PF-06409577 / Pfizer - LARVOL DELTA

Activation of autophagy with PF-06409577 alleviates heatstroke-induced organ injury. (PubMed, Environ Int) - "Additionally, it decreased heat stress-induced macrophage infiltration and IL-6 production in the liver. The results indicate that activation of autophagy serves a protective function during heat stress, and the AMPK activator PF-06409577 exhibits potential in mitigating heatstroke-induced multi-organ damage through its ability to promote autophagy."

Journal • Renal Disease • ATG7 • CLU • IL6 • LCN2 • SPP1

Hypoglycaemic stimulation of macrophage cytokine release is suppressed by AMP-activated protein kinase activation. (PubMed, Diabet Med) - "Taken together, these data indicate that pharmacological AMPK activation suppresses the release of MIF from macrophages caused by energy stress, suggesting that AMPK activation could be a useful strategy for mitigating hypoglycaemia-induced inflammation."

Journal • Cardiovascular • Diabetes • Hypoglycemia • Inflammation • Metabolic Disorders • MIF

Stress-Induced AMPK Interactome Analysis Reveals Novel Protein-Protein Interactions Associated with Chromatin Remodeling and Transcription Machinery in Acute Lymphoblastic Leukemia (ASH 2023) - "We generated HEK293T cells stably expressing TurboID fused to the AMPKα1, AMPKα2, AMPKβ1 or AMPKγ1 (which are the most abundant AMPK subunits expressed in ALL cells), and these stable cell lines were treated with the potent allosteric AMPK activator PF-06409577 for 1 hr, to mimic the cell's rapid response to energy/metabolic stress...To our knowledge, this is the first report describing the AMPK interactome in pediatric ALL. Further elucidation of the uncovered protein-protein interactions may lead to potential epigenetic-based targeted therapies to overcome therapeutic resistance in relapse/refractory ALL and other hematological malignancies."

Acute Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Pediatrics • T Acute Lymphoblastic Leukemia • AMPK • HDAC2 • KDM6A • KMT2A • SETD1A • SETD2

Macrophage AMPK β1 activation by PF-06409577 reduces the inflammatory response, cholesterol synthesis, and atherosclerosis in mice. (PubMed, iScience) - "Treatment of BMDMs with PF-06409577 suppressed fatty acid and cholesterol synthesis and transcripts related to the inflammatory response while increasing transcripts important for autophagy through AMPKβ1. These data indicate that pharmacologically targeting macrophage AMPKβ1 may be a promising strategy for reducing atherosclerosis."

Journal • Preclinical • Atherosclerosis • Cardiovascular • Dyslipidemia • Inflammation • Metabolic Disorders • AMPK

Epithelial metabolic stress in IPF: Identifying intervention strategies using a preclinical murine SftpcI73T model of lung fibrosis (ERS 2023) - "In primary AT2I73T, AMPK agonism (PF06409577) or stimulation of PGC1α (Rosiglitazone), but not mTOR inhibition (Rapamycin) rescued mitochondrial respiration. Delivered once daily to SftpcI73T mice, Metformin reduced mortality, BAL protein, and BAL soluble collagen while improving static lung compliance. Together the data support a role for epithelial metabolic dysfunction in IPF mediated by AT2 glycolytic reprogramming, mitochondrial dysfunction, and altered AMPK signals.; Cell and molecular biology; Transplantation"

Preclinical • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Metabolic Disorders • Respiratory Diseases • Transplantation • PPARG

AMPK activators have compound and concentration-specific effects on brain metabolism. (PubMed, J Neurochem) - "Here, we activated AMPK in guinea pig cortical tissue slices, both directly with A769662 and PF 06409577, and indirectly, using AICAR and metformin. Specific direct activation of β1-containing AMPK isoforms with PF 06409577 resulted in increased Krebs cycle activity, restoring pyruvate metabolism while A769662 increased lactate and alanine production as well as labelling of citrate and glutamine. These results reveal a complex metabolic response to AMPK activators in brain beyond increased aerobic glycolysis and indicate that further research is warranted into their concentration and mechanism-dependent impact."

Journal • Metabolic Disorders • Solid Tumor

PF-06409577 inhibits renal cyst progression by concurrently inhibiting the mTOR pathway and CFTR channel activity. (PubMed, FEBS Open Bio) - "While metformin effectively inhibits renal cyst growth in mouse models of ADPKD it exhibits low potency, and thus an AMPK activator with higher potency is required. Our results demonstrated that PF-06409577 effectively down-regulated mammalian target of rapamycin (mTOR) pathway-mediated proliferation of cyst-lining epithelial cells and reduced cystic fibrosis transmembrane conductance regulator (CFTR)-regulated cystic fluid secretion. Overall, our data suggest that PF-06409577 holds therapeutic potential for ADPKD treatment."

Journal • Autosomal Dominant Polycystic Kidney Disease • Cystic Fibrosis • Diabetic Nephropathy • Fibrosis • Genetic Disorders • Immunology • Nephrology • Polycystic Kidney Disease • Pulmonary Disease • Renal Disease • Respiratory Diseases • CFTR

Opposing effects on regulated insulin secretion of acute vs chronic stimulation of AMP-activated protein kinase. (PubMed, Diabetologia) - "AMPK activation exerts complex, time-dependent effects on insulin secretion. These observations should inform the design and future clinical use of AMPK modulators."

Journal • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus • STK11

AMPK Reprograms Gene Expression and Promotes Adaptation/Survival in Response to Metabolic Stress through Binding to a Chromatin-Associated Transcription Complex in Acute Lymphoblastic Leukemia (ASH 2021) - "Additional experiments were conducted using the allosteric AMPK activators compound 991 and PF-06409577...In conclusion, our data show that in response to metabolic stress, AMPK binds directly to a multi-protein complex on chromatin to reprogram gene expression to promote cellular adaptation/survival in ALL. Further elucidation of AMPK’s interactions with members of the putative AMPK/chromatin-associated transcription complex may lead to unique opportunities for epigenetic-based therapeutic interventions and combination strategies to exploit synthetic lethality in relapse/refractory ALL and other hematological malignancies."

Acute Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • T Acute Lymphoblastic Leukemia • AMPK • CEBPD

PF-06409577 Activates AMPK Signaling and Inhibits Osteosarcoma Cell Growth. (PubMed, Front Oncol) - "AMPK activation, mTORC1 inhibition, autophagy induction, as well as RTK degradation and apoptosis activation were detected in PF-06409577-treated xenografts. In conclusion, activation of AMPK by PF-06409577 inhibits OS cell growth."

Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor

The AMP-Activated Protein Kinase Modulates Hypothermia-Induced J Wave. (PubMed, Eur J Clin Invest) - "AMPK inhibition reduces low-temperature-induced J waves and possible ventricular arrhythmogenesis by modulating I and I channels."

Journal • Atrial Fibrillation • Bipolar Disorder • Cardiovascular • CNS Disorders • Metabolic Disorders • Mood Disorders • Psychiatry

PKR-like Endoplasmic Reticulum Kinase Mediates Apoptosis Induced By Pharmacological AMP-Activated Protein Kinase Activation in Acute Myeloid Leukemia (ASH 2019) - "In vitro drug combination studies further demonstrated synergy between the clinical grade Bcl-2 inhibitor venetoclax (ABT-199) and each of four AMPK activators (GSK621, MK-8722, PF-06409577 and compound 991) in multiple AML cell lines. Finally, the addition of GSK621 to venetoclax enhanced anti-leukemic activity in primary AML patient samples ex vivo and in humanized mouse models in vivo. These findings together clarify the mechanisms of cytotoxicity induced by AMPK activation and suggest that combining pharmacologic AMPK activators with venetoclax may hold therapeutic promise in AML."

IO Biomarker

Acyl Glucuronide Metabolites of 6-Chloro-5-[4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylic Acid (PF-06409577) and Related Indole-3-carboxylic Acid Derivatives are Direct Activators of Adenosine Monophosphate-activated Protein Kinase (AMPK). (PubMed, J Med Chem) - "Inhibition of de novo lipogenesis with representative parent carboxylic acids and their respective acyl glucuronide conjugates in human hepatocytes demonstrated their propensity to activate cellular AMPK. Co-crystallization of the AMPK α1β1γ1 isoform with 1-3 and M1-M3 provided molecular insights into the structural basis for AMPK activation by the glucuronide conjugates."

Journal

Direct Activation of Adenosine Monophosphate-Activated Protein Kinase (AMPK) by PF-06409577 Inhibits Flavivirus Infection through Modification of Host-Cell Lipid Metabolism. (PubMed, Antimicrob Agents Chemother) - "This antiviral effect was associated to an impairment of viral replication due to the modulation of host cell lipid metabolism exerted by the compound. These results support that the pharmacological activation of AMPK, which currently constitutes an important pharmacological target for human diseases, could also provide a feasible approach for broad-spectrum host-directed antiviral discovery."

Journal

Ampk Inhibition Suppresses Hypothermia-induced J Wave And Ventricular Arrhythmogenesis (RHYTHM 2019) - "However, Low temperature is associated with metabolic disorder and 5' AMP-activated protein kinase (AMPK) which modulates ionic currents and cardiac metabolism.Objective: The purpose of this study was to determine if AMPK regulation can modulate the occurrence of the J wave in low temperature. Unipolar and bipolar leads were used to record monophasic action potential (endocardium and epicardium) and pseudo-electrocardiograms (inferior leads) in a study of the cardiac electrical activity in isolated Langendorff rabbit hearts at both low and normal temperature before and after 4-aminopyridine (an ultrarapid delayed rectified potassium current inhibitor, IKur, 50 µM), PF06409577 (an AMPK activator, 1 µM), compound C (an AMPK inhibitor, 10 µM), and glibenclamide (an ATP-sensitive inward rectifier potassium channel inhibitor, IKATP, 20 µM). The amplitude of the J wave (2.46 ± 0.34 mV vs. 1.11 ± 0.23 mV, p<0.01) at low temperature (n=15)..."