Degradation versus Inhibition: Development of Proteolysis-Targeting Chimeras for Overcoming Statin-Induced Compensatory Upregulation of 3‑Hydroxy-3-methylglutaryl Coenzyme A Reductase

3-Hydroxy-3-methylglutaryl
coenzyme A reductase (HMGCR) is an eight-pass
transmembrane protein in the endoplasmic reticulum (ER) and a classical
drug target to treat dyslipidemia. Statins including the well-known
atorvastatin (Lipitor; Pfizer) have been widely used for the prevention
and treatment of cardiovascular disease for decades. However, statins
can elicit a compensatory upregulation of HMGCR protein and cause
adverse effects including skeletal muscle damage. They are ineffective
for patients with statin intolerance. Inspired by the recently emerging
proteolysis-targeting chimeras (PROTACs), we set out to eliminate
HMGCR protein using PROTAC-mediated degradation. One PROTAC designated
as P22A was found to reduce HMGCR protein level and block cholesterol
biosynthesis potently with less compensatory upregulation of HMGCR.
To the best of our knowledge, HMGCR is the first ER-localized, polytopic
transmembrane protein successfully degraded by the PROTAC technique.
This finding may provide a new strategy to lower cholesterol levels
and treat the associated diseases.