Therapeutic Areas

Progenra is focused on drug discovery targeting the ubiquitin pathway and related protein modification systems; screening of small-molecule libraries and natural product extract collections has yielded potent inhibitors of ubiquitin pathway therapeutic targets  associated with various diseases including cancer, inflammatory disease, cystic fibrosis, neurodegenerative diseases such as Parkinson's as Alzheimer’s, metabolic diseases, and cardiovascular disease.

ubiquitin human body

Immune-oncology

Immune-oncology

Cancer accounts for one fourth of all U.S. deaths

Currently the two most promising anticancer strategies are molecular oncology targeted cytotoxic therapies and immune oncology agents. See below for more information

Molecular Oncology targeted cytotoxic therapies

  • Selectively increase tumor suppressing or decrease tumor promoting activity
  • Many tumor promoter and tumor suppressor genes encode ubiquitin pathway enzymes
    • In many cancers, these enzymes are dysregulated, impacting cancer severity/prognosis
  • Progenra is working on several molecular oncology targets (DUBs and E3 Ligases) from the ubiquitin pathway
  • Examples of current marketed therapies: Gleevec, Herceptin

Immune Oncology agents

  • Unleash the patient’s immune cells to attack the tumor rather than eradicating the tumor directly
  • Progenra has discovered small molecule inhibitors of a DUB that are essential for immune cells involved in suppression of anti-tumor immunity. These inhibitors are able to unleash immune effector cells, which eradicate tumors in experimental models
  • Progenra compounds are active singly but, more important, augment the antitumor activity of established immune oncology agents when given in combination
  • Examples of current marketed immune oncology agents: Yervoy, Opdivo, Keytruda

 

Immune oncology image

Inflammatory Diseases

Inflammatory Diseases

  • Inflammation is a component of many diseases and a reaction of the immune system to a specific insult, resulting in disease symptoms
  • Signaling cascades of inflammatory responses often lead to the release of inflammatory cytokines (such as TNF, IL-2, IL-4, IL-17), which in turn activate genes that express proteins responsible for the symptoms of inflammation
    • e.g., the asthmatic response, which affects nearly 20 million in the USA alone and for which only symptomatic relief is available
  • Inflammatory signal pathways are regulated at various points by ubiquitin pathway enzymes, DUBs and E3 Ligases; these enzymes are promising therapeutic targets for preventing or attenuating inflammation.
    • Progenra has discovered, through high throughput screening, compounds that modulate inflammation-related ubiquitin pathway enzymes
    • These compounds are currently in various stages of preclinical development

Inflmmation

Neurological Diseases

Neurodegenerative Disease/Dementia

  • Alzheimer’s disease (AD) is the most common age-dependent neurodegenerative disorder in the world
    • AD affects 11% of the population over 65.
    • There is currently no cure, and the ability to manage symptoms diminishes as the ultimately fatal disease progresses
  • AD manifests primarily as a disease of cognition and memory, resulting from the degeneration and death of neurons in brain areas that are critical for learning and memory.
    • Other neurodegenerative diseases, e.g. Parkinson’s (PD) and Huntington’s (HD) Disease, have similar features and consequences to patients
  • Protein aggregation is believed to underly most forms of neurodegenerative disease
    • In AD, amyloid beta and tau aggregation in conjunction with defective mitochondria leads to eventual neuronal death
    • In Parkinson’s Disease (PD) and Lewy body-associated dementia, a protein known as α-synuclein aggregates pathologically and also corresponds with mitochondrial dysfunction
    • The formation/removal of protein aggregates is regulated at several steps through the ubiquitin pathway, either directly or via autophagic removal of defective mitochondria (mitophagy)
    • Progenra has initiated drug discovery efforts targeting ubiquitin pathway targets (DUBs and E3 ligases) that regulate pathogenic aggregation

 

Cognitive impairment (a component of neurodegenerative diseases)

  • The ubiquitin proteasome pathway is also a promising source of new drugs to treat a variety of diseases characterized by abnormal synaptic activity leading to cognitive impairment
    • For example, alteration of various DUBs affects synaptic activity and downstream physiology by increasing the neurotransmitter receptor density
    • By modulating the activity of select DUBs with small molecules, we hope to increase the post-synaptic membrane density of neurotransmitter receptors, thereby introducing a completely new class of drug to treat neurological disorders such as various forms of anxiety and seizures

Cardiovascular Diseases

Cardiovascular Diseases

  • Atherosclerosis, or Coronary Artery Disease, is the formation of plaques in the walls of arteries
    • Extensive growth of plaques impedes blood flow in the arteries and, in some cases, the plaques can suddenly rupture or detach and lead to occlusive heart attacks or strokes
  • Blocked arteries generated by plaque buildup and blood clots are the leading cause of death in the U.S.
    • Cholesterol is the primary component of arterial plaques
    • It is estimated that more than 35 million Americans (approximately one-sixth of the adult population) have high total cholesterol and thus are at twice the normal risk of cardiovascular disease
  • Cholesterol-lowering drugs, such as statins, are widely prescribed and used
    • Additional drugs that lower cholesterol by mechanisms different from that of statins are desirable, such drugs could offer safer alternatives to statins and/or could be components of combination treatments with improved efficacy
  • Progenra has an active program to develop inhibitors of a ubiquitin pathway enzyme that lowers the membrane population of the low density lipoprotein (LDL) receptor
    • Inhibiting this enzyme increases receptor content and facilitates removal of LDLs, including cholesterol, from the bloodstream

CV Image

Cystic Fibrosis

Cystic Fibrosis

Cystic fibrosis is an incurable genetic disorder manifested by pulmonary impairment due to viscous mucus in the lungs which leads to disability and early death due to breathing problems; additional physical problems associated with CF include digestive difficulties, damage to the pancreas, and infertility

  • Current therapies alleviate some of the pulmonary symptoms of the disease rather than targeting its cause
  • The ideal approach for treating CF is to target the molecular cause of the disease, which is mutant CFTR protein resulting in poor chloride transport
    • Of most interest is CFTRΔF508, the single-residue deletion mutant that accounts for the large majority of CF cases
  • CFTRΔF508 is partially misfolded, and so, in the ER, it is targeted for degradation by the ERAD system and does not reach the cell surface to allow chloride transport (although the protein is partially functional)
    • A goal in CF drug discovery is to preserve and properly localize mutant CFTR protein to the cell surface; currently approved drugs that accomplish this to have some effect on chloride transport but do not improve lung function as a single agents
    • Progenra is working on developing a ubiquitin pathway ligase modifying drug that prevents degradation of misfolded mutated CFTR, providing increased numbers of these molecules for ion transport. Such a drug could augment the efficacy of currently approved treatments and significantly improve patient outcomes

ERAD Pathway