OP-11 / Zenyaku Holdings, Ohara Pharma - LARVOL DELTA

Discovery of hydrazide-based PI3K/HDAC dual inhibitors with enhanced pro-apoptotic activity in lymphoma cells. (PubMed, Eur J Med Chem) - "In this study, we rationally designed and synthesized a series of novel PI3K/HDAC dual-target inhibitors by combining the morpholino-triazine pharmacophore of PI3K inhibitor ZSTK474 with the hydrazide moiety of HDAC1-3 selective inhibitor 11h...In the mantle cell lymphoma Jeko-1 cell line, 31f showed significantly greater efficacy than the single inhibitors in inducing apoptosis. In conclusion, this study provided insights into the development of novel hydrazide-based dual HDAC/PI3K inhibitors."

Journal • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Oncology • PIK3CA

An integrated bioinformatics approach to early diagnosis, prognosis and therapeutics of non-small-cell lung cancer. (PubMed, J Biomol Struct Dyn) - "Finally, 4 KGs-guided repositioning candidate drugs (ZSTK474, GSK2126458, Masitinib, and Trametinib) were proposed. The stability of three top-ranked drug-target interactions (CAV1 vs. ZSTK474, CAV1 vs. GSK2126458, and ASPM vs. Trametinib) were investigated by computing their binding free energies for 140 ns MD-simulation based on MM-PBSA approach. Therefore, the findings of this computational study may be useful for early prognosis, diagnosis and therapies of NSCLC."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CAV1 • CCNB2 • PCLAF

ZSTK474 targeting PIK3R3 inhibits the Wilms' tumor through G0 / G1 phase arrest. (PubMed, PLoS One) - "This research provides insight into the potential of ZSTK474 and other PI3K inhibitors for treating nephroblastoma."

Journal • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Wilms Tumor • CDK4 • CDKN1A • PIK3R3

FUNCTIONAL PHENOTYPE MODEL PREDICTS PROGRESSION FREE SURVIVAL FOR CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH IBRUTINIB + VENETOCLAX IN THE HOVON141/VISION TRIAL (EHA 2024) - " Among the independently performed functional assays, the top-6 most robust and predictive multi-modalfeatures were: sensitivity to vandetanib, ruxolitinib+venetoclax and acalabrutinib+ZSTK474 combination (drugtesting); Bcl-2|BTK (pY223) and p90RSK (pS380)|PLCg2 (pY759) (protein pairs); and a high proportion of CD8+T cells (immune phenotyping). Integration of data from multiple functional assays through regularized regression techniques offers a robustand accurate prediction of PFS in R/R CLL patients treated with ibrutinib+venetoclax combination. Our fPMscore enhanced the predictive accuracy of PFS both in the test and validation sets, indicating its potential toguide personalized management strategies and improve upon conventional prognostic scores."

Clinical • IO biomarker • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • BCL2 • CD8 • PLCG2 • TP53

Blockade of vasoactive intestinal peptide receptor 2 (VIPR2) signaling suppresses cyclin D1-dependent cell-cycle progression in MCF-7 cells. (PubMed, J Pharmacol Sci) - "KS-133 reduced the percentage of cells in the S phase more than treatment with U0126 or ZSTK474 alone and did not affect the effect of the mixture of these inhibitors. Our findings suggest that VIPR2 signaling regulates cyclin D1 levels through the cAMP/PKA/ERK and PI3K/AKT/GSK3β pathways, and mediates the G1/S transition to control cell proliferation."

Journal • CCND1

Preclinical pharmacokinetic and in vitro metabolic stability study of lysosomotropic autophagy inhibitor, IITZ-01 in mice by using UPLC-MS/MS. (PubMed, Anal Biochem) - "Separation of IITZ- 01 and ZSTK474 (IS) from endogenous components with high selectivity and sensitivity (0.5 ng/mL) was achieved using Waters Acquity BEH C-18 column (50 mm × 2.1 mm, 1.7 μm)...The matrix effect was found to be negligible, and the stability data were within acceptable limits. The validated technique supports suitability, reliability, reproducibility, and sensitivity for the pre-clinical investigation of IITZ-01 pharmacokinetics in mice and metabolic stability in human liver microsomes."

Journal • PK/PD data • Preclinical • Breast Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Triple Negative Breast Cancer

Design and Synthesis of 1,3,5-Triazines or Pyrimidines Containing Dithiocarbamate Moiety as PI3Kα Selective Inhibitors. (PubMed, ACS Med Chem Lett) - "In this paper, some new 1,3,5-triazine or pyrimidine skeleton derivatives containing dithiocarbamate were designed and synthesized based on the reasonable drug design strategy from the previously effective compound 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK-474), in order to get effective selective PI3Kα inhibitors that have not been reported in the literature...In addition, compound 13 induced obvious tumor regression in the U87-MG cell line xenografts mouse model, with no obvious signs of toxicity after intraperitoneal injection at a dose of 40 mg/kg. Compound 13 can be an effective selective inhibitor of PI3Kα, and it provides patients with an opportunity to avoid the side effects related to the wider inhibition of the class I PI3K family."

Journal • Oncology • PIK3CA

Structure-based drug design, synthesis, and biological evaluation of novel 1,3,5-triazine or pyrimidine derivatives containing benzoyl hydrazine moiety as PI3Kα selective inhibitors. (PubMed, Bioorg Chem) - "Here, we described a series of PI3Kα inhibitors with 1,3,5-triazine or pyrimidine skeleton containing benzoyl hydrazine based on the pan-PI3K inhibitor ZSTK474 relying on the strategies of structure-based drug discovery (SBDD) and computer-aided drug design (CADD)...Furthermore, compound F8 induced significant tumor regressions in a xenograft mouse model of U87-MG cell line with no clear evidence of toxicity following intraperitoneal injection of 40 mg/kg. Compound F8 may serve as a PI3Kα-selective inhibitor and provided the opportunity to spare patients the side effects associated with broader inhibition of the class I PI3K family."

Journal • Oncology • PIK3CA

Functional impact and molecular binding modes of drugs that target the PI3K isoform p110δ. (PubMed, Commun Biol) - "Accordingly, molecular dynamics simulations indicate that the I777M substitution disturbs conformational flexibility in the specificity or affinity pockets of p110δ that is necessary for binding idelalisib or ZSTK474, but not copanlisib. In summary, cell-based and molecular exploration provide comparative characterization of currently developed PI3Ki and structural insights for future PI3Ki design."

Journal • Oncology

Subtype-selective induction of apoptosis in translocation-related sarcoma cells induced by PUMA and BIM upon treatment with pan-PI3K inhibitors. (PubMed, Cell Death Dis) - "We previously reported that a pan-phosphatidylinositol 3-kinase (PI3K) inhibitor, ZSTK474, was effective for the treatment of sarcomas in a phase I clinical trial...Thus, we conclude that PI3K inhibitors induce apoptosis in selective TRSs such as ES and SS via the induction of PUMA and BIM and the subsequent loss of mitochondrial membrane potential. This represents proof of concept for PI3K-targeted therapy, particularly such TRS patients."

Journal • Alveolar Soft Tissue Sarcoma • Ewing Sarcoma • Non-melanoma Skin Cancer • Oncology • Rhabdomyosarcoma • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • Synovial Sarcoma • BBC3 • BCL2L11 • DUX4

Based on 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474), design, synthesis and biological evaluation of novel PI3Kα selective inhibitors. (PubMed, Bioorg Chem) - "Additionally, compound A10 induced significant tumor regressions in a xenograft mouse model of U87-MG cell line without an obvious sign of toxicity upon 20 mg/kg oral administration. Compound A10 may serve as a PI3Kα-selective inhibitor and provide the opportunity to spare patients the side effects associated with broader inhibition of the class I PI3K family."

Journal • Oncology • PIK3CA • PIK3CB • PIK3CD • PIK3CG

Bioinformatics and network-based screening and discovery of potential molecular targets and small molecular drugs for breast cancer. (PubMed, Front Pharmacol) - "Finally, we proposed 16 candidate repurposing drugs YM201636, masitinib, SB590885, GSK1070916, GSK2126458, ZSTK474, dasatinib, fedratinib, dabrafenib, methotrexate, trametinib, tubastatin A, BIX02189, CP466722, afatinib, and belinostat for BC through molecular docking analysis. Using BC cell lines, we validated that masitinib inhibits the mTOR signaling pathway and induces apoptotic cell death. Therefore, the proposed results might play an effective role in the treatment of BC patients."

Journal • Breast Cancer • Oncology • Solid Tumor • AURKA • BIRC5 • CDK1 • EGFR • KDM5B • MIR16 • MIR23b • MIR34A • SOX2 • TOP2A • TP63

Transcriptome changes in stages of non-alcoholic fatty liver disease. (PubMed, World J Hepatol) - "In this study we describe several molecular processes that may correlate with NAFLD disease and progression. We also identified ricirbine and ZSTK-474 as potential therapy."

Journal • Hepatology • Immunology • Inflammation • Metabolic Disorders • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Oncology • CXCL10 • FABP5 • HMGCS1 • IGF1 • IL1B • TNFA

Tong-Qiao-Huo-Xue decoction activates PI3K/Akt/mTOR pathway to reduce BMECs autophagy after cerebral ischemia/reperfusion injury. (PubMed, J Ethnopharmacol) - "Taken together, these findings demonstrate that TQHXD protects against ischemic insult by inhibiting autophagy through the regulation of the PI3K/Akt/mammalian target of rapamycin (mTOR) pathway and that TQHXD may have therapeutic value for protecting BMECs from cerebral ischemia."

Journal • Cardiovascular • CNS Disorders • Ischemic stroke • Reperfusion Injury • Vascular Neurology • ANXA5

ZSTK474 Sensitizes Glioblastoma to Temozolomide by Blocking Homologous Recombination Repair. (PubMed, Biomed Res Int) - "Meanwhile, ZSTK474 blocked the activity of the PI3K/Akt pathway. Taken together, our findings suggested that the combination of ZSTK474 and TMZ might be a potential therapeutic option for GBM."

Journal • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • BRCA1 • BRCA2 • HRD • PIK3CA • RAD51

Automated prediction of drug response in HCC cell lines with deep learning-based bioactivity modeling and experimental validation (EACR 2022) - "Sorafenib was used as a control. Results and Discussions Among a large group of predicted inhibitors, 4 compounds, 2 investigational drugs (Loperamide N-oxide and Eprinomectin), which were not studied on HCC before, and 2 PI3K/mTOR pathway inhibitors (Rapamycin and ZSTK474), which were previously studied on HCC cell lines, were selected for in vitro validation studies...Conclusion Our prediction model successfully predicts specific small molecule drugs for HCC cell lines. With additional in vitro validation experimentation, we hope to identify new inhibitors that have the potential to be repurposed against HCC."

Preclinical • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • ANXA5

FUNCTIONAL SCREENING OF PI3K INHIBITORS STRATIFIES RESPONDERS TO IDELALISIB AND INDICATES DRUG CLASS ACTIVITY IN IDELALISIB-REFRACTORY CLL (EHA 2022) - "Aims To characterize functional responses to 10 PI3Ki in CLL To study PI3Ki drug class activity in idelalisib-refractory CLL To investigate whether ex vivo drug sensitivity can predict in vivo treatment responses Methods CLL cells from patients that were treatment naïve (n=7), idelalisib refractory (n=9), or on idelalisib treatment (longitudinal samples from n=6 patients) were screened against 10 PI3Ki (buparlisib, compound 7n, copanlisib, duvelisib, idelalisib, nemiralisib, pictilisib, pilaralisib, umbralisib, ZSTK474), both alone and in combination with the B-cell lymphoma 2 (Bcl-2) antagonist venetoclax...Ex vivo drug testing on CLL cells from a patient who presented with relapsed disease after sequential treatment with FCR, ibrutinib, idelalisib and venetoclax revealed sensitivity to PI3Ki+venetoclax treatment...Conclusion Our findings indicate PI3Ki drug class activity in idelalisib-refractory CLL, and suggest that ex vivo drug sensitivity may guide precision..."

IO biomarker • Chronic Lymphocytic Leukemia • Leukemia • Lymphoma • Oncology • BCL2 • CASP3

mTORC1 is a key regulator that mediates OGD- and TGFβ1-induced myofibroblast transformation and chondroitin-4-sulfate expression in cardiac fibroblasts. (PubMed, Exp Ther Med) - "Using the PI3K inhibitor ZSTK474, the Akt inhibitor MK2206, or the mTOR inhibitor AZD8055, it was observed that OGD and TGFβ1 stimulation induced myofibroblast transformation and that C4S synthesis was mTOR-dependent, whereas the upstream canonical PI3K/Akt axis was dispensable by using western blotting and immunofluorescence. Target mTORC1 may provide additional insight into the regeneration of sympathetic nerves and the reduction of fibrosis after MI at the cellular level. These findings may contribute to the understanding of the mechanism by which C4S overproduction in the hearts of patients with MI is associated with myocardial fibrosis."

Journal • Atrial Fibrillation • Cardiovascular • Fibrosis • Immunology • Myocardial Infarction • Reperfusion Injury • SMAD3 • TGFB1

Suppression of MYC by PI3K/AKT/mTOR pathway inhibition in combination with all-trans retinoic acid treatment for therapeutic gain in acute myeloid leukaemia. (PubMed, Br J Haematol) - "We find that ATRA treatment in combination with inhibition of PI3K (ZSTK474), mTOR (WYE132) or PI3K/mTOR (BEZ235, dactolisib) drastically reduces protein levels of the proto-oncogene MYC. While inhibition of the PAM pathway causes MYC phosphorylation at threonine 58 via glycogen synthase kinase 3 beta and subsequent degradation, ATRA reduces its expression. Here, we present an approach using a combination of known drugs to synergistically reduce aberrant MYC levels, thereby effectively blocking proliferation and enabling differentiation in various AML subtypes."

Combination therapy • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Targeting PI3K pathway to reprogram the tumor immune niche in angiosarcoma (AACR 2022) - "We found that PI3K-alpha selective inhibitor BYL719 at 10uM decreased cell proliferation of PIK3CA mutant cells by 40-50% compared with that of wild-type cells. In comparison, no significant difference was observed between mutant and wild-type cells treated with pan PI3K inhibitor, ZSTK474...It also includes establishing single-cell gene expression profiles to identify distinct cell clusters between PIK3CA mutant and wild-type cells, along with chromatin accessibility landscape using ATAC-seq. Tumorigenic capacity and immune regulatory mechanisms of PIK3CA mutations will be determined in angiosarcoma xenograft models."

Angiosarcoma • Oncology • Sarcoma • Solid Tumor • PIK3CA

Protective effect of phillyrin against cerebral ischemia/reperfusion injury in rats and oxidative stress-induced cell apoptosis and autophagy in neurons. (PubMed, Bioengineered) - "Furthermore, phosphatidylinositol-3 kinase (PI3K) inhibitor ZSTK474 weakened the effects of phillyrin on p-mTOR, p-Akt-1, characteristic proteins of autophagy 3-II (LC3-II) and beclin-1 levels, and HO-induced neuronal apoptosis and autophagy. Taken together, phillyrin alleviates I/R injury by inhibiting neuronal cell apoptosis and autophagy pathway, which may provide a new treatment strategy for cerebral I/R injury."

Journal • Preclinical • CNS Disorders • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Reperfusion Injury • BCL2 • BECN1 • CASP3

Structural effects of morpholine replacement in ZSTK474 on Class I PI3K isoform inhibition: Development of novel MEK/PI3K bifunctional inhibitors. (PubMed, Eur J Med Chem) - "Compounds 6r and 6s also demonstrated in vivo tolerability with therapeutic efficacy through reduction of kinase activation and amelioration of disease phenotypes in the JAK2V617F mutant myelofibrosis mouse cancer model. Taken together, these results support further structure optimization of 6r and 6s as promising leads for combination therapy in human cancer as a new class of PI3K/MEK bifunctional inhibitors."

Journal • Myelofibrosis • Oncology • PIK3CA • PIK3CB • PIK3CD • PIK3CG

The phosphoinositide 3-kinase inhibitor ZSTK474 increases the susceptibility of osteosarcoma cells to oncolytic vesicular stomatitis virus VSVΔ51 via aggravating endoplasmic reticulum stress. (PubMed, Bioengineered) - "Finally, the xenograft tumor-bearing mice models were established, and the results showed that ZSTK474-VSVΔ51 combined treatment synergistically hindered tumorigenesis of osteosarcoma cells in vivo. Taken together, our data suggested that ZSTK474 was a novel agent to enhance the cytotoxic effects of VSVΔ51 on osteosarcoma by aggravating ER-stress, and the present study might provide alternative therapy treatments for osteosarcoma in clinic."

IO biomarker • Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor

Cancer immunotherapy with PI3K and PD-1 dual-blockade via optimal modulation of T cell activation signal. (PubMed, J Immunother Cancer) - "PI3K inhibitor in the combination with ICB with the optimized protocol fine-tuned T cell activation signaling for antitumor immunity via decreasing Tregs and optimizing memory CD8 T cell responses, illustrating a promising combination therapy."

IO biomarker • Journal • Immune Modulation • Immunology • Inflammation • Oncology • CD8

Proteomic analysis of extracellular vesicles identified PI3K pathway as a potential therapeutic target for cabazitaxel-resistant prostate cancer. (PubMed, Prostate) - "Proteomic analysis of serum EVs was successfully accomplished by using Tim-4 as a tool to isolate highly purified EVs. Our results suggest that the combination use of CBZ and PI3K inhibitor could be a promising treatment option for CBZ-resistant PC patients."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CD63 • PRDX6 • PTEN