PBT2 / Alterity Therap, The Florey Institute of Neuroscience and Mental Health - LARVOL DELTA

A cyclization-driven ratiometric fluorescent probe for hypochlorite detection: targeted sensing and visualization in plant samples and living cells. (PubMed, Anal Methods) - "The probe demonstrated its utility in visualizing ClO- in plant roots, aiding in the study of hypochlorite's physiological roles, and was further validated in living cells, where it enabled real-time fluorescence imaging of intracellular ClO- with excellent biocompatibility. In addition, PBT-2 was successfully applied to detect ClO- in commercial bleach and environmental water samples, showcasing outstanding photophysical and sensing performance across diverse matrices."

Journal

Short-term fasting and zinc ionophores cooperate to promote ferroptosis in colorectal cancer (EACR 2025) - "Zinc ionophores evaluated in this study included the antiparasitic drug clioquinol, the investigational agent, PBT2, and chloroquine. Our data demonstrate that STF predisposes CRC to zinc-induced ferroptosis by depleting tumor GSH levels and downregulating GPX4 and SLC7A11."

Colorectal Cancer • Oncology • Solid Tumor • GPX4 • IGF1 • LEP • SLC7A11

Baseline swallowing parameters for head and neck patients undergoing Proton Beam Therapy (PBT) at a single tertiary centre. (BAHNO 2025) - "One study reported on the MDADI prior to PBT2 , which showed good patient-reported outcomes (mean of 88.2) corresponding well with our in- strumental and clinician-rated measures. We recognise the current limitations with our heterogenous sample, which included post-operative PBT. We plan to continue to build on this work to offer increasingly refined data for different sub-groups not just at baseline, but also at post-treatment intervals."

Clinical • Head and Neck Cancer • Oncology • Otorhinolaryngology • Solid Tumor

Disruption of zinc homeostasis reverses tigecycline resistance in Klebsiella pneumoniae. (PubMed, Front Cell Infect Microbiol) - "Zinc exhibits potent antimicrobial properties due to its ability to compromise bacterial structure and protein functionality, effectively inhibiting and eradicating bacteria. Furthermore, the inhibition of the cell wall synthesis pathway and restriction of the efflux pump mechanism provide additional mechanisms by which PBT2 reverses antibiotic resistance. These results highlight the potential of zinc ionophores as a novel class of antimicrobial agents and warrant further investigation into their clinical applications."

Journal • Infectious Disease • Pneumonia

Copper homeostasis and neurodegenerative diseases. (PubMed, Neural Regen Res) - "Potential clinically significant therapeutic targets, including superoxide dismutase 1, D-penicillamine (DPA), and 5,7-dichloro-2-[(dimethylamino)methyl]-8-hydroxyquinoline (PBT2), along with their associated therapeutic agents, are further discussed. Ultimately, we collate evidence that copper homeostasis may function in the underlying etiology of several neurodegenerative diseases and offer novel insights into the potential prevention and treatment of these diseases based on copper homeostasis."

Journal • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Genetic Disorders • Hepatology • Huntington's Disease • Inflammation • Metabolic Disorders • Movement Disorders • Multiple Sclerosis • Parkinson's Disease • ATP7A • ATP7B

Comparative Evaluation of Proton Therapy and Volumetric Modulated Arc Therapy for Brachial Plexus Sparing in the Comprehensive Reirradiation of High-Risk Recurrent Breast Cancer. (PubMed, Adv Radiat Oncol) - "A second pair of proton (PBT2) and VMAT (XRT2) plans using standardized target volumes were created, applying uniform prescription dose of 50.4 per 1.8 Gy and a maximum BP constraint <25 Gy...PBS-PT improved BP sparing and target volume coverage versus VMAT. For patients requiring comprehensive re-RT for high-risk, nonmetastatic breast cancer recurrence with BP overlap and reasonable expectation for prolonged life expectancy, PBT may be the preferred treatment modality."

Journal • Breast Cancer • Oncology • Pain • Solid Tumor

Organoboron flank-substituted donor-acceptor polymer anode with ultra-long cycling stability for lithium ion batteries. (PubMed, Phys Chem Chem Phys) - "We successfully introduced an organoboron unit into the thiophene-based polymer PBT-2 to construct a donor-acceptor polymer anode. The charge delocalization and LUMO energy level resulting from the unique structure of this material enabled good redox activity and a very stable electrochemical performance in electrochemical tests, with a reversible capacity of 262 mA h g at 0.5 A g and >10 000 cycles at 1 A g with a decay of 0.056‰ per cycle. Accordingly, targeted structural design to overcome the shortcomings of active units such as thiophene can effectively regulate their electrochemical performance, providing a solution for the development of high-performance anode materials for use in lithium ion batteries."

Journal

Study of novel copper and zinc binding analogue of GMP-1 in Tg4510 tauopathy mouse model (CTAD 2023) - "Metal attenuating compounds such as PBT2 and clioquinol were previously shown to decrease brain tau aggregation and improve memory in the Tg4510 tau transgenic mouse model [3, 4]... We showed that metal-attenuating compounds can rescue tauassociated memory dysfunction in the Tg4510 taoupathy model."

Preclinical • CNS Disorders

Chelator PBT2 Forms a Ternary Cu Complex with β-Amyloid That Has High Stability but Low Specificity. (PubMed, Int J Mol Sci) - "The results have implications for future AD therapeutic strategies and understanding the role of PBT2 in the bulk transport of transition metal ions. Given the repurposing of PBT2 as a drug for breaking antibiotic resistance, ternary Cu(PBT2)N and analogous Zn(PBT2)N complexes may be relevant to its antimicrobial properties."

Journal • Alzheimer's Disease • CNS Disorders

In vitro activity, ultrastructural analysis and in silico pharmacokinetic properties (ADMET) of thiazole compounds against adult worms of Schistosoma mansoni. (PubMed, Acta Trop) - "In the ultrastructural analysis the compounds PBT2 and PBT5 (200 µM) promoted integumentary changes with exposure of the muscles, formation of integumentary blisters, integuments with abnormal morphology and destruction of tubercles and spicules. Therefore, the compounds PBT2 and PBT5 are promising antiparasitics against S. mansoni."

Journal • PK/PD data • Preclinical

Alterity Therapeutics Announces Granting of New Composition of Matter Patent and Exclusive License Agreement for Assets in Alzheimer’s Disease (GlobeNewswire) - "Alterity Therapeutics...today announced that the composition of matter patent previously allowed by the United States Patent and Trademark Office (USPTO) has now been granted. The patent, entitled 'Compounds for and methods of treating diseases' (No. 11,603,364), covers more than 100 novel compounds with an acyl hydrazone (AH) structure and provides 20 years of exclusivity. Alterity also announced a Licensing Agreement for the new patent and a sub-licensing agreement for PBT2 to Professor Colin Masters, M.D., A.O., to advance these compounds for the treatment of Alzheimer’s and related diseases. Under the license agreement, Alterity grants the entire rights to the AH patent as well as an exclusive worldwide license to develop and commercialize both AH and PBT2 in Alzheimer’s disease (AD). In exchange, Alterity is entitled to future royalties of net sales from the assets."

Licensing / partnership • Patent • Alzheimer's Disease • CNS Disorders

Gliotoxin and related metabolites as zinc chelators: implications and exploitation to overcome antimicrobial resistance. (PubMed, Essays Biochem) - "Sulphur-containing metabolites (e.g., auranofin and bacterial dithiolopyrrolones [e.g., holomycin]) and Zn2+-chelating ionophores (PBT2) have emerged as important antimicrobial classes. Since holomycin and gliotoxin can chelate Zn2+, resulting in metalloenzyme inhibition, we propose that this metal-chelating characteristic of these metabolites requires immediate investigation to identify new antibacterial drug targets or to augment the activity of existing antimicrobials. Given that (i) gliotoxin has been shown in vitro to significantly enhance vancomycin activity against Staphylococcus aureus, and (ii) that it has been independently proposed as an ideal probe to dissect the central 'Integrator' role of Zn2+ in bacteria - we contend such studies are immediately undertaken to help address AMR."

Journal

Identification, Characterization, and Control of Black Spot on Chinese Kale Caused by Sphaerobolus cuprophilus sp. nov. (PubMed, Plants (Basel)) - "Inhibitory effects of antagonistic bacteria and chemical fungicides, both allowed for use in plant cultivation under either IFOAM or GAP standards, indicated that Bacillus amyloliquefaciens strains (PBT2 and YMB7), chlorothalonil (20 and 500 ppm) and thiophanate-methyl (500 and 1500 ppm) were the most effective in controlling the growth of the causal fungus by 83 to 93%. However, copper oxychloride (5 to 20 ppm), a recommended chemical in control of downy mildew of Chinese kale, showed hormetic effects on S. cuprophilus by promoting the growth and sporulation of the fungus. The findings of this study provide vital information regarding the association of S. cuprophilus and Chinese kale and will support decisions to manage fungal diseases of this vegetable."

Journal • Infectious Disease

Alzheimer's Drug PBT2 Interacts with the Amyloid β 1-42 Peptide Differently than Other 8-Hydroxyquinoline Chelating Drugs. (PubMed, Inorg Chem) - "It follows that the Cu(II) site in this Cu(II)Aβ(1-42) species is inaccessible to PBT2 and may be less solvent-exposed than in other Cu(II)Aβ(1-42) species. We found no evidence to suggest that these 8HQs form ternary complexes with Cu(II)Aβ(1-42)."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia

Repurposing the Ionophore, PBT2, for Treatment of Multidrug-Resistant Neisseria gonorrhoeae Infections. (PubMed, Antimicrob Agents Chemother) - "Here we show that both N. meningitidis and MDR N. gonorrhoeae are sensitive to killing by PBT2 alone. PBT2 is, thus, a candidate therapeutic for MDR N. gonorrhoeae infections."

Journal • Infectious Disease

Neurodegenerative Disease Treatment Drug PBT2 Breaks Intrinsic Polymyxin Resistance in Gram-Positive Bacteria. (PubMed, Antibiotics (Basel)) - "Here, in combination with zinc, PBT2 was shown to break intrinsic polymyxin resistance in Streptococcus pyogenes (Group A Streptococcus; GAS), Staphylococcus aureus (including methicillin-resistant S. aureus), and vancomycin-resistant Enterococcus faecium. Using a murine model of wound infection, PBT2 in combination with zinc and colistin proved an efficacious treatment against streptococcal skin infection. These findings provide a foundation from which to investigate the utility of PBT2 and next-generation polymyxin antibiotics for the treatment of Gram-positive bacterial infections."

Journal • CNS Disorders • Dermatology • Infectious Disease

An ionophore breaks the multi-drug-resistance of Acinetobacter baumannii. (PubMed, Microb Cell) - "In vitro, the combination of PBT2 and zinc with either tetracycline, doxycycline, or tigecycline was shown to be bactericidal against multi-drug-resistant A. baumannii, and any resistance that did arise imposed a fitness cost. Using a murine model of pulmonary infection, treatment with PBT2 in combination with tetracycline or tigecycline proved efficacious against multidrug-resistant A. baumannii. These findings suggest that PBT2 may find utility as a resistance breaker to rescue the efficacy of tetracycline-class antibiotics commonly employed to treat multi-drug resistant A. baumannii infections."

Journal • Critical care • Infectious Disease • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases

Dysregulation of Streptococcus pneumoniae zinc homeostasis breaks ampicillin resistance in a pneumonia infection model. (PubMed, Cell Rep) - "Using an invasive ampicillin-resistant strain, we demonstrate in a murine pneumonia infection model the efficacy of PBT2 + ampicillin treatment. These findings present a therapeutic modality to break antibiotic resistance in multidrug-resistant S. pneumoniae."

Journal • Infectious Disease • Pneumococcal Infections • Pneumonia • Respiratory Diseases

Rescuing Tetracycline Class Antibiotics for the Treatment of Multidrug-Resistant Acinetobacter baumannii Pulmonary Infection. (PubMed, mBio) - "In vitro, the combination of PBT2 and zinc with either tetracycline, doxycycline, or tigecycline was shown to be bactericidal against multidrug-resistant A. baumannii, and any resistance that did arise imposed a fitness cost. With a rise in antibiotic resistance and a reduction in new antibiotic discovery, it is imperative to investigate alternative therapeutic regimens that complement the use of current antibiotic treatment strategies. Rescuing the efficacy of existing therapies for the treatment of MDR A. baumannii infection represents a financially viable pathway, reducing time, cost, and risk associated with drug innovation."

Journal • Critical care • Infectious Disease • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases

A drug candidate for Alzheimer's and Huntington's disease, PBT2, can be repurposed to render Neisseria gonorrhoeae susceptible to natural cationic antimicrobial peptides. (PubMed, J Antimicrob Chemother) - "Here we show that PBT2, a candidate Alzheimer's and Huntington's disease drug, can be repurposed to render MDR N. gonorrhoeae more susceptible to the endogenous antimicrobial peptides LL-37 and PG-1. In the presence of LL-37, PBT2/zinc can synergize with tetracycline to restore tetracycline susceptibility to gonococci resistant to this antibiotic."

Journal • Alzheimer's Disease • CNS Disorders • Huntington's Disease • Infectious Disease • Movement Disorders

Disruption of Metallostasis in the Anaerobic Human Pathogen Fusobacterium nucleatum by the Zinc Ionophore PBT2. (PubMed, ACS Infect Dis) - "A concentration-dependent protective effect was observed for cells pretreated with hemin (50 μg/mL) prior to PBT2-Zn challenge. The data presented here supports our proposal that targeting the disruption of metallostasis by Zn-translocating ionophores is a strategy worth investigating further for the treatment of Gram-negative anaerobic pathogens."

Journal • Colorectal Cancer • Dental Disorders • Gastrointestinal Cancer • Infectious Disease • Oncology • Periodontitis • Solid Tumor

Copper(II) Binding to PBT2 Differs from That of Other 8-Hydroxyquinoline Chelators: Implications for the Treatment of Neurodegenerative Protein Misfolding Diseases. (PubMed, Inorg Chem) - "We propose that a novel bis-PBT2 Cu(II) complex with asymmetric coordination may coexist in solution with a symmetric four-coordinate Cu(II)-bis-PBT2 complex distorted from coplanarity. Additionally, PBT2 is a more flexible ligand than other 8HQs because it can act as both a bidentate and a tridentate ligand as well as coordinate Cu(II) in both 1:1 and 2:1 PBT2/Cu(II) complexes."

Journal • Alzheimer's Disease • CNS Disorders • Proteinopathy

The Essential Elements of Alzheimer's Disease. (PubMed, J Biol Chem) - "Here we review these essential elements of Alzheimer's disease for their broad potential to contribute to Alzheimer's pathophysiology, and we also highlight more recent attempts to translate these findings into therapeutics. A reinspection of large bodies of discovery in the AD field, such as this, may inspire new thinking about pathogenesis and therapeutic targets."

Journal • Alzheimer's Disease • CNS Disorders

Repurposing a neurodegenerative disease drug to treat Gram-negative antibiotic-resistant bacterial sepsis. (PubMed, Sci Transl Med) - "In comparison to polymyxin alone, the combination of PBT2 + polymyxin improved survival and reduced bacterial dissemination to the lungs and spleen of infected mice. These data present a treatment modality to break antibiotic resistance in high-priority polymyxin-resistant Gram-negative pathogens."

Journal • CNS Disorders • Infectious Disease • Pneumonia • Septic Shock

PBT2 acts through a different mechanism of action than other 8-hydroxyquinolines: an X-ray fluorescence imaging study. (PubMed, Metallomics) - "Moreover, treatment of cells with copper in the presence of CQ or B2Q resulted in copper accumulation in the nuclei, while PBT2-guided copper was distributed near to the cell membrane. These results suggest that PBT2 may be acting through a different mechanism than that of other 8HQs to cause the observed cytotoxicity."

Journal • Alzheimer's Disease • CNS Disorders • Infectious Disease • Oncology