GSK2334470 / GSK - LARVOL DELTA

The PDK-1 inhibitor GSK2334470 induces cell death and G0/1 cell cycle arrest in human pancreatic cancer cells (EACR 2025) - "GSK2334470 PDK-1 inhibitor was found, for the first time worldwide, to exhibit promising in vitro anticancer activity against the PDAC cell line PANC-1, which was further found to be time and dose-dependent. Further studies are underway to understand the mechanism of action of this small molecule. The research work was supported by the Hellenic Foundation for Research and Innovation (HFRI) (Programme Number: 15583)."

Late-breaking abstract • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CCND1

PHOSPHOINOSITIDE DEPENDENT PROTEIN KINASE 1 IS A KEY METABOLIC REGULATOR AND POTENTIAL THERAPEUTIC TARGET IN LYMPHOMA (ICML 2025) - "PDPK1 was pharmacologically inhibited by GSK2334470...PDPK1 inhibition was associated with cell cycle arrest in G1 phase of the cell cycle and was in vitro broadly synergistic with unspecific standard anti-lymphoma chemotherapeutics (doxorubicin, vincristine, and cisplatin) and highly synergistic with more targeted CDK4/6 inhibitor ribociclib... PDPK1 seems to be critically involved in AKT pathway activation and metabolism regulation in lymphoma and may represent an universal and effective therapeutic target."

B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Hodgkin Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • MAP2K1 • MYC • PDPK1 • PIK3CD • PTEN

Vertical targeting of the PI3K/AKT pathway at multiple points is synergistic and effective for non-Hodgkin lymphoma. (PubMed, Exp Hematol Oncol) - "We studied this problem using cell lines representing diffuse large B-cell lymphoma (SUDHL-4 and OCI-Ly7), a genetically-encoded live-cell reporter of AKT activity, and 3 small-molecule inhibitors targeting different levels of the pathway: idelalisib (PI3Kδ), GSK2334470 (PDPK1), and ipatasertib (AKT)...Combining all 3 inhibitors produced sustained inhibition of AKT activity, was broadly synergistic at reducing viable cell number, enabled substantially lower doses of each inhibitor to be used, and was enhanced further by the mTOR inhibitor rapamycin...In a syngeneic mouse cell line model of lymphoma (A20), the triple combination showed antitumor activity and no evidence of toxicity. Our findings provide proof of concept suggesting further study of the safety and efficacy of low-dose multilevel PI3K/AKT pathway inhibition, for lymphoma and perhaps other cancers."

Journal • B Cell Non-Hodgkin Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • PDPK1 • PIK3CD

GSK2334470 attenuates high salt-exacerbated rheumatoid arthritis progression by restoring Th17/Treg homeostasis. (PubMed, iScience) - "Therefore, administration of GSK markedly alleviated HS-exacerbated RA progression in collagen-induced arthritis (CIA) model. Collectively, our data indicate that HS consumption subverts Th17/Treg homeostasis through the PDPK1-SGK1-FoxO1 signaling, while GSK could be a viable drug against RA progression in clinical settings."

Journal • Immunology • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology • CD4 • FOXO1 • IL17A • PDPK1

Toll like receptor 4 mediates the inhibitory effect of SARS-CoV-2 spike protein on proximal tubule albumin endocytosis. (PubMed, Biochim Biophys Acta Mol Basis Dis) - "GSK2334470, a PDK1 inhibitor, decreased albumin endocytosis and megalin expression mimicking S protein effect...LPS-RS prevented the inhibitory impact of pseudovirus containing the S protein on albumin endocytosis but had no influence on virus internalization. Our findings demonstrate that the inhibitory effect of the S protein on albumin endocytosis in PTECs is mediated through TLR4, resulting from a reduction in megalin expression."

IO biomarker • Journal • Acute Kidney Injury • Infectious Disease • Nephrology • Novel Coronavirus Disease • Renal Disease • Respiratory Diseases • TLR4

Disruption of Autophagic Flux and Treatment with the PDPK1 Inhibitor GSK2334470 Synergistically Inhibit Renal Cell Carcinoma Pathogenesis. (PubMed, J Cancer) - "Importantly, GSK470 and chloroquine synergistically inhibited the growth of RCC cells in vitro and in xenograft models, supporting the protective role of autophagy activation upon blockade of the PDPK1-Akt-mTOR signaling pathway. Our study provides new insight into PDPK1 inhibition combined with autophagy inhibition as a useful treatment strategy for RCC."

Journal • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • IGF1 • PDPK1

PDK1 inhibition reduces autophagy and cell senescence through the PI3K/AKT signalling pathway in a cigarette smoke mouse emphysema model. (PubMed, Exp Ther Med) - "Therefore, the present study aimed to investigate the effects of a PDK1 inhibitor (GSK-2334470) on the expression levels of PI3K, AKT, cyclin-dependent kinase inhibitor 2A (p16) and LC3B in a CS + CS extract (CSE)-induced mouse emphysema model...However, there were no significant differences in the expression levels of PI3K between the CS1 and the CS groups. The present study concluded that the inhibition of PDK1 can potentially reduce autophagy and cell senescence by downregulating the expression of PI3K/AKT pathway related proteins in airway epithelial cells, thereby protecting against CS + CSE-induced emphysema in mice."

Journal • Preclinical • Chronic Obstructive Pulmonary Disease • Immunology • Pulmonary Disease • Respiratory Diseases • CDKN2A • PDK1

MiR-139 Affects Radioresistance in Esophageal Cancer by Targeting the PDK1/AKT/Cyclin D1 Signaling Pathway. (PubMed, Bull Exp Biol Med) - "However, PDK1 inhibitor GSK2334470 reversed this effect for p-AKT and cyclin D1 expression...MiR-139 expression significantly correlated with EC and progression-free survival. In conclusion, miR-139 enhances the radiosensitivity of EC by regulating the cell cycle through the PDK1/Akt/Cyclin D1 signaling pathway."

Journal • Esophageal Cancer • Gastrointestinal Cancer • Oncology • CCND1 • MIR139

Combinatorial PI3K/AKT Pathway Inhibition As a Therapeutic Approach in Diffuse Large B-Cell Lymphoma (ASH 2022) - "Currently, DLBCL treatment is based on non-specific chemotherapy combination (cyclophosphamide, doxorubicin, vincristine, and prednisone) with anti-CD20 monoclonal antibody...To provide a proof of principle of multilevel vertical PI3K/AKT inhibition, we tested the effect of four inhibitors targeting the PI3K/AKT pathway at four different levels: PI3Kδ inhibitor idelalisib, PDPK1 inhibitor GSK2334470, AKT inhibitor ipatasertib, and mTOR inhibitor rapamycin on a spectrum of commonly used DLBCL model cell lines...Our data suggest that proposed combinations should allow significant decrease of inhibitors concentrations limiting off-target effect. This approach might overcome above mentioned issues of PI3K/AKT pathway inhibition and allow full therapeutical utilization of this pathway inhibition possibly applicable to other lymphoma types."

Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • PDPK1 • PIK3CD

PI3K/AKT Activation Mediates B-Cell Transformation By the "T" Splice-Variant of Fyn Kinase (ASH 2021) - "Consistently, the AKT inhibitor ipatasertib and PDK1 inhibitor GSK2334470 were highly active against all FYN-transformed lines, and AKT phosphorylation was sensitive to PDK1 inhibition, showing convergence on AKT activation in all transformants. Pan-PI3K inhibition was active against FYN transformants, while the delta isoform-specific inhibitor idelalisib showed only partial activity, suggesting activation of multiple PI3K isoforms downstream of FYN activity. These results suggest that AKT, PI3K, and PDK1 are important targets downstream of FYN, and that the PI3K/AKT pathway is the key survival mechanism in lymphomagenesis mediated by FYN. We show that WT and activating mutants of the FYN T spliceoform specifically, but not FYN B, induce drug-sensitive B lymphocyte malignant transformation by activating PI3K/AKT/MTORC1 signaling."

Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma • EIF4EBP1 • PDPK1

The effects of PDK1-Akt signaling pathway intervention on cardiomyocyte HCN4 ion channels (PubMed, Zhonghua Xin Xue Guan Bing Za Zhi) - "In further studies, the isolated atrial myocytes were cultured and further divided into drug control group (treated with dimethyl sulfoxide (DMSO)) and PDK1 knockdown group (treated with 1 μg/ml PDK1 short hairpin RNA (shRNA) interference plasmid), SC79 group (treated with 8 μmol/ml SC79), GSK2334470 group (treated with 10 nmol/L GSK2334470) and PDK1 knockdown+SC79 group (8 μmol/ml SC79 and 1 μg/ml PDK1 shRNA interference plasmid)...However, the green fluorescence of PDK1 knockdown+SC79 group was lighter than that of PDK1 knockdown group, suggesting that the expression of HCN4 in PDK1-knockdown cell membrane decreased after further activating Akt. PDK1-Akt signaling pathway is involved in the regulation of HCN4 ion channel transcription, expression and function."

Journal • PDPK1

Phosphoinositide-dependent Kinase-1 (PDPK1) regulates serum/glucocorticoid-regulated Kinase 3 (SGK3) for prostate cancer cell survival. (PubMed, J Cell Mol Med) - "Importantly, PDPK1 inhibitors (GSK2334470 and BX-795) significantly reduced tumour-specific cell growth and synergized docetaxel sensitivity in PCa cells. In summary, our results demonstrated that PDPK1 mediates PCa cells' survival through SGK3 signalling and suggest that inactivation of this PDPK1-SGK3 axis may potentially serve as a novel therapeutic intervention for future treatment of PCa."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • PDPK1 • SGK1

The calcium-sensing receptor regulates protein tyrosine phosphorylation through PDK1 in boar spermatozoa. (PubMed, Mol Reprod Dev) - "Treatment with NPS2143, GSK2334470, an inhibitor of PDK1 and H-89, an inhibitor of PKA separately induced an increase in tyrosine phosphorylation of 18 and 32 kDa proteins, a decrease in the serine/threonine phosphorylation of the PKA substrates together with a drop in sperm motility and viability...Our results show that the inhibition of the CaSR induces the inhibition of PDK1 that blocks PKA activity resulting in a rise in tyrosine phosphorylation of p18 and p32 proteins. This novel signalling pathway has not been described before and could be crucial to understand boar sperm capacitation within the female reproductive tract."

Journal

PDK1 inhibitor GSK2334470 exerts antitumor activity in multiple myeloma and forms a novel multitargeted combination with dual mTORC1/C2 inhibitor PP242. (PubMed, Oncotarget) - "In the present study, we show that GSK2334470 (GSK-470), a novel and highly specific inhibitor of PDK1, induces potent cytotoxicity in MM cell lines including Dexamethasone-resistant cell line, but not in human normal cells. In particular, this combination was able to result in a complete inhibition of mTORC1/C2 and full activity of AKT. Together, these findings raise the possibility that combining PDK1 antagonist GSK-470 with mTORC1/C2 inhibitors may represent a novel strategy against MM including drug-resistant myeloma, regardless of PTEN expression status."

Journal • Biosimilar • Hematological Malignancies • Multiple Myeloma • Oncology

PDK1 Inhibitor GSK-470 Exhibits Potent Anticancer Activity in a Pheochromocytoma PC12 Cell Tumor Model via Akt/mTOR Pathway. (PubMed, Anticancer Agents Med Chem) - "Our results showed that GSK-470 exhibited potent anticancer activity in PC12 tumor-bearing mice. Also, we found that this effect appeared to be mediated by inhibition of the Akt/mTOR pathway. The present study once again provides new insights into the therapeutic effects of inhibiting PDK1 in treatment of malignant PCC. Therefore, we propose that GSK-470 might be an effective therapeutic agent for the treatment of malignant PCC."

Journal • Preclinical • PDPK1