PIK-75 / VetDC - LARVOL DELTA

PIK75 effectively reverses PI3K‒AKT activation caused by palbociclib resistance and synergistically inhibits the progression of esophageal squamous cell carcinoma. (PubMed, Sci Rep) - "The combined use of palbociclib and PIK75 synergistically inhibited the expression of the cell cycle proteins CCNE1, CDC6, and CDC25A, as well as the abnormal activation of PIK3CA and AKT phosphorylation. The combination of these two drugs synergistically inhibited tumor cell cycle progression and promoted apoptosis in vitro and in vivo, which provides a promising idea for the treatment of ESCC in the future."

Journal • Breast Cancer • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Oncology • Solid Tumor • Squamous Cell Carcinoma • CCNE1 • CDC25A • GNRP • PIK3CA

Synergistic Inhibition of PI3K and HSP90 Enhanced Antitumorigenic Efficacy in Adrenocortical Carcinoma. (PubMed, Res Sq) - "Quantitative high-throughput drug combination screening identified potent synergy between phosphatidylinositol-3-kinase (PI3K) inhibitor, PIK75 and heat shock protein 90 (HSP90) inhibitors, Ganetespib (STA9090), HSP990, or Luminespib (NVP-AUY922). Further antitumor efficacy was confirmed by the BGT226-STA9090 combination in human ACC xenograft model and five PDOs with different pathogenic mutations. Conclusively, the combinations of PI3K and HSP90 inhibitors were highly effective in preclinical studies, warranting a clinical trial in patients with advanced ACC."

Journal • Adrenal Cortex Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor • CDC37 • HSP90AA1

Targeting treatment-resistant Systemic Lupus Erythematosus through transcriptome-informed drug repurposing (ACR Convergence 2025) - "To guide precision repurposing, we applied a transcriptome-driven strategy to identify compounds that either mimic the molecular effects of standard therapies or reverse gene expression profiles associated with treatment resistance. Paired whole-blood transcriptomes from 31 SLE patients treated with rituximab (n=8), belimumab (n=13), or cyclophosphamide (n=10) were analyzed to define drug-specific signatures (absolute log₂FC > 0.58, p < 0.05)...Rituximab's signature aligned with mTOR blockers (everolimus, dactolisib), PI3K inhibitors (PIK-75, ZSTK474), JAK2 inhibitors (fedratinib) and agents downregulating the p38-MAPK pathway (OXA)... Our analysis delineates molecular correlates of therapeutic response and identifies candidate drugs capable of emulating molecular effects of standard SLE therapies or reversing gene expression patterns associated with treatment failure, offering a framework for drug repurposing in difficult-to-treat SLE."

IO biomarker • Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus • BCL2 • CDC37

Preclinical Investigation Of Phosphatidylinositol-3-kinase And Heat Shock Protein 90 Inhibitors Combination Therapy In Adrenocortical Carcinoma (ENDO 2025) - "We determined the effective doses and cytotoxicity of the HSP90 inhibitors (STA9090, HSP990, NVP-AUY922) and PI3K inhibitors (PIK-75, BGT-226) and their combinations in preclinical models of ACC. Further validation of synergistic efficacy of BGT226 and STA9090 in NOD SCID-gamma mice showed a reduction in the mean volume of ACC xenografts in STA9090-BGT226 treatment group to 28.4% of the vehicle control group and 38.4% and 37.7 % of those in STA9090-only and BGT226-only groups, respectively. In conclusion, the synergistic combinations of the PI3K and HSP90 inhibitors were effective in preclinical studies of ACC, warranting a clinical trial in patients with advanced ACC."

Combination therapy • Late-breaking abstract • Preclinical • Adrenal Cortex Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor • AKT2 • CDC37 • HSP90AB1 • PIK3R1

Preclinical Investigation Of Phosphatidylinositol-3-kinase And Heat Shock Protein 90 Inhibitors Combination Therapy In Adrenocortical Carcinoma (ENDO 2025) - "We determined the effective doses and cytotoxicity of the HSP90 inhibitors (STA9090, HSP990, NVP-AUY922) and PI3K inhibitors (PIK-75, BGT-226) and their combinations in preclinical models of ACC. Further validation of synergistic efficacy of BGT226 and STA9090 in NOD SCID-gamma mice showed a reduction in the mean volume of ACC xenografts in STA9090-BGT226 treatment group to 28.4% of the vehicle control group and 38.4% and 37.7 % of those in STA9090-only and BGT226-only groups, respectively. In conclusion, the synergistic combinations of the PI3K and HSP90 inhibitors were effective in preclinical studies of ACC, warranting a clinical trial in patients with advanced ACC."

Combination therapy • Preclinical • Adrenal Cortex Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor • AKT2 • CDC37 • HSP90AB1 • PIK3R1

Receptor targeted delivery of the multi-kinase inhibitor F7/PIK-75 by organic-core templated lipid nanoparticles as cancer therapy (AACR 2025) - "ocHDL NPs can be successfully loaded with hydrophobic drug cargo, such as PIK-75, to enable SR-B1 targeting and delivery of PIK-75 to cancer cells. PIK-75 ocHDL NPs potently induced cell death across a wide array of malignancies in vitro, and in an in vivo prostate cancer xenograft model. These results provide proof-of-principle that ocHDL NPs can be successfully leveraged to deliver hydrophobic small molecule drugs in a receptor targeted manner."

Acute Myelogenous Leukemia • Castration-Resistant Prostate Cancer • Cutaneous T-cell Lymphoma • Genito-urinary Cancer • Hematological Malignancies • Leukemia • Lymphoma • Oncology • Pancreatic Cancer • Prostate Cancer • Skin Cancer • Solid Tumor • T Cell Non-Hodgkin Lymphoma • APOA1 • PIK3CA

Encapsulation and Delivery of the Kinase Inhibitor PIK-75 by Organic Core High-Density Lipoprotein-Like Nanoparticles Targeting Scavenger Receptor Class B Type 1. (PubMed, ACS Appl Mater Interfaces) - "Additionally, we found that PIK-75 oc-HDL NP, but not free PIK-75 or oc-HDL NP alone, reduced the IC50 in the NCI-60 cell line panel and additional pancreatic cancer cell lines. These data demonstrate the first example of drug-loaded oc-HDL NP that actively target SR-B1 and kill cancer cells in vitro and in vivo, encouraging further development and translation to human patients."

Journal • Cutaneous T-cell Lymphoma • Genito-urinary Cancer • Hematological Malignancies • Hepatology • Lymphoma • Oncology • Pancreatic Cancer • Prostate Cancer • Solid Tumor • T Cell Non-Hodgkin Lymphoma • PIK3CA

EGFR and PI3K Signalling Pathways as Promising Targets on Circulating Tumour Cells from Patients with Metastatic Gastric Adenocarcinoma. (PubMed, Int J Mol Sci) - "UWG02CTCs were highly responsive to the PI3K p110α-subunit targeted drugs PIK-75 (IC50 = 37.0 ± 11.1 nM) or alpelisib (7.05 ± 3.7 µM). PIK-75 plus gefitinib significantly impaired UWG02CTC invasion in an organotypic assay. In conclusion, UWG02CTCs are a powerful ex vivo mGAC drug responsiveness model revealing EGFR/PI3K-targeted drugs as a promising combination treatment option for HER2-negative, RAS wild-type mGAC patients."

Circulating tumor cells • Journal • Metastases • Tumor cell • Gastric Adenocarcinoma • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • HER-2 • PIK3CA

CDK7 modulation of Hippo-YAP activity by RNAPII phosphorylation regulates CDK4/6 inhibitor resistance in hormone positive breast cancer (AACR 2024) - "In vivo studies confirmed that PIK-75 treatment demonstrated tumoricidal efficacy in CDK6 amplified HR (+) breast cancer cells, while the CDK4/6 inhibitor abemaciclib showed minimal cytotoxicity. Molecular studies and multi-omic profiling elucidated the role of CDK7 in hippo pathway and characterizes multiple roles of PIK-75. Our study provides intriguing novel insights into the link between "transcriptional CDKs" and the hippo pathway that could potentially be further probed for therapeutics in HR (+) breast cancer."

Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CDK7 • HER-2

Deciphering the prognostic features of bladder cancer through gemcitabine resistance and immune-related gene analysis and identifying potential small molecular drug PIK-75. (PubMed, Cancer Cell Int) - "The GIRS signature offers a valuable complement to the conventional anatomic TNM staging system and molecular subtype stratification in bladder cancer. The hub gene, RAC3, plays a crucial role in BCa and is significantly associated with resistance to gemcitabine. The small molecular drug, PIK-75 having the potential as a therapeutic agent in the context of gemcitabine-resistant and immune-related pathways."

IO biomarker • Journal • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor

PIK Your Poison: The Effects of Combining PI3K and CDK Inhibitors against Metastatic Cutaneous Squamous Cell Carcinoma In Vitro. (PubMed, Cancers (Basel)) - "This study investigates the potential of targeted inhibition of the p110α-subunit of PI3K with PIK-75 or BGT226 (P13Ki), and of CDK1/2/5/9 with dinaciclib (CDKi) as single agents and in combination. The differential responses between the cell lines correlated with driver gene mutation profiles. These findings suggest that personalised medicine approaches targeting PI3K and CDK pathways in combination may yield some benefit for mcSCC, and that more complex 3D models should be considered for drug responsiveness studies in this disease."

Journal • Metastases • Preclinical • Non-melanoma Skin Cancer • Oncology • Skin Cancer • Squamous Cell Carcinoma • Squamous Cell Skin Cancer • CDK1 • PIK3CA

A NOVEL DRUG TARGET: IL-36 SIGNALLING DRIVES INFLAMMATION AND POOR BACTERIAL CLEARANCE IN COPD (BTS WM 2023) - "To investigate the mechanism regulating IL-36RA expression, MDM were incubated with PIK75 (PI3K inhibitor), UO0126 (ERK inhibitor), VX745 (p38 inhibitor), SP600125 (JNK inhibitor) and TPCA1 (NF-kB inhibitor) for 24h and IL36RN measured. As IL36g is secreted in response to viral stimuli, the effects of IL36g described above could be important in pathogenesis of COPD exacerbations and secondary bacterial infection. IL36RN is reduced in COPD macrophages, which may be due to PI3K expression which is increased in COPD: Further work is needed to identify how this pathway regulates IL36RN to identify a potential drug target."

Chronic Obstructive Pulmonary Disease • Immunology • Infectious Disease • Inflammation • Influenza • Pneumonia • Pulmonary Disease • Respiratory Diseases • CD123 • CXCL1 • CXCL8 • IL6

Loss of PTEN activity in COPD airway epithelial cells is modulated by miR-21 (ERS 2023) - "This suggests miR-21 could be a key regulator of PTEN/PI3K pathway and the deficiency of PTEN expression and activity in COPD can be restored by miR-21 antagomir.; Physiology; Pulmonary function testing; Cell and molecular biology"

Chronic Obstructive Pulmonary Disease • Immunology • Pulmonary Disease • Respiratory Diseases • MIR21 • MIR34A • PIK3CA • PTEN

Discovery of mechanisms that modulate the hippo pathway and CDK6 expression in CDK4/6 inhibitor resistant breast cancer cells (AACR 2023) - "The current standard of care in advanced HR+ breast cancer includes endocrine therapy (tamoxifen, aromatase inhibitors, etc) and CDK4/6 inhibitors...We discovered staurosporine and the PI3K inhibitor PIK-75 as small molecules that potently downregulate CDK6 expression in breast cancer cells...By kinase profiling combined with a small hairpin RNA (shRNA) screen, we discovered the mechanisms that resulted in CDK6 downregulation and modulation of the hippo pathway to reverse the CDK4/6 inhibitor resistance. Our discovery has implications for therapeutic development in this group of patients posing a huge unmet need."

Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor

Synergistic efficacy of HSP90 and PI3K inhibitors in adrenocortical carcinoma (AACR 2023) - "Preclinical in vitro studies were performed to validate the efficacy of HSP90 inhibitors (STA9090, AUY922, HSP990), with PI3K inhibitors; PIK75 (investigational) or clinically available BGT226, and their pairwise combinations, in NCI-H295R and SW13 ACC cells. Conclusively, combination of HSP90 and PI3K inhibitors demonstrated a promising in vitro synergistic efficacy by inhibiting the key oncogenic targets of ACC. Further validation of in vivo efficacy is warranted."

Clinical • Adrenal Cortex Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor • AKT1 • AKT2 • CASP3 • CDH2 • CDK1 • CDK4 • HSP90AA1 • HSP90AB1 • TWIST1 • VIM • ZEB1

Receptor Targeted Delivery of the p38γ Inhibitor PIK-75 By Organic-Core Templated Lipid Nanoparticles in Cutaneous T Cell Lymphoma (ASH 2022) - "ocLNPs can be successfully loaded with drug cargo, in this case hydrophobic PIK-75, enabling active delivery via SR-B1 in CTCL. PIK-75 ocLNPs potently induced cell death in CTCL cells while having minimal negative effects on hepatocytes or macrophages. These results provide proof-of-principle that ocLNPs can be successfully leveraged to deliver hydrophobic small molecule drugs by actively targeting SR-B1."

Cutaneous T-cell Lymphoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Multiple Myeloma • Oncology • T Cell Non-Hodgkin Lymphoma • APOA1 • OCLN • PIK3CA

Drug Repositioning Identifies Six Drug Candidates for Systemic Autoimmune Diseases by Integrative Analyses of Transcriptomes from Scleroderma, Systemic Lupus Erythematosus, and Sjogren's Syndrome. (PubMed, OMICS) - "Six small molecule drug candidates (KU-0063794, YM-155 [sepantronium bromide], MST-312 [telomerase inhibitor IX], PLX-4720, ZM 336372, and 528116.cdx [PIK-75]) were discovered by drug repositioning as potential therapeutics for systemic ADs. We also report here the molecular docking findings on the binding affinity between the repositioned drug candidates and genes from the protein-protein interaction network modules of anticipated target genes. Taken together, this study provides new insights and opens up new possibilities on both pathogenesis and treatment of systemic ADs through drug repositioning."

Journal • Fibrosis • Immunology • Inflammatory Arthritis • Lupus • Scleroderma • Sjogren's Syndrome • Systemic Lupus Erythematosus • Systemic Sclerosis

Targeting dual oncogenic machineries driven by TAL1 and PI3K-AKT pathways in Tcell acute lymphoblastic leukemia. (PubMed, Haematologica) - "TAL1-positive, AKT-activated T-ALL cells were very sensitive to PIK-75, as evidenced by the growth inhibition and apoptosis induction, while T-ALL cells that exhibited activation of the JAK-STAT pathway were insensitive to this drug. Together, our study demonstrates a strategy targeting two types of core machineries mediated by oncogenic transcription factors and signaling pathways in T-ALL."

Journal • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • T Acute Lymphoblastic Leukemia • Thymus Cancer • NOTCH1

Synergistic Combination of HSP90 and PI3K inhibitors in Adrenocortical Cancer (ENDO 2022) - "We found, the combination of Heat Shock Protein 90 (HSP90) inhibitor (STA9090) and PI3K inhibitor (PIK75) showing synergistic efficacy through computerized matrix analysis. Learning Objective 2: The conference will help me establishing new collaborations with other scientific groups. Science Topic(s) for Tumor Biology: Cancer Targets and Therapies"

Adrenal Cortex Carcinoma • Endocrine Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Thyroid Gland Carcinoma • HSP90AA1

Reciprocal regulation of Daxx and PIK3CA promotes colorectal cancer cell growth. (PubMed, Cell Mol Life Sci) - "Further studies revealed that Daxx expression could be attenuated by either treatment with the PIK3CA inhibitor PIK-75 or PIK3CA depletion in CRC cells...We further demonstrated that Daxx activates the promoter activity and expression of PIK3CA. Altogether, our results identify a mechanistic pathway of Daxx overexpression in CRC and suggest a reciprocal regulation between Daxx and PIK3CA for CRC cell growth."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • DAXX • PIK3CA

PIK-75 overcomes venetoclax resistance via blocking PI3K-AKT signaling and MCL-1 expression in mantle cell lymphoma. (PubMed, Am J Cancer Res) - "Furthermore, PIK-75 treatment is efficacious in overcoming primary and acquired venetoclax resistance in xenograft models and inhibited tumor cell dissemination to spleen in mice. Altogether, our data demonstrated that PIK-75 is highly potent in overcoming primary, acquired, or stromal cells-induced venetoclax resistances in MCL cells and revealed a new tumor vulnerability that can be exploited clinically in difficult to treat MCL cases, especially those with venetoclax resistance."

IO biomarker • Journal • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BAX • BCL2 • BCL2L1 • CDK9 • MCL1 • PTEN

Context dependent isoform specific PI3K inhibition confers drug resistance in hepatocellular carcinoma cells. (PubMed, BMC Cancer) - "Simultaneously constructed and analyzed differentially expressed cellular networks presented in this study, revealed distinct consequences of isoform specific PI3K inhibition in PTEN adequate and deficient liver cancer cells. We demonstrated the importance of context dependent and isoform specific PI3K/Akt/mTOR signaling inhibition in drug resistance during combination therapies. ( https://github.com/cansyl/Isoform-spesific-PI3K-inhibitor-analysis )."

Journal • Fibrosis • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Immunology • Liver Cancer • Oncology • Solid Tumor • PIK3CA • PTEN

Combination PI3K/CDK inhibitors potently effect cutaneous squamous cell carcinoma survival and progression in vitro (LCC 2022) - " Multiple PI3K and CDK inhibitors were found to potently inhibit cell line viability, notably the PI3K inhibitors PIK-75 & BGT226, as well as the CDK inhibitor Dinaciclib. Combination PI3K/CDK inhibitors had a profound impact upon metastatic cSCC. Such treatment may alleviate mechanisms of resistance in vivo, although response may be reliant upon the individual mutational status of the patient."

IO biomarker • Preclinical • Genetic Disorders • Non-melanoma Skin Cancer • Oncology • Skin Cancer • Squamous Cell Carcinoma • Squamous Cell Skin Cancer • PIK3CA • PIK3CG

Integrated Genomic Profiling and Drug Screening of Patient-Derived Cultures Identifies Individualized Copy Number-Dependent Susceptibilities Involving PI3K Pathway and 17q Genes in Neuroblastoma. (PubMed, Front Oncol) - "Among 1278 significantly correlated gene-drug pairs, copy number of GNA13 and DNA damage response genes CBL, DNMT3A, and PPM1D were most significantly correlated with cytotoxicity; the drugs most commonly associated with these genes were PI3K/mTOR inhibitor PIK-75, and CDK inhibitors P276-00, SNS-032, AT7519, flavopiridol and dinaciclib. Together, our data defined individualized dose-dependent relationships between copy number gains of PI3K and STAT family genes particularly on 17q and susceptibility to PI3K and cell cycle agents in neuroblastoma. Integration of genomic profiling and drug screening of patient-derived models of neuroblastoma can quantitatively define copy number-dependent sensitivities to targeted inhibitors, which can guide personalized therapy for such mutationally quiet cancers."

Journal • Immunology • Neuroblastoma • Oncology • Pediatrics • Solid Tumor • DNMT3A • GNA13 • PPM1D

Colon Cancer Progression Is Reflected to Monotonic Differentiation in Gene Expression and Pathway Deregulation Facilitating Stage-specific Drug Repurposing. (PubMed, Cancer Genomics Proteomics) - "These findings highlight significant genes and pathways that can be used as stage-specific biomarkers and facilitate the discovery of new potential repurposed drugs for colon cancer. We expect that the computational methodology presented can be applied in a similar way to the analysis of any progressive disease."

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