Proprotein convertase substilisin-like/kexin type 9 (PCSK9) is a serine protease that has been shown to play a critical role in the regulation of plasma low-density lipoprotein (LDL) and ultimately coronary heart disease. Human subjects with specific loss-of-function mutations were found to have low circulating levels of LDL while the reverse holds true for those individuals with certain gain-of-function mutations. Given this level of genetic validation, PCSK9 has garnered considerable interest as a target for treating familial hypercholesterolemia. Our pursuit of small molecule direct binders of PCSK9 utilized affinity selection/mass spectrometry (ASMS) which identified one confirmed hit compound. An x-ray crystal structure revealed this compound was binding in an unprecedented allosteric pocket located between the catalytic and c-terminal domain. Optimization of this initial hit using two distinct strategies led to compounds with high binding affinity to PCSK9. Direct target engagement was evaluated in cell lysate with Cellular Thermal Shift Assay (CETSA). Finally, ligand-induced protein degradation was explored.

From screening to targeted degradation: Strategies for the discovery and optimization of small molecule ligands for PCSK9

ACS Spring Meeting 2021

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