Innovative Portfolio & Pipeline
The Esperion next-generation ACLY inhibitor discovery program is a world-class approach
ACLY Inhibitor Discovery Program Objectives
Use leading edge approaches and technology to identify/design differentiated new chemical entities- Improve potency and selectivity several orders of magnitude vs. current active site inhibitors
- Target several cell types important in disease pathogenesis
- Identify potential indications and patient populations using leading edge bioinformatic approaches
ACLY is the key enzyme in the non-canonical TCA cycle, an energy nexus in all cells1,2
The canonical TCA cycle, also known as the Krebs Cycle, is primarily a catabolic pathway that consumes lipids and carbohydrates to generate ATP for energy production and occurs in mitochondria.1
The non-canonical TCA cycle is primary an anabolic path-way that supports cell states with high demands due to accelerated proliferation and/or effector functions; is utilized by highly proliferative cells, cancer cells, and stem cells; and occurs in mitochondria, cytoplasm, and nucleus.1,2
Allosteric ACLY inhibition is a novel approach to targeting this key enzyme
Active site ACLY inhibitors prevent the substrate (coenzyme A) from binding, thus inhibiting enzyme activity
Allosteric ACLY inhibitors bind allosteric sites distant from the active site which changes the conformation of the active site, thus inhibiting enzyme activity.
Investigating potential advantages of allosteric inhibition
Primary Sclerosing Cholangitis
PSC Staging and Progression6
PSC is a Rare Disease With Increasing Prevalence7
±This data was calculated using previously-published epidemiological data from multiple sources. Inter-regional variability results in differing estimates among European regions.
