PI-103 / Roche - LARVOL DELTA

DSCC1 as a Novel Biomarker in Hepatocellular Carcinoma: Diagnostic Potential, Prognostic Impact, Correlation With Key Pathways, and Association With the Immune Landscape. (PubMed, J Gene Med) - "Overall, this study suggests that DSCC1 may function as a valuable prognostic biomarker, an early diagnostic indicator, and a potential therapeutic target in LIHC, given its diverse involvement in tumor progression, drug responsiveness, immune regulation, and genomic instability."

Biomarker • Journal • Hepatocellular Cancer • Oncology • Solid Tumor • CD4 • CD8

The construction of a prognostic nomogram model for colorectal cancer and the prediction of immune characteristics and immune treatment responses based on the bioinformatics analysis of soluble mediator-related genes. (PubMed, Hum Vaccin Immunother) - "Drug sensitivity analysis suggested PF-4708671, PI-103, and XAV939 as potential treatments for HR patients. There was significant correlation between model gene and MMR genes. The CRC prognostic model based on SMRGs effectively predicts patient prognosis and guides treatment strategies."

Journal • Basal Cell Carcinoma • Colorectal Cancer • Non-melanoma Skin Cancer • Oncology • Solid Tumor

Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) inhibitors reduce vascular inflammation in vitro and in vivo. (PubMed, Br J Pharmacol) - "Selective p110α inhibition of vascular inflammation may provide a novel therapeutic pathway for limiting adverse tissue swelling. Moreover, the limited effect of BYL-719 on C5a-mediated responses implies that this innate component of the immune response will continue to provide essential defence activity during p110α blockade."

Journal • Preclinical • Dermatitis • Inflammation • IL1B • PIK3CA • TNFA

Autophagy and PXR Crosstalk in the Regulation of Cancer Drug Metabolism and Resistance According to Gene Mutational Status in Colorectal Cancer. (PubMed, Genes (Basel)) - " CRC lines were treated with specific inhibitors, such as 3-methyladeninee, hydroxychloroquine PI-103, and irinotecan hydrochloride, and subjected to various assays, including MTT for cell viability, Western blot for protein expression, siRNA-mediated PXR knock-out, and confocal microscopy for autophagic vacuole visualization. Moreover, late-stage autophagy inhibition reduces PXR expression, whereas induction through PI3K/AKT/mTOR inhibition leads to increased expression of PXR. Our experiments uncover a mechanism by which autophagy facilitates the nuclear translocation of the PXR, thereby promoting resistance to Irinotecan across multiple cell lines."

Journal • Colorectal Cancer • Oncology • Solid Tumor

Repurposing of PI3K inhibitors for high-grade serous ovarian cancer: A novel competing endogenous network analysis-based approach. (PubMed, Comput Biol Med) - "Investigation of fine-tune regulation of RNA by non-coding RNAs and TFs uncovered a significant role of ceRNA network in cancer development, highlighting its integration with master regulatory pathways that drive tumor progression and sustainability. The drug repurposing workflow based on ceRNA-limited differentially expressed mRNAs allowed for effective prioritization of compounds with potential to be applied as treatment."

Journal • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • E2F1 • SNAI2

Rapamycin-induced small extracellular vesicles under GelMA scaffolds facilitate diabetic wound repair through accelerating angiogenesis and alleviating macrophage-mediated inflammation via PI3K/Akt signaling pathway. (PubMed, Mater Today Bio) - "Recently, small extracellular vesicles (sEVs) isolated from mesenchymal stem cells (MSCs) show superior therapeutic potential in diabetic wound repair. Mechanistically, the biological activities of RAPA-sEVs were dependent on the PI3K/Akt signaling pathway, and the pro-angiogenic and anti-inflammatory effects of RAPA-sEVs were alleviated after the pathway being inhibited by a PI3K inhibitor PI103. Overall, RAPA-sEVs-based therapy might serve as a promising strategy for diabetic wound healing through fueling angiogenesis and alleviating macrophage-mediated inflammation via activating PI3K/Akt signaling pathway."

Journal • Inflammation • IL1B • TNFA

Identification of AKTIP as a biomarker for fibrolamellar carcinoma using WGCNA and machine learning. (PubMed, 3 Biotech) - "Four compounds (PI-103, BVT-948, Digitoxigenin, and SB-218078) were identified as potential therapeutic agents targeting AKTIP...This study uncovers new perspectives on diagnosing and managing of this rare type of liver carcinoma, offering promising avenues for future research and clinical applications. The online version contains supplementary material available at 10.1007/s13205-025-04323-4."

Biomarker • Journal • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor • AKTIP

DNA-dependent protein kinase inhibitors PI-103 and samotolisib augment CRISPR/Cas9 knock-in efficiency in human T cells. (PubMed, Cytotherapy) - "In addition to the previously reported DNA-dependent protein kinase (DNA-PK) inhibitor M3814, we demonstrated that PI-103 and samotolisib markedly increase KI efficiency in a process that is good manufacturing process (GMP)-compatible. Importantly, samotolisib enabled the generation of a potent T-cell product, having no negative impact on T-cell viability, phenotype, expansion, effector function, and tumor control. Overall, we conclude that our GMP-compatible CRISPR/Cas9 protocol comprising samotolisib to augment TCR KI efficiency is suitable for the generation of genetically modified T cells for clinical use."

IO biomarker • Journal • Gene Therapies • Oncology • Solid Tumor

STAG2 expression imparts distinct therapeutic vulnerabilities in muscle-invasive bladder cancer cells. (PubMed, Oncogenesis) - "We identified 100 total drug hits and found that STAG2 KO sensitized cells to treatment with PLK1 inhibitor rigosertib, whereas STAG2 KO protected cells from treatment with MEK inhibitor TAK-733 and PI3K inhibitor PI-103. Finally, synergy experiments revealed that berzosertib exhibits significant synergistic cytotoxicity in combination with cisplatin against MIBC cells. Altogether, our study presents evidence that berzosertib, PI-103, and the combination of berzosertib with cisplatin may be novel opportunities to investigate as precision medicine approaches for MIBC patients based on STAG2 tumor expression."

Journal • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • STAG2

LncRNA HITT inhibits autophagy by attenuating ATG12-ATG5-ATG16L1 complex formation. (PubMed, Cancer Lett) - "This results in HITT sensitizing PI-103-mediated cell death both in vitro and in vivo in nude mice by attenuating protective autophagy. The data presented herein demonstrate that HITT is a newly identified RNA regulator of autophagy and that it can be used to sensitize the colon cancer response to cell death by blocking the protective autophagy."

Journal • Colon Cancer • Colorectal Cancer • Oncology • Solid Tumor • ATG12 • ATG16L1 • ATG5 • HIF1A • MIR205

The comprehensive potential of AQP1 as a tumor biomarker: evidence from kidney neoplasm cohorts, cell experiments and pan-cancer analysis. (PubMed, Hum Genomics) - "Our study uncovered AQP1 as a biomarker for favorable survival outcomes in renal cancers. Furthermore, the bioinformatic analysis promoted its implication in pan-cancer scope."

Biomarker • Journal • Pan tumor • Kidney Cancer • Oncology • Solid Tumor • AQP1

Identification of Cuproptosis-Related Genes for Molecular Subtyping: Predicting Prognostic and Therapeutic Response in Glioma. (PubMed, Onco Targets Ther) - "We screened PI-103 as the most promising candidate for patients with higher CupScore and confirmed its experimental evidence and clinical trial status...Cuproptosis has the ability to reprogram the tumor microenvironment (TME) in HGG, leading to the stratification of patients into two distinct molecular subgroups. The CupScore model emerged as a robust metric for predicting the prognostic and therapeutic benefits, as well as may therefore facilitate personalized treatment strategies for patients with HGG."

IO biomarker • Journal • Brain Cancer • CNS Tumor • Glioma • Malignant Glioma • Oncology • Solid Tumor • CDKN2A

Antibody nanoparticle conjugate-based targeted immunotherapy for non-small cell lung cancer. (PubMed, Sci Adv) - "An ADN was designed with an anti-CD47 and anti-programmed death ligand 1 (PDL1) antibody pair on the surface of the nanoparticle and a molecularly targeted inhibitor of the PI3K (phosphatidylinositol 3-kinase)/AKT/mTOR (mammalian target of rapamycin) pathway, PI103, entrapped in the nanoparticle. The anti-CD47-PDL1-ADN exhibited greater antitumor efficacy than current treatment options with a PDL1 inhibitor in vivo in an aggressive lung cancer immunocompetent mouse model. Dual antibody-drug-loaded nanotherapeutics can emerge as an attractive platform to improve outcomes with cancer immunotherapy."

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

Molecular Expression and Prognostic Implications of Krüppel-Like Factor 3 (KLF3) in Clear Cell Renal Cell Carcinoma. (PubMed, Crit Rev Eukaryot Gene Expr) - "Based on GDSC database, KLF3 upregulation was identified to be associated with higher sensitivities towards PI3K-Akt-mTOR pathway inhibitors such as PI-103, PIK-93, and OSI-027. In addition, patients with down-regulated KLF3 expressions were found more sensitive towards Trametinib, Cetuximab, and Erlotinib. Collectively, our findings suggest that KLF3 may act as a suitable biomarker for prognosis prediction, tumor microenvironment (TME) phenotype identification, thereby helping ccRCC patients to make better therapeutic decisions."

Journal • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • KLF3 • TGFB1

Suppression of Autophagy Can Augment PIK3 Inhibitor Induced Apoptosis in T Lymphoblastic Leukemia Cell Lines. (PubMed, Ann Clin Lab Sci) - "The results demonstrated that 3-MA could suppress PI3K inhibitor-mediated activation of autophagy to promote the apoptosis of tumor cells. This discovery provided experimental support for constituting a promising strategy for T-cell acute lymphoblastic leukemia (T-ALL) therapy."

Journal • Preclinical • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Oncology • T Acute Lymphoblastic Leukemia • ATG12 • ATG5 • BECN1

Design, Synthesis and Molecular Docking Studies Pyrazoline Derivatives as PI3K Inhibitors. (PubMed, Comb Chem High Throughput Screen) - "Compounds 5 and 3 had the best docking scores (-7.85 and -7.17, respectively). The synthesized compounds have better docking scores than the reference drug AMG-319. As a result, they might be used as lead molecules in investigating PI3K inhibitors."

Journal • Oncology

Overcoming roadblocks of immunotherapy in non-small cell lung cancer (AACR 2023) - "Here, we introduce antibody conjugated drug loaded nanotherapeutics (ADNs) consisting of a targeted therapy drug, phosphatidylinositol 3-kinase (PI3K) inhibitor PI103, and decorated with two ICIs for CD47 and PDL1...Reduced tumor growth and higher survival probability have been observed in the syngeneic LLC tumor model for anti-CD47-PDL1-ADN than monotherapy and traditional immunotherapy.In summary, we have introduced a lung cancer treatment strategy that can be an effective therapy for NSCLC patients, irrespective of the PDL1 expression level. The strategy combining bispecific immunotherapy and targeted therapy for activating the innate and adaptive immune systems and delivering targeted therapy drugs can emerge as a significant advance in the treatment of NSCLC patients."

IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD47 • SIRPA

Modulation of YBX1 phosphorylation determines epidermal stem cell function (ISID 2023) - "Small molecule inhibitors of PI3 kinase (PI3K), such as PI-103 and GDC-0941 inhibit YBX1 phosphorylation levels in epidermal stem cells and consequently reduce the occurrence of cellular senescence in primary epidermal stem cells isolated from adult donors. Furthermore, PI3K inhibitors increase the speed of epidermal wound closure in a wound healing model and epidermal regeneration model utilizing 3D skin equivalents. Our findings have uncovered a new level of posttranscriptional control of aging epidermal stem cell function by YBX1, which is required to maintain epidermal regenerative potential."

YBX1

Contribution of YBX1 phosphorylation in human epidermal stem cell aging (ISID 2023) - "Since YBX1 is phosphorylated by PI3 kinase, the PI3 kinase inhibitors PI-103 and GDC-0941 restrict YBX1 phosphorylation and prevent keratinocyte senescence. In addition, we found a promising cosmetic ingredient that suppresses YBX1 phosphorylation, decreases IL-8 production, and maintains epidermal stem cells. In conclusion, YBX1 phosphorylation contributes to human skin aging, and its inhibition is a novel anti-aging approach to maintaining healthy epidermal stem cells."

CXCL1 • CXCL8 • YBX1

RIDR-PI-103, ROS-activated prodrug PI3K inhibitor inhibits cell growth and impairs the PI3K/Akt pathway in BRAF and MEK inhibitor-resistant BRAF-mutant melanoma cells. (PubMed, Anticancer Drugs) - "Reactive oxygen species (ROS) levels are elevated after acquisition of resistance to v-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitors including dabrafenib and MEK inhibitors such as trametinib in BRAF-mutant melanoma. Addition of the ROS scavenger glutathione to RIDR-PI-103 significantly rescued the cell proliferation in TDR cell lines while addition of the ROS inducer TBHP and RIDR-PI-103 inhibited cell proliferation in WM115 and WM983B TDR cell lines. Examining the efficacy of RIDR-PI-103 on BRAF and MEK inhibitor-resistant cells will expand possible treatment options and open avenues for the development of new ROS-based treatment therapies for BRAF-mutant melanoma patients."

Journal • Melanoma • Oncology • Solid Tumor

Enhancement of the antitumor effect of 5-fluorouracil with modulation in drug transporters expression using PI3K inhibitors in colorectal cancer cells. (PubMed, Life Sci) - "Our data provide evidence that survival signaling pathways represent distinctive targets for the enhancement of chemotherapeutic sensitivity. The antitumor efficacy of 5-FU is enhanced when combined with a PI3K inhibitor, and this effect was mediated by alterations in the expression of specific drug transporters."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • ABCC5 • ABCG2

PIK-24 Inhibits RSV-Induced Syncytium Formation via Direct Interaction with the p85α Subunit of PI3K. (PubMed, J Virol) - "Most importantly, PIK-24 exerted a potent anti-RSV activity, and its antiviral effect was stronger than that of the classic PI3K inhibitor LY294002, PI-103, and broad-spectrum antiviral drug ribavirin. Currently, no effective antiviral drugs or vaccines exist for RSV infection. This study contributes to understanding the molecular mechanism by which PI3K signaling regulates syncytium formation and provides a leading compound for anti-RSV infection drug development."

Journal • Infectious Disease • Respiratory Diseases • Respiratory Syncytial Virus Infections • CDC42

An autophagy-related gene prognostic index predicting biochemical recurrence, metastasis, and drug resistance for prostate cancer. (PubMed, Asian J Androl) - "Drug analysis showed that PI-103 was the common sensitive drug and cell line analysis indicated that PC3 was the common cell line of PI-103 and the definitive gene. In conclusion, we found that ARGPI could predict BCR, metastasis, and chemoresistance in PCa patients who underwent radical radiotherapy or prostatectomy."

Journal • Genito-urinary Cancer • Immune Modulation • Inflammation • Oncology • Prostate Cancer • Solid Tumor • ACSL3 • ALDH2 • SERPINB5 • SPP1

A pyridinesulfonamide derivative FD268 suppresses cell proliferation and induces apoptosis via inhibiting PI3K pathway in acute myeloid leukemia. (PubMed, PLoS One) - "In this study, we demonstrated that FD268 dose-dependently inhibits survival of AML cells with the efficacy superior to that of PI-103 (pan-PI3K inhibitor) and CAL-101 (selective PI3Kδ inhibitor) in the tested HL-60, MOLM-16, Mv-4-11, EOL-1 and KG-1 cell lines. The bioinformatics analysis of the transcriptome sequencing data also indicated a potential involvement of the PI3K/Akt/mTOR pathway. These studies indicated that FD268 possesses high potent activity toward AML cells via inhibition of PI3K/Akt/mTOR signaling pathway, which sheds some light on the pyridinesulfonamide scaffold for further optimization and investigation."

Journal • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • CASP3 • MCL1 • PIK3CD

The ILF3-mediated inhibition of NO production via PI3K/Akt pathway contributes to central cardiovascular regulation in the RVLM in hypertension. (PubMed, Am J Physiol Regul Integr Comp Physiol) - "In addition, inhibition of PI3K by intracisternal infusion of the PI-103 attenuated the increase in Akt phosphorylation and decrease in nNOS expression and NO production caused by overexpressing ILF3, which ultimately blunted high BP induced by overexpressing ILF3. Taken together, this current study suggests that ILF3 participates in high BP via reducing NO production in the RVLM through PI3K/Akt pathway."

Journal • Cardiovascular • Hypertension