Grant length: Two years
Study overview: Since the discovery in 2014 of the fusion gene (DNAJB1-PRKACA) that drives fibrolamellar carcinoma (FLC), a drug that would selectively inhibit or destroy the chimeric protein (DNAJ-PKAc) encoded by that gene has been considered a “holy grail” for FLC therapy. Such a drug must effectively target DNAJ-PKAc, while only having minimal activity against normal protein kinase A (PKA), which is essential for life.
In this study, a team of investigators will work with X-Chem (https://www.x-chemrx.com/), a chemistry service company, to identify molecules that bind tightly to DNAJ-PKAc, but do not bind well to either normal PKA or normal DNAJB1. This will be accomplished through a mass chemical selection process based on X-Chem’s unique asset – a DNA-encoded chemical library (DEL) of compounds. This technology will allow an astounding 12 billion different tool compounds to be reviewed to identify compounds that can selectively bind to FLC’s fusion protein. DEL screens work by coupling chemical compounds to short DNA fragments that serve as “bar codes” that can identify the compounds with affinity to the tested targets. Despite the massive scope of the tests, the screening process can be rapidly carried out using highly automated machines that leverage all the advancements made in genomic analysis over the last decade. X-Chem is a leader in this cutting-edge technology.
If this step can be accomplished successfully, it will yield a set of chemical “hits” that meet strict criteria for selective binding to FLC’s fusion protein. The path from there to a drug would then involve many subsequent steps.