Design and Synthesis of TASIN Analogues Specifically Targeting Colorectal Cancer Cell Lines with Mutant Adenomatous Polyposis Coli (APC)

Despite advances
in targeted anticancer therapies, there are still
no small-molecule-based therapies available that specifically target
colorectal cancer (CRC) development and progression, the second leading
cause of cancer deaths. We previously disclosed the discovery of truncating
adenomatous polyposis coli (APC)-selective inhibitor 1 (TASIN-1),
a small molecule that specifically targets colorectal cancer cells
lines with truncating mutations in the adenomatous polyposis coli
(APC) tumor suppressor gene through inhibition of cholesterol biosynthesis.
Here, we report a medicinal chemistry evaluation of a collection of
TASIN analogues and activity against colon cancer cell lines and an
isogenic cell line pair reporting on the status of APC-dependent selectivity.
A number of potent and selective analogues were identified, including
compounds with good metabolic stability and pharmacokinetic properties.
The compounds reported herein represent a first-in-class genotype-selective
series that specifically target apc mutations present
in the majority of CRC patients and serve as a translational platform
toward a targeted therapy for colon cancer.