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. They uniquely kill tumors indirectly through the immune system or directly by apoptosis induction. 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.
We are also currently exploring novel PROTACs as potential anticancer agents.
Signaling cascades of inflammatory responses often lead to the release of inflammatory cytokines (e.g., TNF, IL-2, IL-4, IL-17), which activate genes expressing proteins responsible for the symptoms of inflammation. Inflammatory signal pathways are regulated at various points by DUBs and E3 Ligases. These enzymes are thus promising therapeutic targets for preventing or attenuating inflammation. Progenra has discovered compounds that show in vivo anti-inflammatory activity in psoriasis and asthma models; several are currently in preclinical development.
We are also evaluating novel PROTAC molecules for testing as anti-inflammatory agents.
Targeting protein aggregation
Dysfunction in the ubiquitin-proteasome system is believed to underlie most forms of neurodegenerative disease. In Alzheimer’s disease and Parkinson’s disease, protein aggregation, in conjunction with defective mitochondria, leads to neuronal death. Progenra is developing drug candidates that target the ubiquitin proteasome system (DUBs and E3 ligases), thereby regulating pathogenic protein 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. 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 leading to severely diminished chloride transport. CFTRΔF508, a single-residue deletion mutant, accounts for most CF cases. CFTRΔF508 protein is partially misfolded and in the endoplasmic reticulum it is targeted for degradation and does not reach the cell surface to allow chloride transport (although the protein is partially functional). CF drug discovery aims to preserve and properly localize mutant CFTR protein, which has a reduced level of chloride transport activity, to the cell surface. Approved drugs that accomplish this slightly improve chloride transport, but not 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.