Atherosclerosis affects more than 18 million Americans and is a major cause of cardiovasculardiseases and acute cardiovascular events, such as heart attack and stroke. Current interventions includechanges to diet and exercise, smoking cessation, and treatment with statins, but many patients struggle toadhere to lifestyle interventions and can experience significant side effects while taking statins. Although lipidlowering drugs have benefited patients with atherosclerosis, the idea that lipid lowering halts the progression ofatherosclerosis is not valid because factors other than hypercholesterolemia have been shown to promoteatherosclerosis. Therefore, there is a clear need for novel therapeutics that can directly inhibit plaque formationthrough a mechanism other than lipid lowering. Fortiscience, Inc. is developing an alternative therapeuticapproach that inhibits fortilin, a key protein involved in atherosclerotic plaque formation. Fortilin protectsmacrophages against apoptosis in atherosclerotic intima, allowing them to proliferate and produce inflammatorycytokines. Strikingly, global knockdown of fortilin protects hypercholesterolemic mice against atherosclerosiswithout lowering cholesterol. Three small molecular weight compounds identified in preliminary work at theUniversity of Washington have been shown to have activity in relevant in vitro and in vivo models, and thesecompounds have been used as the basis for designing and synthesizing 52 additional compounds with higherbinding affinity through a medicinal chemistry approach. In this Phase I STTR project, to be conducted incollaboration with the University of Washington and the University of Notre Dame, 10 prioritized compounds willbe evaluated using cell-based fortilin degradation and foam cell formation assays to assess activity (measuringthe EC50) and cell death assays to determine cytotoxicity (LC50). Based on an analysis of the structure-activityrelationship for these compounds, computational virtual docking assays will be performed to design andproduce 3-5 new compounds with improved fortilin binding affinity. The binding affinity, activity, toxicity, andstability of these compounds will then be measured, and the data will be used to select a lead compound with asingle-nanomolar dissociation constant, a lower EC50 value than the previous best-performing compound, andlow clearance in liver microsome assays (CLint below 15 mL min-1kg-1). Further, pharmacokinetic and toxicityprofiles will be determined for the lead compound in a 15-day oral dose range finding study in C57BL/6 mice.Finally, the anti-atherosclerotic activity of the lead compound will be determined in the aortae ofhypercholesterolemic mice following 12 weeks of oral administration, with the goal of achieving a 50%reduction in atherosclerosis. This work is designed to provide the necessary proof-of-concept data to supportfurther pre-clinical studies in Phase II and a future first-in-human clinical trial to establish the safety of the drug.
Public Health Relevance Statement: PROJECT NARRATIVE
Current treatment approaches that are designed to prevent atherosclerosis progression by reducing LDL
cholesterol levels often fail to prevent the growth and evolution of atherosclerotic plaques in patients' arteries.
Fortiscience, Inc. is taking a novel approach to treating atherosclerosis by developing a drug that inhibits fortilin,
a key protein involved in the survival of macrophages, which contribute to plaque formation and inflammation.
This novel drug, which is intended to prevent plaque progression, will provide an alternative to lipid-lowering
therapies and reduce the risk of life-threatening cardiovascular events in patients with atherosclerosis.
Project Terms: | | | | | 