apilimod (STA-5326) / Madrigal Pharma - LARVOL DELTA

PIKfyve is an essential component of the endolysosomal pathway within photoreceptors and the retinal pigment epithelium. (PubMed, Exp Eye Res) - "Electroretinography (ERG) recordings revealed complete visual impairment in pikfyve crispant larvae and significantly reduced visual function in larvae treated with apilimod post embryogenesis. These findings highlight the critical role of PIKfyve in the development and homeostasis of the RPE and retina."

Journal • Cataract • Ophthalmology • LAMP1

1-Phosphatidylinositol 3-Phosphate 5-Kinase Inhibition by Apilimod Promotes an Adipocyte-Like Vascular Smooth Muscle Cell Phenotype and Prevents Arterial Calcification. (PubMed, Circ Res) - "Pharmacological inhibition of PIKFYVE disrupts YAP-TEAD signaling, thereby reducing arterial calcification by limiting the calcification potential of EVs and suppressing osteogenic SMC programming, but also induces an adipocyte-like SMC phenotype with lipid accumulation. These findings emphasize the need to consider SMC phenotypic plasticity and potential adverse effects when developing therapeutic strategies for arterial calcification."

Journal • Cardiovascular

Lysosomal exocytosis by macrophages as a druggable mechanism for anti-inflammatory clearance of dead adipocytes in adipose tissue. (PubMed, Cell Death Dis) - "Notably, activation of lysosomal exocytosis with the mTOR inhibitor Rapamycin enhanced adipocyte clearance and significantly reduced inflammatory ATM abundance and TNF-α secretion...In contrast, inhibition of lysosomal exocytosis with PIKfyve inhibitor Apilimod or targeted inhibition of LAL using Lalistat-2 disrupted lysosomal function and promoted a pro-inflammatory ATM phenotype. Our findings highlight lysosomal exocytosis as a critical pathway for the resolution of dead adipocytes and the regulation of inflammation in adipose tissue. Pharmacological enhancement of this process may represent a promising therapeutic approach to attenuate inflammation in AT and its metabolic consequences, including insulin resistance and type 2 diabetes."

Journal • Diabetes • Inflammation • Metabolic Disorders • Type 2 Diabetes Mellitus • LAMP1 • LAMP2 • TNFA

How endosomal PIKfyve inhibition prevents viral membrane fusion and entry. (PubMed, bioRxiv) - "Acute PIKfyve inhibition with apilimod or brief hypotonic treatment produced endosomal swelling and impaired infection by interrupting a late endosomal entry step...These data support a simple biophysical mechanism: endo-lysosomal swelling, likely increasing endosomal membrane tension, creates an energy barrier to fusion and genome release. Inducing such swelling may offer a general strategy to inhibit viruses that depend on late endosomal entry."

Journal • Ebola Virus Disease • Infectious Disease • Influenza • Novel Coronavirus Disease • Respiratory Diseases

Tau seeding in neurons enabled by transient endolysosomal perforations are confined within endolysosomes. (PubMed, bioRxiv) - "Pharmacologic inhibition of the endolysosomal lipid kinase PIKfyve with apilimod suppressed seeded tau aggregation and prevented neuronal toxicity. These data indicate that templated conversion proceeds within acidic, membrane-intact endolysosomes; tau seeding in neurons is enabled by transient, self-limited endolysosomal perforations yet remains confined to the endolysosomal lumen, and it requires PIKfyve- dependent PI(3,5)P₂."

Journal • Alzheimer's Disease • CNS Disorders

Targeting lysozyme 2 in endocardium promotes rapid recovery by modulating remote injury signals. (PubMed, Cell Stem Cell) - "Harnessing these insights, we show that both Lyz2 knockout (KO) and pharmacological inhibition of lysosomal degradation confer rapid functional recovery in injured non-regenerative hearts. Thus, targeting a remote injury response in a non-CM cell type rapidly promotes post-MI recovery of non-regenerative hearts."

Journal • Cardiovascular • Myocardial Infarction • LYZ

A New Pikfyve Inhibitor Shows Subnanomolar Potency in Multiple Myeloma (IMS 2025) - "PIK085 also displayed an improved metabolic stability, with increased plasma concentrations following oral and IV administrations in mice when compared to PIK001 and apilimod.PIKfyve inhibitors displayed synergistic activity with relevant anti-MM therapeutics, including selinexor, venetoclax, and iberdomide. We present PIK085 as a promising preclinical candidate with subnanomolar potency in MM. Validation of PIKfyve inhibition as a single agent and in combination with other disease relevant therapeutics in in vivo models are n ongoing. Collectively, our work encourages further exploration of autophagy disruption in MM via PIKfyve inhibition, highlighting the potential of targeting plasma cell biology when investigating innovative treatment strategies."

Hematological Malignancies • Multiple Myeloma • SQSTM1

LUMINEV, SEMI HIGH -THROUGHPUT (96 -WELL) ANALYSIS OF EXTRACELLULAR VESICLES IN PLASMA SAMPLES. (ADPD 2025) - "Using tetraspanin levels as a readout, we noted suppression of EV in cells treated with GW6869 and elevation following Monensin, Bafilomycin -A, and Apilimod treatments... LuminEV is a sensitive, multiplexed assay for measuring EV surface proteins in cell culture media and plasma samples. The current results verify the specificity of the assay, provide a reference standard in healthy individuals, and suggest elevated EV secr etion in neurodegenerative patients."

CNS Disorders • CD63 • CD81 • CD9

Integrative analysis based on CRISPR screen identifies apilimod as a potential therapeutic agent for cisplatin-induced acute kidney injury treatment. (PubMed, Sci China Life Sci) - "Apilimod and elacridar emerged as the top two candidates of mitigating cisplatin-induced nephrotoxicity, with apilimod demonstrating superior efficacy in drug matrix experiments. Additionally, apilimod treatment did not compromise the antitumor effect of cisplatin in cancer cells or tumor-bearing mice. Overall, our study suggests that apilimod could be a promising therapeutic agent for the treatment of cisplatin-induced AKI and revealed its underlying molecular mechanism."

Journal • Acute Kidney Injury • Metabolic Disorders • Nephrology • Oncology • Renal Disease • TFEB

Concurrent Inhibition of the RAS-MAPK Pathway and PIKfyve is a Therapeutic Strategy for Pancreatic Cancer. (PubMed, Cancer Res) - "Inhibition of the KRAS-RAF-MEK-ERK pathway enhances autophagic flux and dependency, and concurrent treatment with the nonspecific autophagy inhibitor chloroquine (CQ) and ERK-MAPK pathway inhibitors can synergistically block PDAC growth...PIKfyve inhibition by the small molecule apilimod resulted in durable growth suppression, with much greater potency than CQ treatment...Growth suppression was due, in part, to potentiated cell cycle arrest and induction of apoptosis following loss of IAP proteins. These findings indicate that concurrent inhibition of RAS and PIKfyve is a synergistic, cytotoxic combination that may represent a therapeutic strategy for PDAC."

Journal • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS

Development of a Second-Generation, In Vivo Chemical Probe for PIKfyve. (PubMed, J Med Chem) - "Coupled with its subnanomolar cellular potency and impressive selectivity in cells, the long half-life of 40 makes it an ideal candidate for the evaluation of the consequences of PIKfyve inhibition in vivo. PIKfyve inhibition has been investigated clinically for indications including rheumatoid arthritis, Crohn's disease, COVID-19, and ALS using a single compound (apilimod), supporting the development of orthogonal PIKfyve inhibitors with in vivo stability."

Journal • Preclinical • Crohn's disease • Gastroenterology • Immunology • Infectious Disease • Inflammatory Arthritis • Inflammatory Bowel Disease • Novel Coronavirus Disease • Rheumatoid Arthritis • Rheumatology

Elucidation of metabolic resistance mechanisms to RAS inhibition (AACRPanCa 2024) - P1, P2 | "We previously determined that concurrent inhibition of autophagy, using the lysosomal inhibitor chloroquine (CQ), and of ERK, using a small molecule ERK inhibitor (ERKi), synergistically suppressed the growth of pancreatic ductal adenocarcinoma (PDAC) cell lines and patient xenograft-derived (PDX) organoids in vitro and PDX tumors in vivo. Our findings provided the rationale for our initiation of Phase I and Phase I/II clinical trials evaluating the combination of MEKi (binimetinib; NCT04132505) or ERKi (LY3214996; NCT04386057) with hydroxychloroquine (HCQ) in PDAC...PIKfyve inhibition with apilimod resulted in a potent reduction of autophagic flux and growth...We hypothesize that further dissection of the dynamic regulation of autophagy and macropinocytosis will improve current anti-nutrient scavenging treatment strategies. We conclude that concurrent suppression of multiple metabolic processes, to block compensatory rebound activities, will be needed for..."

Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • KRAS

Concurrent inhibition of the RAS ERK-MAPK pathway and PIKfyve as a therapeutic strategy for pancreatic cancer (AACRPanCa 2024) - P2 | "Furthermore, we demonstrated that concurrent treatment with the nonspecific autophagy inhibitor chloroquine (CQ) and ERK MAPK inhibitors synergistically blocked PDAC growth. These findings provided rationale for our initiation of Phase I/II clinical trials evaluating the combination of MEKi (binimetinib; NCT4132505) or ERKi (LY3214996; NCT04386057) with HCQ in PDAC...We demonstrated that PIKfyve inhibition by the small molecule apilimod resulted in durable growth suppression, with much greater potency than CQ treatment...Growth suppression was due, in part, to potentiated cell cycle arrest and induction of apoptosis following loss of IAP proteins. These findings implicate PIKfyve as an effective anti-autophagy target when paired with RAS or ERK-MAPK pathway inhibition in pre-clinical models of PDAC."

Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS • LAMP1

Vertical inhibition of the autophagy pathway enhances sensitization to RAS MAPK pathway inhibition in pancreatic ductal adenocarcinoma (AACRPanCa 2024) - P1, P2 | "Based on these findings, combined ERK/MEK inhibition and hydroxychloroquine (HCQ) is currently under clinical evaluation (NCT03825289, NCT04386057)...Additionally, both ULK1 and VPS34 inhibitor treatment sensitized cells to PIKfyve inhibition with apilimod, a chemically and mechanistically distinct inhibitor of the termination phase of the autophagic pathway...Finally, vertical inhibition of the autophagic pathway via VPS34 inhibition and CQ sensitized PDAC cells to RAS inhibition to further reduce PDAC proliferation. Ongoing and future studies are aimed at elucidating the mechanism leading to decreased proliferation of combined anti-autophagy and RAS inhibitor therapies, as well as mechanistically understanding the effect of autophagy inhibition at multiple nodes on autophagic flux."

Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • KRAS • PIK3C3

Poly-GP accumulation due to C9orf72 loss of function induces motor neuron apoptosis through autophagy and mitophagy defects. (PubMed, Autophagy) - "Chemical boosting of autophagy using rapamycin or apilimod, is able to rescue motor deficits. Finally, we report apoptotic-related increased amounts of cleaved Casp3 (caspase 3, apoptosis-related cysteine peptidase) and rescue of motor neuron degeneration by constitutive inhibition of Casp9 or treatment with decylubiquinone. Here we provide evidence of key pathogenic steps in C9ALS-FTD that can be targeted through pharmacological avenues, thus raising new therapeutic perspectives for ALS patients."

Journal • Amyotrophic Lateral Sclerosis • CNS Disorders • CASP3 • CASP9 • SQSTM1

PIKfyve, expressed by CD11c-positive cells, controls tumor immunity. (PubMed, Nat Commun) - "Furthermore, the combination of a vaccine adjuvant and apilimod reduced tumor progression in vivo. Thus, PIKfyve negatively regulates the function of CD11c+ cells, and PIKfyve inhibition has promise for cancer immunotherapy and vaccine treatment strategies."

IO biomarker • Journal • Gene Therapies • Oncology • ITGAX

Novel Therapies for ANCA-associated Vasculitis: Apilimod Ameliorated Endothelial Cells Injury through TLR4/NF-κB Pathway and NLRP3 Inflammasome. (PubMed, Curr Pharm Des) - "This study sheds light on the potential pathogenesis of AAV and highlights the protective role of apilimod in mitigating MPO-ANCA-IgG-induced vascular endothelial cell injury by modulating the TLR4/ NF-kB and NLRP3 inflammasome-mediated pyroptosis pathway. These findings suggest that apilimod may hold promise as a treatment for AAV and warrant further investigation."

Journal • ANCA Vasculitis • Glomerulonephritis • Inflammation • Lupus Nephritis • Nephrology • Vasculitis • CCL20 • CD8 • CD86 • COL5A2 • ITGAM • KIF20A • NLRP3 • PTPRC • TLR4 • TYROBP

IL-23 inhibitor enhances the effects of PTEN DNA-loaded lipid nanoparticles for metastatic CRPC therapy. (PubMed, Front Pharmacol) - "And the combination of LNP@PTEN with Apilimod could achieve anti-tumor effects and improve tumor microenvironment. This combinational strategy opens new avenues for the treatment of mCRPC."

Journal • Metastases • Castration-Resistant Prostate Cancer • Gene Therapies • Genito-urinary Cancer • Metastatic Castration-Resistant Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor • CD4 • CD8 • IL23A • PTEN

Evaluation of the PIKfyve kinase inhibitor Apilimod against hepatitis E virus infections (EASL-ILC 2024) - "Despite its high risks especially among immunosuppressed patients and pregnant women, the treatment of HEV is limited to the off-label use of nucleoside-analogue ribavirin (RBV) and PEGylated interferon-α... All three tested PIKfyve kinase inhibitors, Apilimod, YM201636 and APY0201 lowered HEV infectivity at nanomolar efficacy in hepatoma cells... Overall, our data suggests that PIKfyve plays a crucial role during the viral entry of HEV. Considering the proven safety profile of Apilimod in previous human clinical trials (unrelated to viral conditions), the pharmacological targeting of PIKfyve kinase activity might guide novel antiviral strategies against HEV infections."

Late-breaking abstract • Ebola Virus Disease • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Infectious Disease • Inflammation • Liver Cancer • Novel Coronavirus Disease • Respiratory Diseases • Solid Tumor

Unexpected inhibition of the lipid kinase PIKfyve reveals an epistatic role for p38 MAPKs in endolysosomal fission and volume control. (PubMed, Cell Death Dis) - "p38 mitogen-activated protein kinases (MAPKs) participate in autophagic signaling; and previous reports suggest that pyridinyl imidazole p38 MAPK inhibitors, including SB203580 and SB202190, induce cell death in some cancer cell-types through unrestrained autophagy. The rate of vacuole dissolution (i.e., LEL fission), following the removal of apilimod, was also significantly reduced in cells treated with BIRB-796, a structurally unrelated p38 MAPK inhibitor. Thus, our studies indicate that pyridinyl imidazole p38 MAPK inhibitors induce cytoplasmic vacuolation through the combined inhibition of both PIKfyve and p38 MAPKs, and more generally, that p38 MAPKs act epistatically to PIKfyve, most likely to promote LEL fission."

Journal • Oncology • PIK3C3

Pan-antiviral effects of a PIKfyve inhibitor on respiratory virus infection in human nasal epithelium and mice. (PubMed, Antimicrob Agents Chemother) - "PIKfyve inhibitors Apilimod mesylate (AM) and YM201636 concentration-dependently inhibited several influenza strains in an MDCK cell-cytopathic assay...In PR8-infected mice, AM (2 mg/mL), when intranasally treated, exhibited a significant reduction of viral load and inflammation and inhibited weight loss caused by influenza infection, with effects being similar to oral oseltamivir (10 mg/kg). In addition, AM demonstrated antiviral effects in RSV A2-infected human nasal epithelium in vitro and mouse in vivo, with an equivalent effect to that of ribavirin. AM also showed antiviral effects against human rhinovirus and seasonal coronavirus in vitro. Thus, PIKfyve is found to be involved in influenza and RSV infection, and PIKfyve inhibitor is a promising molecule for a pan-viral approach against respiratory viruses."

Journal • Preclinical • Ebola Virus Disease • Infectious Disease • Inflammation • Influenza • Novel Coronavirus Disease • Respiratory Diseases • Respiratory Syncytial Virus Infections

Orphan Designation: Treatment of amyotrophic lateral sclerosis (ALS) (FDA) - Date Designated: 08/29/2023

Orphan drug • Amyotrophic Lateral Sclerosis • CNS Disorders

Apilimod activates the NLRP3 inflammasome through lysosome-mediated mitochondrial damage. (PubMed, Front Immunol) - "Furthermore, we found that apilimod induces TRPML1-dependent calcium flux in lysosomes, leading to mitochondrial damage and the NLRP3 inflammasome activation. Thus, our results revealed the pro-inflammasome activity of apilimod and the mechanism of calcium-dependent lysosome-mediated NLRP3 inflammasome activation."

Journal • IL1B • NLRP3

Pseudomonas Aeruginosa Utilizes a Nitric Oxide Metabolic Pathway to Evade Killing by Neutrophils in the Lung (ATS 2023) - "This decreased survival was abrogated in neutrophils lacking iNOS or treated with phagosome-maturation inhibitor apilimod... P.aeruginosa utilizes nitrite as a source of ammonia/ammonium, which facilitates its survival inside neutrophils by inhibiting phagosome maturation. While iNOS-mediated generation of NO has been suggested to be beneficial for neutrophil activation, our results suggest that NO promotes the survival of P.aeruginosa in the lung."

Infectious Disease • Pneumonia • Respiratory Diseases

Anti-inflammation mechanism of electro-scalp acupuncture in treatment of ischemic stroke based on IL-12 mediated JAK/STAT signaling pathway (PubMed, Zhongguo Zhen Jiu) - "Electro-scalp acupuncture may improve the neurological function of the rats with ischemic stroke. The modulation to IL-12 mediated JAK/STAT signaling pathway is the potential molecular mechanism of this therapy for the inflammatory response in ischemic cortical lesion."

Journal • Cardiovascular • Inflammation • Ischemic stroke • Oncology • IFNG • IL12A • IL2 • IL4 • STAT4 • TBX21 • TNFA