Proteolysis targeting chimeras (PROTACs) in ‘beyond rule-of-five’ chemical space: Recent progress and future challenges

Edmondson, Scott D.; Yang, Bin; Fallan, Charlene

doi:10.1016/j.bmcl.2019.04.030

Cited by 274 publications

(246 citation statements)

References 76 publications

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“…50 The resulting IAP-and MDM2-based degraders 35 and 37 are depicted in Tables 3 and S5 Previous reports on principles of PROTAC design highlighted the importance of different physiochemical properties to achieve successful degradation. 46,51,52 In order to assess activity determining physicochemical properties, we calculated molecular descriptors, i.e. the molecular weight, the topological polar surface area (TPSA), the number of rotatable bonds (NRotB), as well as hydrogen bond donors (HBD) and acceptors (HBA) of all compounds (Tables S1-S4, ESI †).…”

Section: Chemistrymentioning

confidence: 99%

Systematic exploration of different E3 ubiquitin ligases: an approach towards potent and selective CDK6 degraders

et al. 2020

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Section: Chemistrymentioning

confidence: 99%

Systematic exploration of different E3 ubiquitin ligases: an approach towards potent and selective CDK6 degraders

et al. 2020

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“…ternary complex formation between substrate, PROTAC and E3, making informed decisions on PROTAC design difficult. Lastly, as PROTACs are typically composed of two ligands connected by a linker, these molecules usually violate Lipinski's rule of five and, thus, often suffer from permeability and metabolic liabilities (12).…”

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confidence: 99%

bioPROTACs as versatile modulators of intracellular therapeutic targets including proliferating cell nuclear antigen (PCNA)

Lim¹,

Khoo²,

Peh³

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

102

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Targeted degradation approaches such as proteolysis targeting chimeras (PROTACs) offer new ways to address disease through tackling challenging targets and with greater potency, efficacy, and specificity over traditional approaches. However, identification of high-affinity ligands to serve as PROTAC starting points remains challenging. As a complementary approach, we describe a class of molecules termed biological PROTACs (bioPROTACs)—engineered intracellular proteins consisting of a target-binding domain directly fused to an E3 ubiquitin ligase. Using GFP-tagged proteins as model substrates, we show that there is considerable flexibility in both the choice of substrate binders (binding positions, scaffold-class) and the E3 ligases. We then identified a highly effective bioPROTAC against an oncology target, proliferating cell nuclear antigen (PCNA) to elicit rapid and robust PCNA degradation and associated effects on DNA synthesis and cell cycle progression. Overall, bioPROTACs are powerful tools for interrogating degradation approaches, target biology, and potentially for making therapeutic impacts.

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“…With VHL based‐PROTACs, several studies have shown that there exists a very large concentration window between PROTAC‐mediated degradation (in the pM–nM range with the best degraders) and stabilization of HIF‐1α, which is only observed at high micromolar range, which is >1000 fold higher than that required for degradation (Bondeson et al, ; Frost et al, ; Maniaci et al, ; Zengerle, Chan, & Ciulli, ). However, the physical and PK properties of PROTACs, which, given their relatively higher MW, are distinct from traditional small‐molecule drugs and achieving appropriate PK will be challenging (Edmondson, Yang, & Fallan, ). Despite the catalytic mode of action, obtaining the desired exposure and exposure duration, for example, when targeting POI with high turnover, could necessitate plasma C max values of ten‐fold, or greater, the minimum effective concentration (see Raina et al, ).…”

Section: Safety Challenges For Protacsmentioning

confidence: 99%

Proteolysis‐targeting chimeras in drug development: A safety perspective

Moreau

Coen

Zhang

et al. 2020

British J Pharmacology

125

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Proteolysis‐targeting chimeras are a new drug modality that exploits the endogenous ubiquitin proteasome system to degrade a protein of interest for therapeutic benefit. As the first‐generation of proteolysis‐targeting chimeras have now entered clinical trials for oncology indications, it is timely to consider the theoretical safety risks inherent with this modality which include off‐target degradation, intracellular accumulation of natural substrates for the E3 ligases used in the ubiquitin proteasome system, proteasome saturation by ubiquitinated proteins, and liabilities associated with the “hook effect” of proteolysis‐targeting chimeras This review describes in vitro and non‐clinical in vivo data that provide mechanistic insight of these safety risks and approaches being used to mitigate these risks in the next generation of proteolysis‐targeting chimera molecules to extend therapeutic applications beyond life‐threatening diseases.

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Proteolysis targeting chimeras (PROTACs) in ‘beyond rule-of-five’ chemical space: Recent progress and future challenges

Cited by 274 publications

References 76 publications

Systematic exploration of different E3 ubiquitin ligases: an approach towards potent and selective CDK6 degraders

Systematic exploration of different E3 ubiquitin ligases: an approach towards potent and selective CDK6 degraders

bioPROTACs as versatile modulators of intracellular therapeutic targets including proliferating cell nuclear antigen (PCNA)

Proteolysis‐targeting chimeras in drug development: A safety perspective

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