Modulators of Class IIa HDACs

Histone deacetylases (HDACs) are enzymes that mediate the removal of acetyl groups from numerous acetylated proteins (including histones) and some are associated with the cell cycle, inflammation, apoptosis and cancer. HDACs have been found to be involved in a wide range of diseases and conditions and represent promising drug targets.  There are eleven zinc-binding mammalian HDACs including 4 class I, 4 class IIa and 2 class IIb proteins.

The Fairlie Research Group at The University of Queensland (UQ) has exploited structural differences between Class I and IIa HDACs to develop two generations of new compounds that are potent and selective inhibitors of class IIa HDACs.

Inhibitors of Class IIa HDACs have the potential to treat many inflammation-related pathologies.

Key features

  • New potent and selective inhibitors of class IIa HDAC enzymes
  • No induction of cellular histone H4 acetylation, unlike most inhibitors of HDACs
  • Potential for modulating class IIa HDAC functions in vivo with fewer cytotoxic side effects than other HDAC inhibitors.


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IBD therapeutic derived from gut microbial metabolites

Inflammatory bowel disease (IBD) is a chronic and incurable disease characterised by episodic and disabling inflammation of the gut.  Current therapeutic strategies aim to decrease the frequency and severity of inflammatory episodes to prevent progression of bowel damage and avoid disabling disease with need for surgery.  However, these therapeutic options suffer from poor compliance, toxicity or cost.

There is an urgent need for better therapeutics.  With clear evidence that intestinal immunity is regulated through microbiome-immune crosstalk, the microbiome has now emerged as a valuable potential source for immune-modifying IBD therapeutics.

Researchers at The University of Queensland (UQ) have isolated gut bacteria that secreted soluble suppressors of the pro-inflammatory NF-κβ pathway, and identified a novel class of NF-κβ inhibitory bioactives.  Based on the bioactives, a lead compound – ‘Compound HC’ – with potent NF-κβ activity (IC50 = 1 nM) was synthesised.

Preliminary pharmacokinetic profiling in mice shows that Compound HC is detectable at active concentrations throughout the ileum and colon less than 1 hour following oral administration and remains at concentrations >100×IC50 for >6 hours.

Key features

  • Leverage benefits of microbiome to treat IBD
  • Novel molecules potently inhibit NF-κβ pathway throughout the colon
  • Comparable reduction in disease severity to biologic therapies
  • Orally active, with >6 hours gut stability and favourable PK profile.


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Peptide activator of ACE-2 for kidney diseases and inflammation

The prevalence of diabetes mellitus continues to increase in both Australia and worldwide and it remains the number one cause of chronic kidney disease.  There are currently no treatments for diabetes induced kidney fibrosis and current treatments for diabetic nephropathy only slow down the disease progression, with the patients still progressing to end-stage renal disease and requiring renal replacement therapy.

University of Queensland researchers have developed a 10 amino acid ACE-2 stimulator peptide derived from snake venom useful for the treatment of kidney diseases and inflammation.  Preliminary data demonstrated that the lead peptide 2A has strong anti-inflammatory effects and prevents the expression of markers of fibrosis and inflammation in culture cells.  2A also attenuated kidney fibrosis and inflammation in diabetic mouse models and reduced blood glucose levels without any effect on body weight.

Key Features

  • ACE-2 stimulator with strong anti-inflammatory effects
  • Stable: peptide detected in multiple organs after 24 hours
  • Safe: no observed adverse effects in diabetic mice.


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Potent and selective inhibitors of human β-factor XIIa

Cyclotides, which are plant-derived peptides, are attractive pharmaceutical candidates with promising proteolytic stability and cell permeability.  Despite extensive efforts, generation of designer cyclotides with novel activity and specificity against pharmaceutically demanding targets of interest has proven to be challenging due to their structural complexity.

One particularly appealing target is coagulation factor Xlla (FXlla), a trypsin-like serine protease that initiates the intrinsic clotting cascade, the inhibition of which could be effective in thromboembolic and inflammatory disease.

Researchers from The University of Queensland have used an alternative approach generating a library of diversities in excess of >1012, screened against FXIIa and identified selective and potent cyclotide-based FXIIa inhibitors.  One of the analogues is not only able to inhibit the protease activity of FXIIa with a high potency (Ki=0.37 nM) and exclusivity over related proteases, but also has an improved stability profile in human serum with half-lives of more than 24 hours.

Key features:

  • Sub-nM potent and selective (3000x over plasmin and other proteases) peptide inhibitors of human β-factor XIIa
  • Discovered with an alternative approach which generates a diverse library in excess of >1012


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Nav1.7 Inhibitor

Researchers at the Institute for Molecular Bioscience (IMB) at The University of Queensland (UQ) have developed a novel peptide-based inhibitor of the voltage-gated sodium channel 1.7 (Nav1.7). Loss-of-function mutations of SCN9A, the gene encoding Nav1.7, have been identified as the cause of congenital insensitivity to pain, a rare condition characterized by the inability to sense pain in otherwise normal individuals.  Gain-of-function mutations of SCN9A are the cause of two hereditary pain disorders, inherited erythromelalgia and paroxysmal extreme pain disorder. Both disorders are associated with redness, swelling and burning pain and thus, pharmacological inhibition of Nav1.7 is a promising therapeutic strategy for the treatment pain.

Key features

  • A peptide-based inhibitor targeting the resting state of voltage-gated sodium channel 1.7 (Nav7)
  • Potent (nanomolar activity) and selective for Nav7 over other Nav isoforms
  • Proof of concept data in post-surgical and other rodent models of pain
  • Potential for use in other indications.

Applications

Therapeutic applications of the Nav1.7 inhibitor include:

  • Post-operative pain;
  • Acute pain;
  • Chronic cough;
  • Cancer, and
  • Itch.


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PAR2 Antagonists

Novel, selective, orally active small molecule antagonists (and agonists) of the human protease-activated receptor 2 (PAR2) have been developed for the potential treatment of inflammatory diseases, metabolic syndrome and cancer.

Key Features

  • Novel small molecules
  • Orally active
  • Effective in models of acute and chronic inflammation, IBD and obesity
  • Selective and potent
  • Novel target and unique mechanism of action.


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Endocytosis inhibitors to improve anti-cancer monoclonal antibody immunotherapy responses

Many oncology patients receiving monoclonal antibody immunotherapy receive no therapeutic benefit, or rapidly develop resistance to therapy. Direct killing of tumour cells by antibodies (antibody dependent cell cytotoxicity, ADCC) requires strong engagement between antibodies bound to tumour cell surface receptors and NK cells. In studies with the anti-epidermal growth factor receptor (EGFR) antibody, cetuximab at the University of Queensland, head and neck cancer patients who have dysfunctional EGFR receptor internalisation (and hence have EGFR clustered on the tumour surface) respond to cetuximab treatment. However, those with normal EGFR receptor biology do not respond. Clustering of receptors on the tumour surface increases NK-antibody interactions, and hence ADCC, resulting in increased tumour cell killing.

Inhibition of dynamin (a key enzyme involved in internalisation of receptors such are EGFR, PD-L1, HER2 and VEGF) leads to receptor enrichment and clustering on the cell membrane. Specific dynamin inhibitors or the anti-nausea drug prochlorperazine (Stemetil),  a dopamine receptor antagonist with off target activity as a dynamin inhibitor, inhibit dynamin activity in vitro, leading to receptor clustering and in the presence of a therapeutic antibody (e.g. avelumab, cetuximab or trastuzumab), leading to enhanced NK-cell mediated antibody dependent cell cytotoxicity (ADCC). In mouse tumour models published in Cell (Mar 2020) prochlorperazine treatment in combination with either avelumab or cetuximab resulted in tumour clearance and reduced metastases. In addition, treated mice became resistant to the same tumour.

A clinical proof of mechanism study in head and neck cancer patients demonstrated that high dose i.v. prochlorperazine is able to cluster receptors on tumours. A phase 1b combination safety study of cetuximab and prochlorperazine is ongoing.

Key features

  • Dynamin inhibition enhances the ability of anti-cancer antibodies that target tumour cell surface proteins to kill tumour cells by ADCC, increasing efficacy, reducing target heterogeneity and overcoming resistance.
  • In vitro, in vivo and clinical data demonstrate that co-administration of prochlorperazine with a therapeutic mAb has the potential to be a transformative oncology treatment strategy.


Further information:

Cell:

Media release:

New drug combination could support better cancer treatments – The University of Queensland, 6 March, 2020

Media coverage:

Hopes one-two punch cancer treatment will prove knockout blow – Brisbane Times, 6 March 2020

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UniQuest is seeking licensing, collaborative partners or investment for preclinical and clinical development of dynamin inhibitors (reformulated prochlorperazine and NCEs) to be used in combination with any existing and future monoclonal antibody therapies that mediate tumour killing via ADCC and target appropriate receptor to increase their efficacy and patient response rates.

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Hematopoietic prostaglandin D2 synthase (HPGD2S) inhibitors for inflammatory disease including DMD and asthma

Small molecule inhibitors of hematopoietic prostaglandin D2 synthase (HPGD2S) for inflammatory disease including DMD and asthma.

Key Features

  • Potent, selective and orally administrable small molecule compounds
  • Down-regulates multiple clinically validated targets
  • Selective expression resulting in improved safety – HPGD2S is primarily expressed peripheral tissues (mast and Th2 cells)
  • First in class opportunity for the treatment of asthma and allergic rhinitis


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C3a receptor modulators

Diseases driven by chronic inflammation are major health burdens and controlling inflammation is an important preventative and therapeutic goal. A network of over 40 ‘Complement’ proteins is produced in blood and on cell surfaces in response to infection/injury. Complement protein C3 is a central mediator of all avenues of complement activation leading to pathogen destruction and elimination. However, blocking C3 also blocks beneficial roles of complement cascade in fighting infection.

University of Queensland (UQ) researchers have developed multiple series of novel, potent and selective, small organic molecules that mimic C3a (agonists) or inhibit its action (antagonists).

Key Features

  • Novel small molecule modulators of C3aR
  • Potent and selective for human/mouse C3aR
  • Orally active in inflammatory disease models
  • Distinct ‘Complement’ target and mechanism of action.

Potential applications

The C3aR antagonists have potential as treatments for inflammation-related diseases where C3aR has been implicated as important, including but not limited to:

  • Asthma, allergies, respiratory diseases
  • Arthritis, diseases of musculoskeletal system
  • Metabolic Syndrome (including obesity, diabetes and cardiovascular disease)
  • Inflammatory Bowel Disease (IBD), ulcerative colitis
  • Autoimmune diseases (e.g. lupus, multiple sclerosis)
  • Neurodegenerative diseases
  • Cancers.


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Enhanced antibiotics for MDR/XDR gram-negative infections

UQ researchers have identified a novel class of octapeptin derivatives with improved activity against multiple gram-negative bacteria strains that cannot be treated by any other tested antibiotic.

Key features
  • Novel lipopeptide antibiotics that target multi and extensively drug resistant (MDR, XDR) gram negative bacteria
  • Greater efficacy with significantly reduced nephrotoxicity compared to current standard of care
  • Targets the most critical pathogens identified by WHO: Carbapenem-resistant Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacteriaceae
  • Potential for these novel lipopeptides as a “resistance breaker” to synergise with existing antibiotics to potentiate their activity against MDR/XDR bacteria.

BioCurate Award - Best Translational Research

Winning pitch

'Octapeptin X – a novel antibiotic for Gram-negative bacterial infections' claimed the 2020 BioCurate Award for Best Translational Research Pitch at the recent AusBiotech Early Stage Investment Forum.

Congratulations to Dr Tamsin Terry for presenting the winning pitch from a field of 13 early stage technologies in the area of human therapeutics, medical devices and diagnostics, digital health and enabling technologies.

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To enquire about this technology, please contact Dr Tamsin Terry.

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