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

Wentian Wang, Lu Zhang, Lorraine Morlock, Noelle S. Williams, Jerry W. Shay, Jef K. De Brabander

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5217-5241
Number of pages25
JournalJournal of Medicinal Chemistry
Volume62
Issue number10
DOIs
StatePublished - May 23 2019

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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