Autotaxin produces the bioactive lipid lysophosphatidic acid (LPA) and is a drug target of considerable interest for numerous pathologies. We report the expedient, structure-guided evolution of weak physiological allosteric inhibitors (bile salts) into potent competitive Autotaxin inhibitors that do not interact with the catalytic site. Functional data confirms that our lead compound attenuates LPA mediated signaling in cells and reduces LPA synthesis in vivo, providing a promising natural product derived scaffold for drug discovery.
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Article Synopsis
- Autotaxin (ATX) is being targeted for new liver disease treatments, and drug candidates were identified through high-throughput screening methods.
- Researchers synthesized a small molecule called KR-40795, designed to inhibit ATX's activity by binding to specific regions of the enzyme.
- KR-40795 effectively reduced collagen formation and lipid accumulation in liver cells, showcasing its potential to treat liver conditions like fibrosis and steatosis.
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