Success of the MIMESIS programme (European Union’s Horizon 2020 research and innovation programme under grant agreement n° 739086-MIMESIS, 2016-2018) has verified that ENYO’s approach can be considered a drug discovery platform delivering novel targets and chemistries as starting points for drug discovery. ENYO Pharma has identified and optimized three novel chemistries that potently inhibit RSV replication and induce Immunogenic Cell Death in treated tumor cells. The library has also been screened in phenotypic assays against Zika virus, Influenza virus, Human Rhinovirus and Tuberculosis although these programmes remain at an earlier stage.
All phenotypic screens carried out as part of the MIMESIS programme delivered sub-uM promising hits with no cytotoxicity.
Thanks to the scale-up of its drug discovery engine, ENYO Pharma has discovered a novel chemical series that potently targets the F protein of Respiratory syncytial virus (RSV-F) mediated fusion and cell entry. Inhibitors bind to a three-fold-symmetric pocket within the central cavity of RSV F glycoprotein to inhibit membrane fusion and have picomolar potency in in vitro fusion and viral production assays. The molecules are active on RSV A & B sub-types.
Immunogenic cell death (ICD) is a regulated cell death that engages the adaptive arm of the immune system. It is characterized by the release soluble factors and mis-localisation of membrane-bound proteins to enhance so-called Damage Associated Molecular Patterns (DAMPs) that boost the function of immune cells.
We have screened our collection of molecules that induce ICD in three tumor cell lines (two human, MDA-MB-231 & U2-OS and one mouse, Hepa1-6). We have identified two novel chemical series potently activating DAMPs in all three tumor cell lines. Our priority chemical series potently (100nM EC50) induces human DC phagocytosis confirming that ENYO’s molecules stimulate the adaptive immune response to treated tumor cells. Additional evidence that ENYO’s molecules induce ICD comes from a preliminary in vivo study demonstrating that compound treatment results in a reduced rate of growth of an explanted MDA-MB-231 tumor and also results in enhanced immune cell recruitment into the tumor.
We predict that poorly immunogenic tumors will be more responsive to immunotherapy when combined with ICD inducers and that molecules with such actions will become an important part of clinical combination approaches to enable maximal immune response to malignant cells.