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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 (DC₅₀ = 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.

SUBMITTER: Luo G

PROVIDER: S-EPMC8148065 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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

Luo Guoshun G Li Zhenbang Z Lin Xin X Li Xinyu X Chen Yu Y Xi Kun K Xiao Maoxu M Wei Hanlin H Zhu Lizhe L Xiang Hua H

Acta pharmaceutica Sinica. B 20201106 5

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 ...[more]

PMID: 34094835

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Project description:BackgroundRenal fibrosis is the pathological foundation of various chronic kidney diseases progressing to end stage renal failure. However, there are currently no nephroprotective drugs targeted to the fibrotic process in clinical practice. Proteolytic targeting chimeras (PROTACs), which reversibly degrade target proteins through the ubiquitin-proteasome pathway, is a novel therapeutic modality. Smad3 is a key pathogenic factor in fibrogenesis while HIF-2α exhibits prominent renal protective effects, which is the natural substrate of von Hippel-Lindau (VHL) E3 Ligase. We hypothesied the construction of VHL-recruiting, Smad3-targeting PROTAC might combine the effects of Smad3 degradation and HIF-2α stabilization, which not only improving the clinical efficacy of PROTAC but also avoiding its potential off-target effects, could greatly improve the possibility of its translation into clinical drugs.MethodsBy joining the Smad3-binding small molecule compound (SMC) to VHL-binding SMC with a linker, we designed and synthesized a Smad3-targeting, VHL-based PROTAC. The effects of this PROTAC on targeted proteins were verified both in vitro and in vivo. The toxicity and pharmacokinetic (PK) evaluations were conducted with both male and female mice. The renal protection effects and mechanism of PROTAC were evaluated in unilateral ureteral obstruction (UUO) and 5/6 subtotal nephrectomy (5/6Nx) mouse model.ResultsBy optimizing the linker and the Smad3-binding SMC, we got a stable and high efficient PROTAC which simultaneously degraded Smad3 and stabilized HIF-2α both in vivo and in vitro. The acute toxicity evaluation showed a pretty large therapeutic window of the PROTAC. The prominent renal protection effects and its underlying mechanism including anti-fibrosis and anti-inflammatory, improving renal anemia and promoting kidney repair, had all been verified in UUO and 5/6Nx mouse model.ConclusionBy accurate combination of PROTAC targeted protein and E3 ligase, we got a Smad3-targeting, VHL-recruting PROTAC which caused Smad3 degradation and HIF-2α stabilization effects simultaneously, and led to the strong renal function protection effects.

Dataset Information

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

Publications

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

Similar Datasets

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