Discovery of an orally active VHL-recruiting PROTAC that achieves robust HMGCR degradation and potent hypolipidemic activity in vivo

Abstract

HMG-CoA reductase (HMGCR) protein is usually upregulated after statin (HMGCR inhibitor) treatment, which inevitably diminishes its therapeutic efficacy, provoking the need for higher doses associated with adverse effects. The proteolysis targeting chimera (PROTAC) technology has recently emerged as a powerful approach for inducing protein degradation. Nonetheless, due to their bifunctional nature, developing orally bioavailable PROTACs remains a great challenge. Herein, we identified a powerful HMGCR-targeted PROTAC ( 21c ) comprising a VHL ligand conjugated to lovastatin acid that potently degrades HMGCR in Insig-silenced HepG2 cells (DC 50 = 120 nmol/L) and forms a stable ternary complex, as predicated by a holistic modeling protocol. Most importantly, oral administration of the corresponding lactone 21b reveled favorable plasma exposures referring to both the parent 21b and the conversed acid 21c . Further in vivo studies of 21b demonstrated robust HMGCR degradation and potent cholesterol reduction in mice with diet-induced hypercholesterolemia, highlighting a promising strategy for treating hyperlipidemia and associated diseases.

Targeting of the FOXM1 Oncoprotein by E3 Ligase-Assisted Degradation

“…Demethylation of 5 yielded compound 6 , which was reacted with ethyl bromoacetate and then hydrolyzed to afford the key intermediate 7 . Condensation of compound 7 with our previously synthesized pomalidomide analogs 9a – 9d produced the target compounds 10a – 10d .…”

“…Demethylation of 5 yielded compound 6, which was reacted with ethyl bromoacetate and then hydrolyzed to afford the key intermediate 7. Condensation of compound 7 with our previously synthesized pomalidomide analogs 9a−9d 50 Preliminary SAR. To test the binding ability of both the parent inhibitors and degraders, we conducted an electrophoretic mobility shift assay (EMSA) to determine the extent of FOXM1-DBD/DNA inhibition.…”

PROTACs: great opportunities for academia and industry (an update from 2020 to 2021)

“…In 2021, Xiang group developed the VHL-based PROTAC targeting HMGCR. 494 By combining VHL with Lovastatin they demonstrated the most potent degrader 246 (Fig. 81 ) with IC 50 of 0.25 µM.…”

Discovery of small molecule ligands for the von Hippel-Lindau (VHL) E3 ligase and their use as inhibitors and PROTAC degraders

“…More recently, another example of VHL-recruiting PROTACs featuring a benzylic exit vector was reported by the Ciulli laboratory/Boehringer Ingelheim collaboration in the design of orally bioavailable SMARCA2 selective degraders. 103 Convenience of administration, ideally oral administration, is highly relevant for therapeutic development and applicability of PRO-TAC degraders, and has been -apart from very few reports of orally bioavailable VHL-recruiting PROTACs 103,126,173 -limited to CRBN-recruiting degraders. 174 To access orally bioavailable SMARCA2 degraders, a novel SMARCA2/4 BD binder featuring a bare minimum of hydrogen bonds was designed and linked via either the phenolic or benzylic position to VHL recruiters.…”