Design and Synthesis of TASIN Analogues Specifically Targeting Colorectal Cancer Cell Lines with Mutant Adenomatous Polyposis Coli (APC)
Year: 2019
Type: article
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.
Source: Journal of Medicinal Chemistry
Authors: Wentian Wang, Lu Zhang, Lorraine Morlock, Noelle S. Williams, Jerry W. Shay, Jef K. De Brabander
Institution: The University of Texas Southwestern Medical Center
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: green
Awards: G308532787, Development of Therapeutics Targeting Truncated Adenomatous Polyposis Coli (APC) as a Novel Prevention and Intervention Strategy for Colorectal Cancer, G5028114694, Development of Therapeutics Targeting Truncated Adenomatous Polyposis Coli (APC) as a Novel Prevention and Intervention Strategy for Colorectal Cancer, UT Southwestern Medical Center Simmons Comprehensive Cancer Center, G995644284
OpenAlex ID: W2944051149