Progenra is focused on drug discovery targeting the ubiquitin proteasome system and related protein modification systems; screening of small-molecule libraries and natural product extract collections has yielded potent inhibitors and activators of ubiquitin proteasome system 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 proteasome system enzymes. In many cancers, these enzymes are dysregulated, impacting cancer severity and prognosis. Progenra is working on several molecular oncology targets (DUBs and E3 Ligases) from the ubiquitin proteasome system; small molecule inhibitors or activators of these targets selectively increase tumor suppressing or decrease tumor promoting activity.
Immune Oncology agents
Progenra has discovered small molecule inhibitors of a DUB that is essential for regulatory immune cells to suppress anti-tumor immune cells. Progenra USP7 inhibitors block tumor immune evasion by suppressing the regulatory T cells, thereby unleashing the body’s natural immune system to recognize and kill the tumor. We believe that small molecules will replace biologicals such as Keytruda and Opdivo in immune oncology. Progenra’s USP7 inhibitor can kill tumors indirectly through the immune system or directly by apoptosis induction. This dual mechanism of action is unique to the class of USP7 inhibitor discovered by Progenra. Small molecules that can be delivered orally will significantly reduce the cost of care and will replace biologicals as a front-line therapy in oncology. Progenra’s 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 (e.g., 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 proteasome system enzymes, such as DUBs and E3 Ligases. These enzymes are therefore promising therapeutic targets for preventing or attenuating inflammation. Progenra has discovered, through high throughput screening, compounds that modulate inflammation-related ubiquitin proteasome system enzymes. These drug candidates are currently in various stages of preclinical development
Colitis and Crohn’s Diseases
Aberrant expression of the cytokine IL-17 in colonic mucosa is associated with colonic inflammation and cancer. The Th17 subtype of helper T cells, innate lymphoid cells (ILCs) and γδ T cells are major sources of IL-17. An E3 ligase expressed in these cells negatively regulates their IL-17 production by promoting degradation of the transcription factor RORγT. Progenra has discovered small molecule modulators of this E3 ligase that exhibit potent anti-inflammatory properties and are being developed for treating colitis.
Both dysregulated Th17 activation and cytokine driven keratinocyte proliferation are implicated in psoriatic skin inflammation. Progenra’s E3 ubiquitin ligase modulators, which suppress Th17 differentiation, are being evaluated in psoriatic models. Selected small molecules demonstrating a novel mechanism of action and proof of concept will be progressed to clinical trial.
Targeting protein aggregation
Dysfunction in the ubiquitin-proteasome system 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 is correlated with mitochondrial dysfunction.
The formation/removal of protein aggregates is regulated at several steps through the ubiquitin proteasome system, either directly or via autophagic removal of defective mitochondria (mitophagy). Progenra is developing drug candidates that target the ubiquitin proteasome system (DUBs and E3 ligases), thereby regulating pathogenic aggregation. Small molecules discovered by Progenra constitute a breakthrough MOA and a novel approach to treating neurodegenerative diseases.
Improving synaptic activity
The ubiquitin proteasome system 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 Fibrosis (CF) is the result of mutations in the CFTR protein that lead to severely diminished chloride transport. CFTRΔF508, a single-residue deletion mutant, accounts for the large majority of CF cases. CFTRΔF508 protein 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 E3 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.