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

Autor:	Petrilli WL; Discovery Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: whitney_petrilli@merck.com., Adam GC; Pharmacology, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA. Electronic address: gregory_adam@merck.com., Erdmann RS; Discovery Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA; Discovery Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA. Electronic address: roman.erdmann@merck.com., Abeywickrema P; Computational and Structural Chemistry, Merck & Co. Inc., 770 Sumneytown Pike, West Point, PA 19486, USA., Agnani V; In Vitro Pharmacology, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA., Ai X; Cardio Metabolic Diseases, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA., Baysarowich J; In Vitro Pharmacology, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA., Byrne N; Computational and Structural Chemistry, Merck & Co. Inc., 770 Sumneytown Pike, West Point, PA 19486, USA., Caldwell JP; Discovery Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA., Chang W; Discovery Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA., DiNunzio E; In Vitro Pharmacology, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA., Feng Z; Discovery Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA., Ford R; Computational and Structural Chemistry, Merck & Co. Inc., 770 Sumneytown Pike, West Point, PA 19486, USA., Ha S; Computational and Structural Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA., Huang Y; Cardio Metabolic Diseases, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA., Hubbard B; Cardio Metabolic Diseases, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA., Johnston JM; Computational and Structural Chemistry, Merck & Co. Inc., 770 Sumneytown Pike, West Point, PA 19486, USA., Kavana M; In Vitro Pharmacology, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA., Lisnock JM; In Vitro Pharmacology, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA., Liang R; Discovery Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA., Lu J; Computational and Structural Chemistry, Merck & Co. Inc., 770 Sumneytown Pike, West Point, PA 19486, USA., Lu Z; Discovery Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA., Meng J; Computational and Structural Chemistry, Merck & Co. Inc., 770 Sumneytown Pike, West Point, PA 19486, USA., Orth P; Computational and Structural Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA., Palyha O; Cardio Metabolic Diseases, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA., Parthasarathy G; Computational and Structural Chemistry, Merck & Co. Inc., 770 Sumneytown Pike, West Point, PA 19486, USA., Salowe SP; In Vitro Pharmacology, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA., Sharma S; Computational and Structural Chemistry, Merck & Co. Inc., 770 Sumneytown Pike, West Point, PA 19486, USA., Shipman J; Computational and Structural Chemistry, Merck & Co. Inc., 770 Sumneytown Pike, West Point, PA 19486, USA., Soisson SM; Computational and Structural Chemistry, Merck & Co. Inc., 770 Sumneytown Pike, West Point, PA 19486, USA., Strack AM; Cardio Metabolic Diseases, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA., Youm H; Discovery Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA., Zhao K; Discovery Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA., Zink DL; In Vitro Pharmacology, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA., Zokian H; In Vitro Pharmacology, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA., Addona GH; In Vitro Pharmacology, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA., Akinsanya K; Cardio Metabolic Diseases, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA., Tata JR; Discovery Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA., Xiong Y; Discovery Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA., Imbriglio JE; Discovery Chemistry, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Jazyk:	angličtina
Zdroj:	Cell chemical biology [Cell Chem Biol] 2020 Jan 16; Vol. 27 (1), pp. 32-40.e3. Date of Electronic Publication: 2019 Oct 22.
DOI:	10.1016/j.chembiol.2019.10.002
Abstrakt:	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. Blocking this protein-protein interaction prevents LDL receptor degradation and thereby decreases LDL cholesterol levels. Our pursuit of small-molecule direct binders for this difficult to drug PPI target utilized affinity selection/mass spectrometry, which identified one confirmed hit compound. An X-ray crystal structure revealed that 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 the cell lysate with a cellular thermal shift assay. Finally, ligand-induced protein degradation was shown with a proteasome recruiting tag attached to the high-affinity allosteric ligand for PCSK9. (Copyright © 2019 Elsevier Ltd. All rights reserved.)
Databáze:	MEDLINE
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