Discovery of Novel PCSK9‐LDLR PPI Inhibitors by a Structural Modification Approach

Proprotein convertase subtilisin/kexin 9 (PCSK9) mediating the degradation of the hepatic low‐density lipoprotein receptor (LDLR), has emerged as a novel therapeutic target for the treatment of hyperlipidemia. Herein, to disrupt the protein‐protein interactions (PPIs) between PCSK9 and LDLR, a total of 43 compounds were designed and synthesized by structural modification of previous derived PCSK9 inhibitors. In the PCSK9‐LDLR PPI interfering test, compounds B7 , B23 , and B27 showed inhibitory potency with IC 50 values of 8.86 μM, 3.95 μM, and 5.02 μM, respectively, compared with the positive control SBC‐115,337 (IC 50 value of 11.36 μM). Molecular docking predicted binding mode of compound B27 on the PCSK9‐LDLR interaction interface, and hydrophobic interactions play an important role in the binding of B27 to PCSK9. Moreover, compounds B7 , B23 , and especially B27 restored the expression of LDLR and increased LDL uptake of HepG2 cell in the presence of PCSK9. Collectively, lead compounds with lipid‐lowering potential were developed for further design of PCSK9‐LDLR PPI inhibitors.