A Medicinal Chemistry-Driven Approach Identified the Sterol Isomerase EBP as the Molecular Target of TASIN Colorectal Cancer Toxins

TASIN
(Truncated APC-Selective Inhibitors) compounds are selectively
toxic to colorectal cancer cells with APC mutations,
although their mechanism of action remains unknown. Here, we found
that TASINs inhibit three enzymes in the postsqualene cholesterol
biosynthetic pathway including EBP, DHCR7, and DHCR24. Even though
all three of these enzymes are required for cholesterol biosynthesis,
only inhibition of the most upstream enzyme, EBP, led to cancer cell
death via depletion of downstream sterols, an observation that was
confirmed by genetic silencing of EBP. Pharmacologic inhibition or
genetic silencing of either DHCR7 or DHCR24 had no impact on cell
viability. By using photoaffinity probes to generate a relationship
between chemical structure and probe competition, we identified compounds
that selectively inhibit either EBP or DHCR7. These studies identify
EBP, but not downstream enzymes in the cholesterol biosynthetic pathway,
as a target in APC mutant colorectal cancer and also have implications
for the clinical development of highly selective EBP inhibitors.