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.
Molecular Oncology targeted cytotoxic therapies
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; small molecule inhibitors or activators of these targets would selectively increase tumor suppressing or decrease tumor promoting activity.
Progenra has discovered small molecule inhibitors of a DUB that is essential for regulatory immune cells to suppress anti-tumor immune cells. These inhibitors are thus able to reverse immune evasion by unleashing immune effector cells, which then attack the tumor.
Progenra compounds have demonstrated activity not only as single agents, but also as potentiators of antitumor activity of established immune oncology agents when given in combination.
Signaling cascades of inflammatory responses, which constitute a reaction of the immune system to a specific insult, often lead to the release of inflammatory cytokines (i.e. TNF, IL-2, IL-4, IL-17), which in turn activate genes that express proteins responsible for the symptoms of inflammation. Inflammatory signal pathways are regulated at various points by ubiquitin pathway enzymes, such as 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
Targeting protein aggregation
Dysfunction in the ubiquitin-proteasome pathway is believed to underly most forms of neurodegenerative disease. In Alzheimer's disease (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.
Improving synaptic activity
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, a component of neurodegenerative diseases. 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.
Cystic Fibroris (CF) is the result of a mutant CFTR protein, responsible for poor chloride transport. CFTRΔF508, a single-residue deletion mutant, accounts for the large majority of CF cases. CFTRΔF508 is partially misfolded, and so, in the endoplasmic reticulum (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 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.