TGX-221 / Enzo, Wuhan University, Pfizer - LARVOL DELTA

A fibroblast-specific gene signature as a therapeutic target for glioblastoma developed based on the characteristics of tumor microenvironment. (PubMed, Eur J Med Res) - "We constructed a RiskScore model for predicting the survival outcomes based on fibroblasts-related genes. These findings highlighted the role of fibroblasts in GBM development and offered six potential therapeutic targets (VWA1, DUSP6, LOXL1, IGFBP4, CYGB, and ZIC3) for GBM treatment. Additionally, immune infiltration analysis and drug sensitivity prediction further supported the model's utility in guiding personalized treatment of GBM."

Biomarker • Gene Signature • Journal • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • DUSP6

NK CELL-RELATED GENE-DRIVEN NOVEL MOLECULAR SUBTYPING AND PROGNOSTIC MODEL FOR WILMS TUMOR: UNCOVERING THE THERAPEUTIC POTENTIAL OF TGX-221 AND BIOMARKER ROLE OF HS2ST1 (SIOP 2025) - "Additionally, TGX-221 emerged as a promising therapeutic candidate, while a prognostic signature based on NKGs was established, highlighting HS2ST1 as a key biomarker with potential clinical applications. Future efforts aim to translate these findings into clinical practice."

Biomarker • IO biomarker • Nephrology • Oncology • Solid Tumor • Wilms Tumor • NRAS • PPP3CA

NK cell-related genes-driven novel molecular subtyping and prognostic signatures for Wilms tumor: uncovering the therapeutic potential of TGX-221 and biomarker role of HS2ST1. (PubMed, Front Oncol) - "Moreover, TGX-221 represents a promising novel therapeutic candidate, while HS2ST1 serves as a potential prognostic biomarker. These findings collectively provide tools for risk stratification and targeted therapy, advancing precision oncology for WT."

Biomarker • Journal • Nephrology • Oncology • Solid Tumor • Wilms Tumor • PPP3CA

NK cell-related genes-driven novel molecular subtyping and prognostic signatures for Wilms tumor: uncovering the therapeutic potential of TGX-221 and biomarker role of HS2ST1 (Front Oncol) - "TGX-221 significantly inhibited the malignant progression of WT through a dual-action mechanism: blocking the key oncogenic Wnt/β-catenin signaling pathway and sensitizing tumor cells to NK cell-mediated cytotoxicity."

Biomarker • Preclinical • Wilms Tumor

Role and Therapeutic Potential of miR-301b-3p in Regulating the PI3K-AKT Pathway via PIK3CB in Eosinophilic Chronic Rhinosinusitis. (PubMed, J Inflamm Res) - "The role of PIK3CB was assessed using the PIK3CB inhibitor TGX-221...miR-301b-3p regulates type 2 inflammation and EMT in ECRS by targeting PIK3CB and modulating the PI3K-AKT pathway, suggesting both miR-301b-3p and PIK3CB as promising therapeutic targets. Given the limited sample size of this study, we plan to expand our cohort and implement a longitudinal follow-up design to monitor dynamic changes in miR-301b-3p expression and their relationship to disease progression."

Journal • Inflammation • Otorhinolaryngology • Respiratory Diseases • Sinusitis • PIK3CB

Integrated single-cell and bulk RNA sequencing reveals prognostic and immunotherapy-associated myofibroblastic cancer-associated fibroblast subtypes in head and neck squamous cell carcinoma. (PubMed, Transl Cancer Res) - "Additionally, a higher myCAF score was related to the higher half-maximal inhibitory concentration (IC50) values of D-4476, GW-583340, spautin-1, and VER-155008, and the lower IC50 values of JTE-607, TG100-115, ML320, and TGX-221. This study, which was based on single-cell and bulk RNA-seq analyses, showed the plasticity and metabolic heterogeneity of CAFs in HNSCC. Our findings may contribute to understandings of the immunotherapy response in HNSCC."

Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CAFs

Double Swords in One: Novel Selective PI3K/110β PROTAC Degraders for the Treatment of Multidrug-Resistant Cancer by Activating ERS and Inhibiting P-gp. (PubMed, J Med Chem) - "Herein, we describe the design, synthesis, and structure-activity relationship studies of a series of small-molecule PI3K/110β PROTACs degraders by combining the selective inhibitor TGX221 of PI3K/110β with VHL ligands...Meanwhile, the expression and activity of P-glycoprotein were significantly inhibited, leading to a strong synergistic antitumor effect with adriamycin or cisplatin...In vivo studies also verified that the two degraders inhibited the growth of MCF-7/ADM xenograft tumors with high safety. Hence, this study and further optimization of these PI3K/110β PROTAC degraders have broad prospects for the development of new cancer therapies."

IO biomarker • Journal • Oncology • Targeted Protein Degradation • PTEN

Folate receptor-targeted pH-sensitive liposomes loaded with TGX-221 against prostate cancer by inhibiting PI3K/110β signaling. (PubMed, Nanoscale Adv) - "Meanwhile, in vitro and in vivo experiments suggested that FA-Lip-TGX221 could activate the PERK-ATF4-CHOP signaling pathway by inhibiting PI3K/110β signaling in PCa, thus significantly promoting endoplasmic reticulum (ER) stress-mediated cancer cell death. In conclusion, FA-Lip-TGX221 is a promising nano-delivery vehicle for the treatment of PCa, and also provide valuable references for all tumors overexpressing folate receptors."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • ATF4

Migrasome-related ITGA5 for predicting prognosis, immune infiltration and drug sensitivity of hepatocellular carcinoma. (PubMed, Apoptosis) - "Drug sensitivity, molecular docking, and molecular dynamics analyses indicated that ITGA5 may enhance the sensitivity of HCC to drug TGX221. Finally, cell phenotype experiments confirmed that ITGA5 knockdown suppressed the proliferation, migration, and invasion of HCC cells, and while overexpression exacerbated malignant phenotypes. Our analyses showed that ITGA5 is a key migrasome-related gene involved in the proliferation and metastasis of HCC that has promise as a therapeutic target and candidate prognostic indicator."

Journal • Hepatocellular Cancer • Oncology • Solid Tumor • ITGA5

Identification of Five NK Cell-Related Hub Genes in COPD Using Single-Cell RNA Sequencing Analysis. (PubMed, J Inflamm Res) - "The potential therapeutic agents for COPD may be zalcitabine, PP-2, PD-98059, and TGX-221 based on the CMap database prediction. We proposed that peripheral NK cells may play a role in the pathogenesis of COPD through bioinformatic analysis. These hub genes may provide insights into mechanistic research and new targets for new therapies in patients with COPD."

Journal • Chronic Obstructive Pulmonary Disease • Immunology • Pulmonary Disease • Respiratory Diseases • ANXA1 • IGFBP7 • S100A6

Discovery of key molecular signatures for diagnosis and therapies of glioblastoma by combining supervised and unsupervised learning approaches. (PubMed, Sci Rep) - "Finally, we recommended KGs-guided four repurposable drug molecules (Fluoxetine, Vatalanib, TGX221 and RO3306) against GBM through molecular docking, drug likeness, ADMET analyses and molecular dynamics simulation studies. Thus, the discoveries of this study could serve as valuable resources for wet-lab experiments in order to take a proper treatment plan against GBM."

Biomarker • Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • AURKA • CCNB2 • CDCA8 • CDK1 • CHEK1 • MCM10 • RAD51 • RAD51AP1 • TOP2A

The molecular background determines LSD1 inhibition sensitization of AML cells to gilteritinib and other kinase inhibitors (EACR 2024) - "Here, we hypothesise that the molecular background of AML determines the precise combinations of epigenetic and kinase targeting drugs that more effectively disrupt the dependencies that drive AML.Material and Methods Mega-erythroid (HEL, KMOE2 and CMK) and monocytic (MV4-11, P31 and NOMO1) AML cells were treated with the LSD1 inhibitor (LSD1i) GSK-2879552 for five days, followed by treatments with inhibitors of FLT3 (midostaurin and gilteritinib), MEK (trametinib), and PI3K (alpelisib, TGX-221, duvelisib, idelalisib and pictilisib aimed for α, β, δ/ɣ, δ and all isoforms) for three days. LSD1i reduced histone H3K79 methylation only in P31 cells and inhibitors of DOT1L, the enzyme that methylates H3K79, sensitized P31 cells to MEKi but not HEL cells to PI3Ki. These data suggest that the LSD1i induced sensitization to MEKi in P31 cells involves DOT1L, while the sensitization to PI3Kis in HEL cells may involve the lost of erythroid differentiation and energy metabolism..."

Acute Myelogenous Leukemia • DOT1L • FLT3 • PIK3CD

Combined inhibition of CDK4/6 and AKT is highly active against the luminal androgen receptor (LAR) subtype of triple negative breast cancer (TNBC) (AACR 2024) - "Enzalutamide, an AR antagonist, exerted no growth inhibitory activity (IC50, 15-25 μM)...The combination of palbociclib+capivasertib synergistically inhibited the proliferation of MDAMB453 and MFM223 cells (synergistic scores 7.34, p=5.81-11, and 4.78, p=0.012, respectively) better than palbociclib+alpelisib...PI3Kβ inhibitors (TGX221, GSK2636771) did not block AKT substrate upregulation, suggesting PI3Kβ does not mediate adaptive responses...Treatment with palbociclib and the PDGFRβ small-molecule antagonist CP673451 arrested LAR TNBC growth similar to palbociclib+capivasertib, suggesting an adaptive response involving PDGFRβ signaling. In conclusion, this study supports the clinical testing of the palbociclib and capivasertib combination for LAR TNBC patients and reveals adaptive responses after palbociclib treatment through PDGFRβ signaling."

Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • AKT1S1 • AR • CDK4 • PDGFRB • PIK3CA • PIK3CB • STAT3

SP1 Mediated PIK3CB Upregulation Promotes Gastric Carcinogenesis. (PubMed, J Cancer) - "TGX-221, a PIK3CB-selective inhibitor, which can block this signaling transduction pathway, was found to inhibit the growth of GC cells and induce apoptosis in vitro, implying that it may act as a potential development agent for GC. These collective findings provide a new insight into PI3K/AKT signaling that SP1 may function as an upstream factor on PI3K, forming a new signaling axis to promote the progression of GC or other malignancies."

Journal • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • PIK3CB

Bioinformatics analysis identifies coagulation factor II receptor as a potential biomarker in stomach adenocarcinoma. (PubMed, Sci Rep) - "Drug sensitivity analysis demonstrated positive correlations between F2R and several drugs, including BEZ235, CGP-60474, Dasatinib, HG-6-64-1, Aazopanib, Rapamycin, Sunitinib and TGX221, while negative correlation with CP724714, FH535, GSK1904529A, JNK-9L, LY317615, pyrimidine, rTRAIL and Vinorelbine. In conclusion, this study underscores the significance of F2R as a potential biomarker in gastric adenocarcinoma, shedding light on its molecular mechanisms in tumorigenesis. F2R holds promise for aiding in the diagnosis, prognosis, and targeted therapy of STAD."

Biomarker • Journal • Gastric Adenocarcinoma • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • Thrombosis • F2R • TGFB1

Overcoming temozolomide resistance in glioblastoma through selective inhibition of phosphoinositide 3-kinase catalytic subunit. (ASCO 2023) - "Newly cultured wild-type cells were treated with IC50 doses of selective p110β inhibitor TGX-221 and TMZ. Inhibition of p110β via CRISPR-Cas9 knockout or pharmaceutical blockade restores TMZ sensitivity in p110β-high glioblastoma cells and xenograft glioblastoma tumors. These results demonstrate the varying importance of PI3K catalytic subunits and necessitate further exploration into p110β as a potential drug target to overcome chemoresistance in glioblastoma."

Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • PIK3CA • PIK3CG

Advances in lung adenocarcinoma: A novel perspective on prognoses and immune responses of CENPO as an oncogenic superenhancer. (PubMed, Transl Oncol) - "CENPO was found to be positively associated with the expression levels of immune checkpoints and drug IC50 value (Roscovitine and TGX221), but negatively associated with the fraction levels of several immature cells and drug IC50 value (CCT018159, GSK1904529A, Lenaildomide, and PD-173074). The removal of CENPO significantly suppressed metastasis and induced arrest and apoptosis of LUAD cells. The involvement of CENPO in the immunosuppression of LUAD provides a prognostic signature for LUAD patients."

Journal • Immune Modulation • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Glucose 6 phosphatase dehydrogenase (G6PD): a novel diagnosis marker related to gastrointestinal cancers. (PubMed, Am J Transl Res) - "G6PD is highly expressed in gastrointestinal cancers. It is a carcinogenic indicator related to prognosis and can be used as a potential diagnostic marker of gastrointestinal cancers, so as to provide new strategy for cancer treatment."

Journal • Biliary Cancer • Cholangiocarcinoma • Colon Cancer • Colorectal Adenocarcinoma • Esophageal Adenocarcinoma • Esophageal Cancer • Gastric Adenocarcinoma • Gastric Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Hepatocellular Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • CD276 • CD4 • G6PD • GAPDH • HHLA2 • TP53

Probing the Potential of Defense Response-Associated Genes for Predicting the Progression, Prognosis, and Immune Microenvironment of Osteosarcoma. (PubMed, Cancers (Basel)) - "This study elucidated the role and mechanism of BNIP3, PTGIS, and ZYX in OS progression and was well verified by the experimental results, enabling reliable prognostic means and treatment strategies to be proposed for OS patients."

Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • CD8

Construction of the Interaction Network of Hub Genes in the Progression of Barrett's Esophagus to Esophageal Adenocarcinoma. (PubMed, J Inflamm Res) - "Finally, the results of drug sensitivity analysis based on hub genes showed that drugs such as PI3K inhibitor TGX221, bleomycin, PKC inhibitor Midostaurin, Bcr-Abl inhibitor Dasatinib, HSP90 inhibitor 17-AAG, and Docetaxel may be potential candidates to inhibit the progression of BE to EAC. This study is based on a large number of clinical samples with high credibility, which is useful for revealing the probable carcinogenic mechanism of BE to EAC and developing new clinical treatment strategies."

Journal • Barrett Esophagus • Esophageal Adenocarcinoma • Esophageal Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Immune Modulation • Oncology • Solid Tumor • ABL1 • BCR • COL1A1 • COL4A1 • Collagen Type IV • CXCL1 • MMP1 • TGFBI

Uses of Vascular Endothelial Growth Factor C as a Lung Adenocarcinoma Prognostic Biomarker. (PubMed, World J Oncol) - "The sensitivity of 5-fluorouracil was positively correlated with VEGF-C, and the sensitivity of TGX221 was negatively correlated with VEGF-C. The activity of BI-2536 and BRD-A94377914 was positively correlated with VEGF-C. Novel LUAD prognostic biomarkers such as VEGF-C mRNA may aid diagnosis and treatment, and may help identify optimal LUAD populations for therapeutic treatments."

Biomarker • Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD4 • EGFR • NF1 • TP53 • VEGFA • VEGFC

Blocking of PI3-kinase beta protects against cerebral ischemia/reperfusion injury by reducing platelet activation and downstream microvascular thrombosis in rats. (PubMed, Sci Rep) - "The results showed that TGX221, a selective PI3Kβ inhibitor, treatment immediately before the onset of reperfusion dose-dependently reduced infarct volume and improved neurological function. The protective effects were associated with blocking platelet activation and thrombotic response, thereby reducing downstream microvascular thrombosis, and maintaining reperfusion efficiency. These results suggest that PI3Kβ might be a promising target for treating downstream microvascular thrombosis induced by cerebral I/R injury and offer a novel adjunctive treatment to improve reperfusion therapy for acute ischemic stroke."

Journal • Preclinical • Cardiovascular • Hematological Disorders • Ischemic stroke • Reperfusion Injury • Thrombosis • PIK3CB

Platelet p110β mediates platelet-leukocyte interaction and curtails bacterial dissemination in pneumococcal pneumonia. (PubMed, Cell Rep) - "Using a mouse model of Streptococcus pneumoniae-induced pneumonia, we find that both platelet-specific p110β deficiency and pharmacologic inhibition of p110β with TGX-221 exacerbate disease pathogenesis by preventing platelet-monocyte and neutrophil interactions, diminishing their infiltration and enhancing bacterial dissemination...Our results demonstrate that platelet p110β dysfunction exacerbates pulmonary infection by impeding leukocyte functions. Thereby, our findings provide important insights into the immunomodulatory potential of PI3K inhibitors in bacterial infection."

Journal • Immune Modulation • Immunology • Infectious Disease • Inflammation • Oncology • Pneumococcal Infections • Pneumonia • Respiratory Diseases

Study on the prognosis, immune and drug resistance of m6A-related genes in lung cancer. (PubMed, BMC Bioinformatics) - "In conclusion, m6A-related genes are important participants in LC and the expression levels of ZC3H13, CBLL1, ELAVL1 and YTHDF1 are significant for prediction and treatment of LC. Researches of drug resistance based on m6A-related genes need to pay more attention for producing new therapeutic strategies of LC and CBLL1 may contribute to target treatment for further research."

Journal • Lung Cancer • Oncology • Solid Tumor • CD4 • ELAVL1 • HNRNPC • YTHDF2

Heparin and heparin proteoglycan-mimetics activate platelets via PEAR1 and PI3Kbeta (ISTH 2022) - "We show that a heparin proteoglycan-mimetic causes platelet aggregation and phosphorylation of PEAR1 and Akt in washed platelets, and aggregation in platelet-rich plasma. The response to the heparin proteoglycan-mimetic was abolished by a novel anti-PEAR1 nanobody and by a selective inhibitor of PI3Kbeta, TGX 221. Unfractionated heparin stimulated full aggregation in washed platelets in 4 out of 7 donors after a delay of more than 30 minutes but not in platelet-rich plasma."

Cardiovascular • EGF • PIK3CB