AZ67 / Gero Discovery - LARVOL DELTA

Pharmacological Inhibition of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) in Aged Male and Female Mice Confers Neuroprotection after Ischemic Stroke (ISC 2025) - " We induced permanent distal middle cerebral artery occlusion in aged female and male C57BL/6J mice (18-20mo), followed by treatment with a highly selective PFKFB3 inhibitor AZ67 (30mg/kg; Female N=10; Male N=7) or vehicle (Female N=9; Male N=7)... Our findings show a neuroprotective effect of PFKFB3 inhibition after stroke in both female and male aged mice. Mice receiving the PFKFB3 inhibitor showed significantly smaller infarcts and improved functional recovery after stroke. These results, in conjunction with our previous data in young males, further support the hypothesis that PFKFB3 inhibitors could be a viable option for the treatment of ischemic stroke."

Preclinical • Cardiovascular • Inflammation • Ischemic stroke • PFKFB3

Pharmacological Inhibition of 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 3 (PFKFB3) is Neuroprotective in an Acute Mouse Model of Ischemic Stroke (ISC 2024) - " We administered a 45-minute transient middle cerebral artery occlusion in male C57BL/6J mice, followed by treatment with a highly selective PFKFB3 inhibitor AZ67 (N=10) or vehicle (N=11)... Our findings show a neuroprotective effect of PFKFB3 inhibition in ischemic stroke with improved functional and behavioral recovery and smaller infarct sizes. These results support the hypothesis that PFKFB3 inhibitors may be used as a novel pharmacological treatment for reducing delayed cell death after ischemic stroke. Future studies are underway to investigate the molecular mechanisms and cell types involved in the protection conferred by PFKFB3 blockade in the context of ischemic stroke."

Preclinical • Cardiovascular • Inflammation • Ischemic stroke • PFKFB3

6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) blockade is neuroprotective in an acute mouse model of ischemic stroke (Neuroscience 2023) - "We administered a 45-minute transient middle cerebral artery occlusion in male C57BL/6J mice followed by treatment with a highly selective PFKFB3 inhibitor, AZ67 (N=10) or vehicle (N=11)...These results support the hypothesis that PFKFB3 inhibitors may be used as a novel pharmacological treatment for reducing delayed cell death after ischemic stroke. Future studies are underway to investigate the molecular mechanisms and cell types involved in the protection conferred by PFKFB3 blockade in the context of ischemic stroke."

Preclinical • CNS Disorders • PFKFB3

Combination of 3PO analog PFK15 and siPFKL efficiently suppresses the migration, colony formation ability, and PFK-1 activity of triple-negative breast cancers by reducing the glycolysis. (PubMed, J Cell Biochem) - "In summary, our present in vitro study demonstrated that 3PO derived PFK15 mechanism of action is totally different from AZ67 in TNBC cells. However, we advocate that the PFK15-mediated inhibition (along with PFKL) on the TNBCs migration, colony formation, and PFK-1 activity can be further explored for the therapeutic advantage of TNBC patients."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • PFKFB3 • PFKL • PFKP

Suppression of myeloid Pfkfb3-driven glycolysis protects mice from choroidal neovascularization. (PubMed, Br J Pharmacol) - "Modulation of PFKFB3-mediated macrophage glycolysis and activation is a promising strategy for the treatment of nAMD."

Journal • Preclinical • Age-related Macular Degeneration • Macular Degeneration • Ophthalmology • Retinal Disorders • Wet Age-related Macular Degeneration • EPAS1 • HIF1A • PFKFB3

Aberrant upregulation of the glycolytic enzyme PFKFB3 in CLN7 neuronal ceroid lipofuscinosis. (PubMed, Nat Commun) - "Administration of the highly selective PFKFB3 inhibitor AZ67 in Cln7 mouse brain in vivo and in CLN7 patients-derived cells rectifies key disease hallmarks. Thus, aberrant upregulation of the glycolytic enzyme PFKFB3 in neurons may contribute to CLN7 pathogenesis and targeting PFKFB3 could alleviate this and other lysosomal storage diseases."

Journal • CNS Disorders • Lysosomal Storage Diseases • Metabolic Disorders • Rare Diseases

The PFKFB3 Inhibitor AZ67 Inhibits Angiogenesis Independently of Glycolysis Inhibition. (PubMed, Int J Mol Sci) - "Strikingly however, even the lowest dose of AZ67 demonstrated significant inhibition of angiogenesis in vivo. To our knowledge, this is the first study to demonstrate that the process of angiogenesis can be disrupted by targeting PFKFB3 independently of glycolysis inhibition."

Journal

Targeting PFKFB3 alleviates cerebral ischemia-reperfusion injury in mice. (PubMed, Sci Rep) - "Furthermore, in vivo administration of AZ67 to mice significantly alleviated the motor discoordination and brain infarct injury in the middle carotid artery occlusion ischemia/reperfusion model. These results show that pharmacological inhibition of PFKFB3 is a suitable neuroprotective therapeutic strategy in excitotoxic-related disorders such as stroke."

Journal • Preclinical • Cardiovascular • CNS Disorders • Reperfusion Injury

Small molecule 3PO inhibits glycolysis but does not bind to 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3). (PubMed, FEBS Lett) - "However, 3PO did not bind to PFKFB3, even up to 750 µM, in contrast to 3 µM of AZ67, which is a potent and specific PFKFB3 inhibitor. Instead, 3PO accumulated lactic acid inside the cells, leading to a decrease in the intracellular pH and an inhibition of enzymatic reactions of the glycolytic pathway."

Journal

Newly added product (Huntington’s Disease News) - Preclinical, Alzheimer's disease, Amyotrophic lateral sclerosis, Huntington's disease

Pipeline update

New small molecule AZ67 may help prevent brain cell death, early data show (Huntington’s Disease News) - “‘These results show that pharmacological inhibition of PFKFB3 is a suitable neuroprotective therapeutic strategy in excitotoxic-related disorders such as stroke [and neurological illnesses]’…”

Biomarker • Preclinical