Tuesday, April 30, 2024
4/30/2024
ABSTRACT We are pursuing the first anti-tumor small molecules that act specifically against human Sonic Hh protein autoprocessing, a unique biosynthetic event that is necessary to drive oncogenic hedgehog (Hh) ligand dependent cell/cell signaling. Sonic Hh protein autoprocessing involves a precursor form of Hh and is responsible for liberating the mature Sonic Hh signaling ligand while also modifying the ligand’s terminal carboxyl group with cholesterol. The long-standing challenge has been to discover small molecules that specifically antagonize this key reaction within the tumor cell. To facilitate discovery, we have devised the first in-cell assay system to screen for antagonists of human Hh autoprocessing at high throughput. Our assay couples intracellular Sonic Hh autoprocessing to the extracellular secretion of a bioluminescent reporter enzyme. We recently miniaturized this assay for 1536-well plates and in preliminary work, completed a successful pilot screen against LOPAC. Here we propose a two-year high risk/gain strategy that integrates: (AIM 1) In-cell quantitative high throughput screening in collaboration with the National Center for Advancing Translational Science (NCATS) to discover the first bioactive drug-like antagonists of human Sonic Hh autoprocessing; (AIM 2) Pre-clinical evaluation of the anti-tumor effects of those novel Hh autoprocessing inhibitors toward human multiple myeloma and human colon cancer cells, which exhibit Hh-ligand dependent growth. We hypothesize that specific antagonists of Sonic Hh autoprocessing will deplete extracellular Sonic Hh ligand. Tumor apoptosis is the expected result of this ligand deprivation strategy. In summary, using an innovative assay and novel anti-Hh approach, we are poised to address a significant gap in the field of Hh signaling while pursuing a new class of cancer therapeutics.
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