Q1*
First-in-Class Lead PROTAC ERK5 Degrader for Treatment of Solid Tumours
Dr Katherine Finnegan, University of Manchester; Dr Sam Butterworth, University of Manchester
Cancer Research Horizons
Challenge
High levels of the mitogen-activated protein kinase ERK5 (MAPK7) are associated with poorer patient outcomes, metastatic spread and reduced response to standard chemotherapy across a range of cancers. ERK5 loss induces a strong anti-tumour phenotype, and consequently there have been multiple efforts to develop ERK5-targeted drugs, predominantly focused on ERK5 kinase inhibitors and MEK5 inhibitors. However, these induce minimal anti-cancer phenotypes, due to many of these being driven by ERK5’s kinase-independent functions. ERK5 is unique in the MAPK family as it contains both a kinase domain and a transcriptional activation domain. A therapeutic approach that is able to recapitulate the dramatic impact of genetic ablation would hold great promise as a treatment for a range of cancers.
Technology
PROTACs (Proteolysis Targeting Chimeras) are heterobifunctional small molecules that induce targeted protein degradation by hijacking the cell's ubiquitin-proteasome system. We have developed a lead PROTAC-ERK5 compound, named OS11 which is an AX-CRBN PROTAC with a lenalidomide-like CRBN ligand. OS11 has nano-molar potency in vitro (DC50 <1 nM), provides selectivity against known off-targets such as BRD4 and AurA, and >90% ERK5 degradation efficiency in several in vivo tumour models. PROTAC-ERK5 treatment induces no adverse effects, even in response to daily dosing in tumour bearing animals, for up to a month. Our work has demonstrated a new immune-oncology mechanism of action through modulation of the tumour microenvironment, differentiated from ERK5 inhibition alone.
Commercial Opportunity
OS11 is a first-in-class ERK5 PROTAC molecule with potential application in a range of large cancer markets. There are no clinical stage ERK5 degrader molecules, and OS11 displays superior activity compared to other preclinical disclosed programs. Though there are no FDA approved PROTAC molecules to date, Arvinas/Pfizer’s Vepdegestrant has submitted NDA to the FDA and approval for the treatment of breast cancer is widely anticipated, and there are several further Phase III agents in development. Despite the infancy of the market, across various reports the PROTAC and general proximity-based molecules market are estimated at between $0.4B and $1.5B USD with forecasts in the early 2030s between $4B-$6B USD. Our ERK5-PROTAC molecules have the potential in a range of solid tumour markets.
We are seeking licensing and co-development partners, or venture builders interested in driving the program through preclinical development and beyond.
Development Status
The current drug discovery program has identified a lead ERK5-PROTAC, and demonstrated preliminary anti-cancer activity in animal models of triple-negative breast cancer, mesothelioma and osteosarcoma. The team are currently bolstering this through further in vivo experimentation to fully characterise the activity of the ERK5-PROTAC, characterise impacts of ERK5-PROTAC on the immune-contexture, develop a robust patient selection biomarker strategy using patient-derived samples.
Patent Situation
A composition of matter patent filing, covering the lead molecule OS11 and related molecules was filed on 17th August 2021 and has entered national phase of prosecution in US, Europe, China, Japan, Canada, and Australia. The international search report did not raise any challenges on novelty, inventive step nor industrial applicability and therefore the outlook for the chances of grant is positive.
Further Reading
Finegan et al 2015 (PMID: 25649771) Patent application
WO 2023/156791 A1 “Heterocyclic compounds useful for treating a ERK5-mediated disease”
