Fundamental aspects of DMPK optimization of targeted protein degraders

Cantrill, Carina; Chaturvedi, Prasoon; Rynn, Caroline; Schaffland, Jeannine Petrig; Walter, Isabelle; Wittwer, Matthias

doi:10.1016/j.drudis.2020.03.012

Cited by 103 publications

(114 citation statements)

References 88 publications

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“…While this rapidly developed technique has been widely employed in the degradation of various oncogenic proteins 37 , 38 , 39 , 40 , its application in CVD, the leading cause of global deaths, remains relatively less explored 41 . Moreover, examples of PROTACs with potent in vivo activity and favorable pharmacokinetic (PK) properties are scarce 42 , with most administered via injection rather than via the oral route 43 , 44 , 45 . Inspired by the native Insig-mediated degradation process, we envisioned a feasible way to eliminate HMGCR by using artificial conjugates (HMGCR-targeting PROTACs) that hijack different E3 ligases such as von Hippel-Lindau (VHL) and CRBN ( Fig.…”

Section: Introductionmentioning

confidence: 99%

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

Luo

Lin

et al. 2021

Acta Pharmaceutica Sinica B

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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.

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Section: Introductionmentioning

confidence: 99%

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

Luo

Lin

et al. 2021

Acta Pharmaceutica Sinica B

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“… 7 − 9 While our understanding of the bioactivity of PROTACs is rapidly increasing, the physicochemical properties of these molecules have received relatively little attention. 10 , 11 …”

mentioning

confidence: 99%

Understanding and Improving the Membrane Permeability of VH032-Based PROTACs

Klein

Townsend

Testa

et al. 2020

ACS Med. Chem. Lett.

127

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Proteolysis targeting chimeras (PROTACs) are catalytic heterobifunctional molecules that can selectively degrade a protein of interest by recruiting a ubiquitin E3 ligase to the target, leading to its ubiquitylation and degradation by the proteasome. Most degraders lie outside the chemical space associated with most membrane-permeable drugs. Although many PROTACs have been described with potent activity in cells, our understanding of the relationship between structure and permeability in these compounds remains limited. Here, we describe a label-free method for assessing the permeability of several VH032-based PROTACs and their components by combining a parallel artificial membrane permeability assay (PAMPA) and a lipophilic permeability efficiency (LPE) metric. Our results show that the combination of these two cell-free membrane permeability assays provides new insight into PROTAC structure–permeability relationships and offers a conceptual framework for predicting the physicochemical properties of PROTACs in order to better inform the design of more permeable and more effective degraders.

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“…Plasma protein binding (PPB) in vitro assays (using equilibrium dialysis, for example) are applied in drug discovery to help understand in vivo unbound levels. 22,44 PPB is often used mistakenly as a surrogate of the nonspecific binding propensity of small molecules more generally, but this can vary considerably depending on the biological system being investigated and will lead to erroneous conclusions. For instance, phospholipids are a major sink of nonspecific drug binding and their components vary considerably across different cell types.…”

Section: Pillar 1: Site Of Actionmentioning

confidence: 99%

“…The high lipophilicity of many PROTACs 14 will increase metabolic turnover and reduce aqueous solubility, factors that also limit systemic exposures and hinder degrader performance. 22…”

Section: Introductionmentioning

confidence: 99%