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A selective and orally bioavailable VHL-recruiting PROTAC achieves SMARCA2 degradation in vivo.

ABSTRACT: Targeted protein degradation offers an alternative modality to classical inhibition and holds the promise of addressing previously undruggable targets to provide novel therapeutic options for patients. Heterobifunctional molecules co-recruit a target protein and an E3 ligase, resulting in ubiquitylation and proteosome-dependent degradation of the target. In the clinic, the oral route of administration is the option of choice but has only been achieved so far by CRBN- recruiting bifunctional degrader molecules. We aimed to achieve orally bioavailable molecules that selectively degrade the BAF Chromatin Remodelling complex ATPase SMARCA2 over its closely related paralogue SMARCA4, to allow in vivo evaluation of the synthetic lethality concept of SMARCA2 dependency in SMARCA4-deficient cancers. Here we outline structure- and property-guided approaches that led to orally bioavailable VHL-recruiting degraders. Our tool compound, ACBI2, shows selective degradation of SMARCA2 over SMARCA4 in ex vivo human whole blood assays and in vivo efficacy in SMARCA4-deficient cancer models. This study demonstrates the feasibility for broadening the E3 ligase and physicochemical space that can be utilised for achieving oral efficacy with bifunctional molecules.

SUBMITTER: Kofink C

PROVIDER: S-EPMC9551036 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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A selective and orally bioavailable VHL-recruiting PROTAC achieves SMARCA2 degradation in vivo.

Kofink Christiane C Trainor Nicole N Mair Barbara B Wöhrle Simon S Wurm Melanie M Mischerikow Nikolai N Roy Michael J MJ Bader Gerd G Greb Peter P Garavel Géraldine G Diers Emelyne E McLennan Ross R Whitworth Claire C Vetma Vesna V Rumpel Klaus K Scharnweber Maximilian M Fuchs Julian E JE Gerstberger Thomas T Cui Yunhai Y Gremel Gabriela G Chetta Paolo P Hopf Stefan S Budano Nicole N Rinnenthal Joerg J Gmaschitz Gerhard G Mayer Moriz M Koegl Manfred M Ciulli Alessio A Weinstabl Harald H Farnaby William W

Nature communications 20221010 1

Targeted protein degradation offers an alternative modality to classical inhibition and holds the promise of addressing previously undruggable targets to provide novel therapeutic options for patients. Heterobifunctional molecules co-recruit a target protein and an E3 ligase, resulting in ubiquitylation and proteosome-dependent degradation of the target. In the clinic, the oral route of administration is the option of choice but has only been achieved so far by CRBN- recruiting bifunctional degr ...[more]

PMID: 36216795

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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.

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A selective and orally bioavailable VHL-recruiting PROTAC achieves SMARCA2 degradation in vivo.

Publications

A selective and orally bioavailable VHL-recruiting PROTAC achieves SMARCA2 degradation in vivo.

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