Progenra has discovered unique PROTAC drugs by employing novel ubiquitin ligases other than cereblon and VHL ligases. Progenra has established new MOA and wholly owned IP position on novel PROTACs. Progenra is also at the forefront of discovering and developing molecular glues, molecules that bind to ubiquitin ligases and change ubiquitination properties of the E3 ligases. Progenra has discovered potent inhibitors and activators of ubiquitin proteasome system therapeutic targets associated with various diseases including cancer, inflammatory disease, neurodegenerative diseases such as Parkinson’s, Alzheimer’s, and cardiovascular disease.
More than 30 percent of all human cancers – including 95 percent of pancreatic cancers and 45 percent of colorectal cancers — are driven by mutations of the RAS family of genes. It is well known that RAS family of proteins are prone to drug resistance with covalent or non-covalent monotherapies. Other companies are developing K-RAS PROTACs by utilizing cereblon and VHL ligands, a crowded and chemically well explored strategy that does not offer freedom to operate. Progenra has adopted a unique approach by exploiting a novel ubiquitin E3 ligase that is associated with plasma membrane. Progenra K-RAS PROTACs are highly effective and potent in degrading K-RAS derivatives.
Targeting Tyrosine Kinase Receptors and Membrane Proteins with unique PROTACs
Most of Pharma and Biotech PROTAC Strategies are focused on cereblon (VHL, HDM2 ligases). Big roadblocks exist with IP issues and cereblon-based PROTACs are not suitable for chronic non-oncology applications due to potential teratogenic risks of cereblon binders. There no membrane associated ubiquitin ligases exploited for membrane protein degradation. A membrane ubiquitin ligase that is associated with Receptor Tyrosine Kinases and PROTACs developed by this ligase are highly potent as compared to other ligands in the field. Progenra team is excited by the unique approach that stands apart from the industry and offers potency and selectivity and IP position not available with other molecules under development.
Gene therapy and Immune Oncology
Recent approaches with RNA-based vaccines have established that gene therapy to stimulate to unleash anti-tumor immune responses is a viable strategy. Progenra is developing a novel ubiquitin ligase mediated approaches to pioneer a new way approach anti-cancer therapy.
Progenra’s USP7 inhibitors block tumor immune 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 single agent antitumor activity and potentiates activity of immune oncology agents when given in combination.
Inflammatory signal pathways are regulated at various points by DUBs and E3 ligases. Progenra has developed compounds that show in vivo anti-inflammatory activity in psoriasis and asthma models; several are currently in preclinical development. We are also developing novel PROTACs against proinflammatory target proteins for advancing them as anti-inflammatory agents.
Molecular Glues for Neurodegenerative Diseases
Targeting mitophagy and protein aggregation
Dysfunction in the protein and organelle degradation system is believed to underlie most forms of neurodegenerative disease. In Alzheimer’s disease and Parkinson’s disease, protein aggregation, in conjunction with accumulation of defective mitochondria, leads to neuronal death. Progenra is developing molecular glues and PROTAC drug candidates that promote mitophagy and reduce pathogenic protein aggregation. Small molecules discovered by Progenra constitute a breakthrough MOA and a novel approach to treating neurodegenerative diseases.
Covid-19: Drug Development During a Pandemic
The Covid-19 pandemic caused by SARS Coronavirus-2 (SARS-Cov2) has rekindled the urgency to search for coronavirus drugs. Protection against SARS-CoV-2 requires regular bosting of vaccines. To reduce the burden and cost of vaccination requires development of potent small molecule anti-viral drugs. Targets include coronavirus main proteinase (3CLPro), papain-like protease (PLPro) and RNA-dependent RNA Polymerase (RdRP). While nucleoside analogues currently show promise, coronaviruses encode a proofreading exoribonuclease that blocks inhibition by many nucleoside analogues. Given the lack of Covid-19 targeted drugs, Progenra, Inc. is taking a radical approach in exploiting the ubiquitin proteasome system for rapid development of Covid-19 therapeutics. Leveraging its UbiPro™ Drug Discovery Platform we have developed novel, molecules with potent antiviral drug properties.