A nearly $1.8 million grant given a research team at The Scripps Research Institute (TSRI) in Florida will be used to study an enzyme that controls cell survival and death, with the goal of developing drug candidates to treat inflammatory diseases like rheumatoid arthritis, and cardiovascular and neurodegenerative disorders.
The grant for the three-year project, “Development of in vivo active small molecule selective inhibitors of ASK1,” was awarded by the National Institute of General Medical Sciences of the National Institutes of Health (NIH).
Research will focus on an enzyme called ASK1, which is part of a larger family of enzymes that help control a cell’s response to stress. ASK1 is specifically involved in mediating cell survival and programmed cell death (apoptosis). The targeting is designed to inhibit, or block, ASK1 activity.
Prior studies in animal models have demonstrated that a lack of ASK1 can lessen the size of heart attack (myocardial infarction) and make heart cells more resistant to apoptosis.
“ASK1 has been highlighted as a therapeutic target in several stress-related diseases and we expect that inhibitors of its activity will provide significant benefit in multiple disease states,” Derek Duckett, the project’s co-principal investigator and an associate professor at the institute, said in a TSRI news release.
In preliminary research, the team used a high-throughput screening to identify lead molecules targeting ASK1. Researchers produced a series of small molecule inhibitors from six different structural classes to be used in this study.
In the project, the researchers will begin by optimizing the potency, selectivity, and in vivo (in an animal model) properties of ASK1 inhibitors aimed at peripheral targets, and those that can penetrate the central nervous system (CNS).
Next, potential inhibitors will be evaluated in preclinical studies of both peripheral and CNS exposure, with tests in mice planned for dose-ranging effects and toxicity at 28 days of use.
The goal is to develop inhibitors for preclinical testing that might be brought into clinical trials.
“This is an exciting project, and I think our combined efforts are well-positioned to make significant progress over the next three years,” said William R. Roush, also a co-principal investigator. “The starting point for our effort to develop a selective and brain penetrant ASK1 inhibitor originated from high throughput screening, molecular modelling for compound design, and initial rounds of synthesis and testing.”