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PCSK9 manuscript.pdf (3.41 MB)

From Screening to Targeted Degradation: Strategies for the Discovery and Optimization of Small Molecule Ligands for PCSK9

submitted on 08.07.2019, 18:25 and posted on 09.07.2019, 14:33 by Whitney L. Petrilli, Gregory Adam, Roman S. Erdmann, Pravien Abeywickrema, Viju Agnani, Xi Ai, Jen Baysarowich, Noel Byrne, John Caldwell, Wonsuk Chang, Edward DiNunzio, Zhe Feng, Rachel Ford, Sookhee Ha, Yongcheng Huang, Brian Hubbard, Jennifer M. Johnston, Michael Kavana, Jean-Marie Lisnock, Rui Liang, Jun Lu, Zhijian Lu, Juncai Meng, Peter Orth, Oksana Palyha, Gopal Parthasarathy, Scott P. Salowe, Sujata Sharma, Jennifer Shipman, Stephen Soisson, Alison Strack, Hyewon Youm, Kake Zhao, Debbie Zinc, Hratch Zokian, George Addona, Karen Akinsanya, James R. Tata, Yusheng Xiong, Jason E. Imbriglio
Proprotein convertase substilisin-like/kexin type 9 (PCSK9) is a serine protease involved in a protein-protein interaction with the low-density lipoprotein (LDL) receptor that has both human genetic and clinical validation. Our pursuit of small molecule direct binders for this difficult to drug PPI target utilized affinity selection / mass spectrometry (AS/MS) 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 demonstrated in cell lysate with a cellular thermal shift assay (CETSA). Finally, ligand-induced protein degradation was shown with a proteasome recruiting tag attached to the high-affinity allosteric ligand for PCSK9.


Email Address of Submitting Author


Merck & Co., Inc


United States

ORCID For Submitting Author


Declaration of Conflict of Interest

All authors are/were employees of Merck & Co., Inc.