PF-04691502 / Pfizer - LARVOL DELTA

PF-04691502, a PI3K/mTOR Dual Inhibitor, Ameliorates AD-like Pathology in a Mouse Model of AD. (PubMed, Cells) - "Treatment with PF-04691502 increased the LC3-II/LC3-I ratio, upregulated Beclin-1, and elevated LAMP-2 levels, indicative of stimulated autophagosome formation and lysosomal activity. Overall, these preclinical results suggest that PF-04691502 holds promise as a potential therapeutic agent for AD and other aging-related neurodegenerative diseases involving mTOR pathway dysregulation."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • BECN1

Drug sensitivity patterns across FAB subtypes and molecular mutations in AML. (ASCO 2025) - "M1 samples (n=22 patients) demonstrated higher sensitivity to Navitoclax (σsDSS = 15.89), while combinations with mTOR inhibitors like Navitoclax + PF-04691502 (σsDSS = 13.97) and Navitoclax + Vistusertib (σsDSS = 13.72) showed promise...M4 subtypes (n=2 patients) were most sensitive to BAY 87-2243 (σsDSS = 15.98), with dual combinations like BAY 87-2243 + Cerdulatinib (σsDSS = 14.21) and BAY 87-2243 + Pevonedistat (σsDSS = 14.13) maintaining strong responses...In M4 eos (n=9 patients), Pimasertib demonstrated notable effectiveness (σsDSS = 14.43), with dual-agent combination such as Pimasertib + SCH772984 (σsDSS = 14.24) supporting RAS/ERK pathway inhibition. Despite rare M4/M5 subtypes (n=2 patients) showing limited Refametinib sensitivity (σsDSS = 8.75), their minimal sample size precludes definitive conclusions...Likewise, mutation analysis revealed that NPM1-mutated samples showed increased sensitivity to Venetoclax (σsDSS = 13.28) and PF-04691502 (σsDSS =..."

Acute Myelogenous Leukemia • FLT3 • NPM1

PI3K/mTOR Signaling Pathway Dual Inhibition for the Management of Neuroinflammation: Novel Insights from In Vitro Models. (PubMed, Biomolecules) - "Here, we investigated the consequences of PI3K/mTOR pathway inhibition on neuroinflammation employing PF-04691502, an agent with combined PI3K and mTOR inhibitory activity...Our results indicate that inhibition of the PI3K/mTOR signaling axis may alleviate neurodegenerative processes by modulating both neuroinflammatory responses and apoptotic pathways. These findings highlight the therapeutic promise of targeting PI3K/mTOR in the context of neurodegenerative disorders and support the need for further validation through in vivo and clinical investigations."

Journal • Preclinical • CNS Disorders • Inflammation • Movement Disorders • Parkinson's Disease • IFNG

PF-04691502, A PI3K/MTOR DUAL INHIBITOR, AMELIORATES AD -LIKE PATHOLOGY IN A MOUSE MODEL OF AD (ADPD 2025) - "These results provide preclinical data indicating that PF -04691502 may be a valid therapeutic for AD and other neurodegenerative disorders associated with aging and mTOR hyperactivity."

Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders

PF-04691502, A PI3K/MTOR DUAL INHIBITOR, IMPROVES LEARNING DEFICITS IN APP/PS1 MICE (ADPD 2024) - "These results provide preclinical data indicating that PF-04691502 may be a valid therapeutic approach for AD and other neurodegenerative disorders associated with aging and mTOR hyperactivity."

Preclinical • Alzheimer's Disease • CNS Disorders • Inflammation

Inhibitor PF-04691502 works as a senolytic to regulate cellular senescence. (PubMed, Exp Gerontol) - "These results suggest that PF-04691502 holds promise as a new senolytic drug. This paper provides important insights into the potential application of PF-04691502 in the study of cell senescence."

Journal

Glucose metabolic upregulation via phosphorylation of S6 ribosomal protein affects tumor progression in distal cholangiocarcinoma. (PubMed, BMC Gastroenterol) - "Upregulation of glucose metabolism via phosphorylation of S6 ribosomal protein appeared to play a role in tumor progression in dCCA. mTORC1 may be a therapeutic target for dCCA."

Journal • Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • SLC2A1

HMGA1 augments palbociclib efficacy via PI3K/mTOR signaling in intrahepatic cholangiocarcinoma. (PubMed, Biomark Res) - "Our study reveals the potential therapeutic role of dual inhibition of CDK4/6 and PI3K/mTOR pathways in iCCA, and proposes a new paradigm for the clinical treatment of iCCA."

Journal • Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Hepatology • Oncology • Solid Tumor • CCND1 • HMGA1

Engineering prodrug nanomicelles as pyroptosis inducer for codelivery of PI3K/mTOR and CDK inhibitors to enhance antitumor immunity. (PubMed, Acta Pharm Sin B) - "PNM was engineered by integrating the PI3K/mTOR inhibitor PF-04691502 (PF) and the broad spectrum CDK inhibitor flavopiridol (Flav) into a single nanoplatform, which showed tumor-specific accumulation, activation and deep penetration in response to the high glutathione (GSH) tumoral microenvironment. Furthermore, the combination of PNM-induced immunogenic pyroptosis with anti-programmed cell death-1 (αPD-1) immunotherapy further boosted the antitumor effect and prolonged the survival time of mice. Collectively, these results indicated that the pyroptosis-induced nanoplatform codelivery of PI3K/mTOR and CDK inhibitors can reprogram the immunosuppressive tumor microenvironment and efficiently improve checkpoint blockade cancer immunotherapy."

Journal • Oncology • GSDME

Evaluation of a Dual PI3K/mTOR Inhibitor PF-04691502 against Bladder Cancer Cells. (PubMed, Evid Based Complement Alternat Med) - "In addition, PF-04691502 increased the apoptosis induced by various chemotherapeutic agents in BC cells. Taken together, PF-04691502 could be used alone or in combination with other chemotherapeutic agents in the treatment of BC."

Journal • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • MCL1 • PTEN

PIK3R3, a regulatory subunit of PI3K, modulates ovarian cancer stem cells and ovarian cancer development and progression by integrative analysis. (PubMed, BMC Cancer) - "PIK3R3 plays a pivotal role in ovarian cancer development and is therefore a potential candidate for developing novel therapeutic approaches."

Cancer stem cells • Journal • Gynecology • Oncology • Ovarian Cancer • Solid Tumor • Women's Health • EGFR • ERBB3 • PIK3CA • PIK3R3 • POU5F1

Pdgf/Pi3k/akt axis activation by hey1-ncoa2 fusion and potential target in the treatment of mesenchymal chondrosarcoma (AACR 2022) - "In summary, both CP-673451 and PF-04691502 were active against the in vitro mesenchymal chondrosarcoma model tested. Based on these data, the potential benefit of targeting PDGF/PI3K/AKT signaling pathways in the treatment of mesenchymal chondrosarcoma was suggested."

Late-breaking abstract • Oncology • Sarcoma • Solid Tumor • NCOA2 • PDGFB

SPR965, a PI3K/mTORC1/C2 inhibitor for treatment of chordoma (AACR 2022) - "SPR965 was more active at 1uM than PI3K/mTOR inhibitors VS-5584, Bimiralisib, PF-04691502, WYE-687, Dactolisib, and Voxtalisib in the Kinase Chemogenomic Set. In SF8894 PDX model SPR965 was more efficacious as it produced similar tumor growth inhibition at 12- and 17-fold lower dose than Buparlisib (PI3K) and Palbociclib (CDK4/6) respectively, both these compounds are in phase 2 clinical trials. In CF459 PDX model SPR965 exhibited dose-dependent tumor growth inhibition, and at 10mg/kg profoundly slowed tumor growth compared to Palbociclib. Studies are underway to elucidate potential mechanisms of SPR965 sensitivity."

Late-breaking abstract • Chordoma • Oncology

Synergistic cytotoxicity of dual PI3K/mTOR and FLT3 inhibition in FLT3-ITD AML cells. (PubMed, Adv Biol Regul) - "Here, we report on the preclinical activity of the combination of the FLT3 inhibitor quizartinib with the dual PI3K/mTOR inhibitor PF-04691502 in FLT3-ITD cells. Briefly, we show that the association of these two molecules displays synergistic cytotoxicity in vitro in FLT3-ITD AML cells, triggering 90% cell death at nanomolar concentrations after 48 h."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3

Next generation proteomics with drug sensitivity screening identifies sub-clones informing therapeutic and drug development strategies for multiple myeloma patients. (PubMed, Sci Rep) - "35 CD138-purified MM samples were taken from patients with newly diagnosed or relapsed MM and exposed to therapeutic agents from five therapeutic drug classes including Bortezomib, Quizinostat, Lenalidomide, Navitoclax and PF-04691502. Using Receiver Operating Characteristic curve analysis, strong predictive power for the specificity and sensitivity of these potential biomarkers was identified. This approach has the potential to yield predictive theranostic protein panels that can inform therapeutic decision making."

Clinical • Journal • Hematological Malignancies • Multiple Myeloma • Oncology • SDC1

PI3K/mTOR Dual Inhibitor PF-04691502 Is a Schedule-Dependent Radiosensitizer for Gastroenteropancreatic Neuroendocrine Tumors. (PubMed, Cells) - "Our results demonstrate that schedule-dependent administration of a PI3K/mTOR inhibitor, combined with XRT, can enhance cytotoxicity by promoting the radiosensitivity of NET cells. Moreover, our findings suggest that radiotherapy, in combination with timed PI3K/mTOR inhibition, may be a promising therapeutic regimen for patients with GEP-NET."

Journal • Endocrine Cancer • Neuroendocrine Tumor • Oncology • Pancreatic Cancer • Solid Tumor

ARHGAP25 Inhibits Pancreatic Adenocarcinoma Growth by Suppressing Glycolysis via AKT/mTOR Pathway. (PubMed, Int J Biol Sci) - "Treatment with PF-04691502, a dual PI3K/mTOR inhibitor, hampered the increased cell growth and glycolysis due to ARHGAP25 knockdown in PAAD cells. Altogether, these results conclude that ARHGAP25 acts as a tumor suppressor by inhibiting the AKT/mTOR signaling pathway, which might provide a therapeutic target for PAAD."

Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • HIF1A

A comprehensive panel of patient-derived xenografts representing the molecular heterogeneity and diversity of triple-negative breast cancer (AACR 2018) - "PDX carrying targetable genomic alterations in the PI3K/AKT/mTOR and MAPK signaling pathways were treated by specific inhibitors (selumetinib, BAY 80-6946 and PF-04691502). At the gene expression level, TNBC PDX represent all the different TNBC subtypes identified by the Lehmann classification. TNBC PDX reproduce the molecular heterogeneity and diversity of TNBC patients. This large collection of PDX is a clinically relevant platform for drug testing, biomarker discovery and translational research."

Clinical • Heterogeneity • IO Biomarker • Triple Negative Breast Cancer

[VIRTUAL] Synergistic Cytotoxic Effect of a Novel mTOR/PI3K Dual Inhibitor PF-04691502 and Radiation Therapy on Neurondocrine Tumor Cells (ASTRO 2020) - "Embargoed Information"

Oncology

Evaluation of the dual mTOR/PI3K inhibitors Gedatolisib (PF-05212384) and PF-04691502 against ovarian cancer xenograft models. (PubMed, Sci Rep) - "Both drugs produced apoptosis but minimally influenced markers of proliferation (Ki67, phospho-histone H3). These results indicate that mTOR/PI3K inhibition can produce broad spectrum tumour growth stasis in ovarian cancer xenograft models during continuous chronic treatment and this is associated with apoptosis."

Journal • Preclinical • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor

Bi-allelic loss of FAM46C triggers tumor growth with concomitant activation of Akt signaling in multiple myeloma cells. (PubMed, Cancer Sci) - "PF-04691502, a selective PI3K inhibitor, suppressed the augmented phosphorylation of Akt and its substrate FoxO3a. Treatment with afuresertib (a specific Akt inhibitor) in combination with bortezomib additively decreased FAM46C MM cell survival. Collectively, this study is the first to demonstrate that loss of FAM46C triggers the concomitant activation of PI3K-Akt signaling pathway, which might be a therapeutic target for MM with abnormalities in FAM46C gene."

Journal • Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Oncology

[VIRTUAL] Effect of novel mTOR-PI3K dual inhibitors on neuroendocrine tumor cell proliferation and apoptosis (AACR-II 2020) - "The mammalian Target of Rapamycin (mTOR) and phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway has a well-established role in NETs that was supported by the clinical efficacy, shown by the rapamycin analog, Everolimus.  Our results demonstrate that both PF-04691502 and PKI-402 have a cytostatic inhibitory effect on proliferation in both BON and QGP-1 cells. In addition, treatment with PF-04691502 causes cytotoxic induction of apoptosis in QGP-1 cells, but not in BON cells. Our results suggest that PI3K/mTOR inhibition with PF-04691502 could be a novel therapeutic approach to the treatment of NETs."

Carcinoid Tumor • Neuroendocrine Tumor • Oncology • Pancreatic Cancer • Solid Tumor • CCND1 • EIF4EBP1 • PARP1

A multi-arm phase 1 dose escalation study of safety, pharmacokinetics, and pharmacodynamics of the dual PI3K/mTOR inhibitors PF-04691502 (oral) and PF-05212384 (IV) in combination with the MEK inhibitor PD-0325901 or irinotecan in patients with advanced c (EORTC-NCI-AACR 2012) - Presentation time: Thursday, Nov 08, 2012; P1, N=24; Study ID: B1271002; In Arm A, PD901 8mg was administered with PF502 4mg; MTD was exceeded & a 5mg dose of PD901 is now being explored; In Arms B & C, Ir 180mg/m2 (IV days 1–15) was combined with PF502 4mg & 6mg & PF384 95, 110 & 130mg, respectively; Fatigue, GI and cutaneous toxicity are the most relevant toxicities associated with the study combination in Arm A; Fatigue & GI toxicity are the most significant toxicities in Arms B & C; Early signs of efficacy require further data to confirm the antitumor activity of the study combinations; MTD confirmation is ongoing”

P1 data • Oncology

Evaluation of novel combinations of PI3K-mTOR inhibitors with dacomitinib (dac) or chemotherapy in PTEN-deficient genomically characterized patient-derived tumor xenografts (gPTX) (AACR 2014) - Presentation time: Tuesday, Apr 08, 2014, 8:00 AM -12:00 PM; Abstract #3121; "In gPTX with PTEN loss, the addition of a PI3K-mTOR inhibitor [PF-04691502 or PF-05212384] may improve the TGI% when compared to chemotherapy or dac alone. This benefit was largely offset in the NSCLC gPTX harboring KRAS G12C and/or TP53 mutations."

Preclinical • Oncology

A study of two dual PI3K/mTOR inhibitors, PF-04691502 and PF-05212384 in patients with recurrent endometrial cancer (clinicaltrials.gov) - P2, N=144; Sponsor: Pfizer; Recruiting; Primary completion date: Sep 2014 -> Apr 2014.

Trial primary completion date • Oncology