ESM™ p38MAPK inhibitor
MPL-5821 is a preclinical macrophage-targeted p38 MAP kinase inhibitor. Extended activation of p38 MAP kinase in tumour associated macrophages indicates this is a key regulatory mechanism in the tumour microenvironment contributing to T-cell “exhaustion”. p38 MAP kinase has been extensively characterised as a master regulator of cytokine production such as IL-10 in macrophages leading to tumour mediated immunosuppression and impaired immunosurveillance. Inhibition of p38 MAPK reverses this immunosuppression and restores anti-tumour T-cell function by restoring levels of IL-12. In addition, p38 MAPK is an important signalling element in suppressing tumour dendritic cells and impairing antigen presentation.
Because the p38 MAPK pathway is important in key anti-tumour immune cells such as effector T-cells and NK cells selective delivery to the macrophage is crucial to ensure the maximum benefit of target inhibition. MPL-5821 has been demonstrated to repolarize macrophage to a M1-phenotype, significantly decreasing their IL-10 production increase their IL-12 production and MHC-II antigen presentation capacity, thereby recuing T-lymphocytes from immunosuppression. MPL-5821 shows synergy with checkpoint inhibitors in solid tumours models. In addition to oncology, MPL-5821 is evaluated in acute and chronic liver disease settings. A significant safety window has been demonstrated for MPL-5821 in pivotal toxicology studies.
PI3 kinase is an important signalling molecule in macrophages and lymphocytes. Our preclinical PI3 Kinase inhibitor programme evaluates a macrophage-targeted pan-PI3 kinase inhibitor designed to repolarize macrophages to a M1-like phenotype and also decrease macrophage and myofibroblast contribution to fibrosis. The PI3 kinase is a key signalling molecule in T-cells and NK cells macrophage-selective delivery of Pi£ inhibitors is crucial to ensure the maximum benefit of target inhibition and limit undesired pharmacology. Preclinical evaluation is ongoing in solid tumours and a range of fibrosis models.
Our inflammasome discovery project targets a novel undisclosed target playing a central role in immunoregulation in NAFLD and NASH.
ESM™ immune kinase inhibitor
Our immune kinase inhibitor discovery programme aims to develop lead molecules with improved therapeutic window, by reducing the unwanted pharmacology and adverse event profile associated with existing families of non-targeted immune kinase inhibitors, while maintaining the desired pharmacology though macrophage targeting.