Background: The MAPK signaling pathway is commonly upregulated in human cancers due to oncogenic mutations of upstream components such as BRAF or KRAS. Targeting of the MAPK pathway has been clinically validated, with agents targeting BRAF and MEK approved. As the final node in the MAPK pathway, ERK is also an attractive therapeutic target for the treatment of MAPK-activated cancers. We have previously described the discovery of a chemical series targeting ERK using fragment-based drug design. ASTX029 is a highly potent and selective ERK inhibitor from this series, which is now being tested in a Phase 1/2 clinical trial (NCT03520075). Here, we describe the activity of ASTX029 in a number of MAPK-activated cell-based and in vivo models.

A reliable, oral cure for hepatitis C infection is still a major unmet medical need.The approval of the NS3 protease inhibitors, telaprevir and boceprevir, in 2011 has been a welcome step in the right direction, but removing the need for pegylated interferon and ribavirin to suppress the emergence of resistance mutations remains an issue.Future treatment is expected to require a combination of drugs acting via different mechanisms.By applying our proprietary fragment screening platform, Pyramid™, to the crystal structure of the full length NS3/4a protein we identified a novel allosteric site at the protease-helicase interface, distinct from the active site targeted by the recently launched drugs boceprevir and telaprevir.Using structure-based design strategies, the initial weakly binding fragment hits were optimised against the full length NS3/4a protein, resulting in leads with low nM potency.Potent compounds demonstrated robust anti-viral activity when evaluated in the cell-based genotype 1b sub-genomic replicon assay, with a wide cytotoxicity window.The physicochemical properties of these early leads were then optimised to gain suitable pharmacokinetics for oral dosing.The resulting key compounds with sub 10nM potency in the replicon assay have MW <400 and cLogP <2a distinct contrast to many known protease inhibitors.During this conference we will show the allosteric binding site with bound compounds and the rationale for targeting this site.Key replicon data, including combination studies, will be shown along with pharmacokinetic data for our preclinical compounds.