared to A. japonicus in the ultraviolet-irradiated and Capt groups, the Akt inhibitor (perifosine, KRX) significantly reduced the expression of the PI3K-Akt and NF-κB pathways, thereby inhibiting the autolysis process. Additionally, DIZE attenuated ROS levels, thereby inhibiting the autolysis of A. japonicus. This study provides better insight into the autolysis mechanism of A. japonicus."

Journal • AKT1

Combination of Gene Therapy and Chemotherapy in a New Targeted Hybrid Nanosystem to Hepatocellular Carcinoma. (PubMed, Int J Nanomedicine) - "The combination of targeted therapy drugs, such as selumetinib and perifosine that inhibit cell signaling pathways involved in cell survival and proliferation, with the expression of tumor suppressor transgenes, such as PTEN, may result in an efficient therapeutic approach against HCC. Moreover, the achieved data revealed that this innovative nanosystem presents a high antitumor effect, demonstrated not only by the enhancement on the programmed cell death, but also by the reduction in cell proliferation capacity. The generated formulation shows a high anticancer effect, demonstrating a high translational potential for future clinical application in HCC treatment."

Gene therapy • Journal • Gene Therapies • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • PTEN

The combination of temozolomide and perifosine synergistically inhibit glioblastoma by impeding DNA repair and inducing apoptosis. (PubMed, Cell Death Discov) - "In recurrent glioma patients, higher BRCA1 expression is associated with worse prognosis, especially the ones that received TMZ-treated. These findings underscore the potent antitumor activity of the AKT inhibitor perifosine when combined with TMZ and suggest that this approach is a promising strategy for clinical glioblastoma treatment."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor • BRCA1

Targeting the RAS upstream and downstream signaling pathway for Cancer treatment. (PubMed, Eur J Pharmacol) - "For instance, RTK inhibitors such as imatinib and afatinib selectively target these receptors, hindering ligand binding and reducing signaling initiation...Other inhibitors, like lonafarnib targeting Farnesyltransferase and GGTI 2418 targeting geranylgeranyl Transferase, disrupt post-translational modifications of proteins...Targeting downstream components with RAF inhibitors such as vemurafenib, dabrafenib, and sorafenib, along with MEK inhibitors like trametinib and binimetinib, has shown promising outcomes in treating cancers with BRAF-V600E mutations, including myeloma, colorectal, and thyroid cancers. Furthermore, inhibitors of PI3K (e.g., apitolisib, copanlisib), AKT (e.g., ipatasertib, perifosine), and mTOR (e.g., sirolimus, temsirolimus) exhibit promising efficacy against various cancers such as Invasive Breast Cancer, Lymphoma, Neoplasms, and hematological malignancies. This review offers an overview of small molecule inhibitors targeting specific proteins..."

Journal • Review • Breast Cancer • Colorectal Cancer • Endocrine Cancer • Hematological Disorders • Hematological Malignancies • Lung Cancer • Lymphoma • Multiple Myeloma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thyroid Gland Carcinoma • BRAF • PIK3CA • PTEN

Wogonin preconditioning of MSCs improved their therapeutic efficiency for colitis through promoting glycolysis. (PubMed, Inflammopharmacology) - "Consistent with these results, qPCR data indicated that wogonin treatment induced the expression of immunomodulatory molecules IL-10, IDO, and AGR1, which were reduced by perifosine. Together, our data demonstrated that wogonin preconditioning strategy further augmented the therapeutic efficacy of MSCs via promoting glycolysis, which should be a promising strategy for optimizing MSCs therapy in IBDs."

Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • IL10

Study on the mechanism of CXCL12/CXCR4-axis-mediated upregulation of IL-8 and IL-6 on the biological function of acute T lymphocyte leukaemia cells. (PubMed, Cytotechnology) - "Treatment of cells with AMD3100, a CXCR4 antagonist, and G-CSF blocked the CXCL12/CXCR4 axis, inducing biological changes in the leukaemia cells and altering IL-8 and IL-6 levels...ELISA results confirmed that MG-132 (10 μm) inhibits IL-8 expression and that the NF-κB signalling pathway contributes to this effect...Treatment with SP600125, a Jun N-terminal kinase inhibitor, and Perifosine also inhibited IL-8 expression; however, this effect occurred later...IL-6 and IL-8 are physiologically regulated by the CXCL12/CXCR4 axis, while the NF-κB and JNK/AP-1 pathways are required for IL-8 expression in T-cell acute lymphoblastic leukaemia. Accordingly, by upregulating IL-8, the bone marrow microenvironment and CXCL12/CXCR4 axis may contribute to T-cell acute lymphoblastic leukaemia pathogenesis."

Journal • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • T Acute Lymphoblastic Leukemia • CXCL12 • CXCL8 • IL6

Neuroprotective effects of Rehmannia glutinosa polysaccharide on chronic constant light (CCL)-induced oxidative stress and autophagic cell death via the AKT/mTOR pathway in mouse hippocampus and HT-22 cells. (PubMed, Int J Biol Macromol) - "Importantly, the AKT inhibitor Perifosine significantly weakened the neuroprotective of RGP on Light-induced oxidative stress and autophagy in HT-22 cells by inhibiting AKT/mTOR pathway and increasing the content of autophagy-related protein. Our data demonstrated, for the first time, that oxidative stress and the AKT/mTOR pathway plays a critical role in Light-induced apoptosis and autophagic cell death in mice and HT-22 cells."

Journal • Preclinical • Cognitive Disorders • Mood Disorders • Psychiatry

ROS/mtROS promotes TNTs formation via the PI3K/AKT/mTOR pathway to protect against mitochondrial damages in glial cells induced by engineered nanomaterials. (PubMed, Part Fibre Toxicol) - "Despite their biophysical properties, various types of nanomaterials promote TNTs formation and mitochondrial transfer, preventing cell apoptosis and disrupting ATP production induced by nanomaterials. ROS/mtROS and the activation of the downstream PI3K/AKT/mTOR pathway are common mechanisms to regulate TNTs formation and mitochondrial transfer. Our study reveals that engineered nanomaterials share the same molecular mechanism of TNTs formation and intercellular mitochondrial transfer, and the proposed adverse outcome pathway contributes to a better understanding of the intercellular protection mechanism against nanomaterials-induced neurotoxicity."

Journal

Mitochondrial Functionality Is Regulated by Alkylphospholipids in Human Colon Cancer Cells. (PubMed, Biology (Basel)) - "These alterations led to higher mitochondrial membrane potential, which was potentiated by decreased uncoupling protein 2 (UCP2) levels and increased reactive oxygen species (ROS) production. Consequently, perifosine induced an imbalance in mitochondrial function, resulting in higher ROS production that ultimately impacted cellular viability."

Journal • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Germline PTEN genotype-dependent phenotypic divergence during the early neural developmental process of forebrain organoids. (PubMed, Mol Psychiatry) - "Perifosine, an AKT inhibitor, reduced over-activated AKT and partially corrected the abnormalities in cellular organization observed in PTEN organoids...These findings demonstrate that different PTEN missense mutations can have a profound impact on neurodevelopment at diverse stages which in turn may predispose PHTS individuals to ASD. Further study will shed light on ways to mitigate pathological impact of PTEN mutants on neurodevelopment by stage-specific manipulation of downstream PTEN signaling components."

Journal • Autism Spectrum Disorder • Genetic Disorders • Oncology • PTEN

A high-throughput Gaussia luciferase reporter assay for screening potential gasdermin E activators against pancreatic cancer. (PubMed, Acta Pharm Sin B) - "Based on this system, ponatinib and perifosine are screened out from the FDA-approved anti-cancer drug library containing 106 compounds. Further, we demonstrate that perifosine suppresses pancreatic cancer by promoting pyroptosis via caspase-3/GSDME pathway both in vitro and in vivo. Collectively, this study reveals the great significance of hGLuc-hGSDME-PCA in identifying compounds triggering GSDME-dependent pyroptosis and developing promising therapeutic agents for PDAC."

Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CASP3 • GSDME

Therapeutic Targeting of Regulated Signaling Pathways of Non-Small Cell Lung Carcinoma. (PubMed, ACS Omega) - "We highlighted the therapeutic potential of Epigallocatechin gallate (EGCG), Perifosine, ABT-737, Thymoquinine, Quercetin, Venetoclax, Gefitinib, and Genistein. These compounds are implicated in the therapeutic management of NSCLC. This review further offers deeper mechanistic insights into different signaling pathways that could be targeted for NSCLC therapy by phytochemicals and small-molecule inhibitors."

Journal • Review • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • STAT3