Using Engineered Cancer Cells to Identify How Orphan Cytotoxins Work: Preclinical Findings

Synopsis

Orphan cytotoxins are small molecules whose exact targets or mechanisms are unknown. Understanding how they work can reveal new research tools and potential therapies. To help identify their targets, researchers engineered cancer cell lines with controllable mismatch repair defects, allowing them to adjust mutation rates and screen for cells that resist these compounds. This approach helped pinpoint targets for multiple orphan cytotoxins, including natural products and new compounds from high-throughput screens. In one example, nicotinamide riboside (NR) was able to rescue cells from the toxicity of NAMPT inhibitors, confirming that these compounds kill cells by blocking NAMPT and demonstrating how this system can efficiently reveal mechanisms of action.

Journal

Cell Chemical Biology