PROTACHMGCR Degrader-1 is an orally active HMGCRPROTAC degrader with an IC50 of 1.32 μM. It is a lactone prodrug derived from PROTACHMGCR Degrader-2. In vivo, PROTACHMGCR Degrader-1 achieves high plasma exposure of the active compound, leading to potent HMGCR degradation and demonstrating effective cholesterol-lowering properties. This compound is applicable for research related to hyperlipidemia.

PROTAC HMGCR Degrader-1 (compound 21 b) is an orally active prodrug derived from PROTAC HMGCR Degrader-2 (compound 21 c). PROTAC HMGCR Degrader-2 functions as an HMGCR PROTAC degrader, utilizing a VHL-dependent pathway to degrade HMGCR in Insig gene-silenced HepG2 cells, with a DC50 of 120 nM. When applied at concentrations of 0.01-3 μM for 16 hours in HepG2 cells, PROTAC HMGCR Degrader-1 exhibits a tendency to act as an HMGCR inhibitor rather than a degrader at higher doses, achieving a maximum degradation rate (Dmax) of 56% at 1 μM. Additionally, PROTAC HMGCR Degrader-1 (1 μM, 16-hour treatment) effectively prevents compensatory HMGCR upregulation in engineered HepG2 liver cells.

PROTAC HMGCR Degrader-1 (compound 21 b) administered orally at doses of 20 or 60 mg/kg once daily for 5 weeks effectively inhibits de novo cholesterol synthesis by degrading HMGCR in a mouse model induced with a medium-fat diet (MFD). When combined with lovastatin, it enhances the excretion of excess lipids absorbed from the MFD27 diet and demonstrates excellent safety.