Light-Controllable PROTACs for Temporospatial Control of Protein Degradation

Liu, Jing; Peng, Yunhua; Wei, Wenyi

doi:10.3389/fcell.2021.678077

Cited by 22 publications

(29 citation statements)

References 178 publications

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“…To overcome the off-tissue issues, which represent one of the major limitations of PROTACs, a new generation of controllable PROTACs was devised (63). Phospho-dependent PROTACs (phosphoPROTACs), the first controllable PROTACs, were developed by Hines et al (64) in 2013 to specifically degrade targets by activating kinase-signaling (Figure 4).…”

Section: Third-generation Controllable Protacsmentioning

confidence: 99%

Targeting Oncoproteins for Degradation by Small Molecule-Based Proteolysis-Targeting Chimeras (PROTACs) in Sex Hormone-Dependent Cancers

et al. 2022

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Sex hormone-dependent cancers, including breast, ovary, and prostate cancer, contribute to the high number of cancer-related deaths worldwide. Steroid hormones promote tumor occurrence, development, and metastasis by acting on receptors, such as estrogen receptors (ERs), androgen receptors (ARs), and estrogen-related receptors (ERRs). Therefore, endocrine therapy targeting ERs, ARs, and ERRs represents the potential and pivotal therapeutic strategy in sex hormone-dependent cancers. Proteolysis-targeting chimeras (PROTACs) are a novel strategy that can harness the potential of the endogenous ubiquitin-proteasome system (UPS) to target and degrade specific proteins, rather than simply inhibiting the activity of target proteins. Small molecule PROTACs degrade a variety of proteins in cells, mice, and humans and are an emerging approach for novel drug development. PROTACs targeting ARs, ERs, ERRs, and other proteins in sex hormone-dependent cancers have been reported and may overcome the problem of resistance to existing endocrine therapy and receptor antagonist treatments. This review briefly introduces the PROTAC strategy and summarizes the progress on the development of small molecule PROTACs targeting oncoproteins in sex hormone-dependent cancers, focusing on breast and prostate cancers.

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Section: Third-generation Controllable Protacsmentioning

confidence: 99%

Targeting Oncoproteins for Degradation by Small Molecule-Based Proteolysis-Targeting Chimeras (PROTACs) in Sex Hormone-Dependent Cancers

et al. 2022

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“…( 9) Arvinas developed the first PROTAC tested in clinical trials. Photocontrol groups were incorporated into PROTACs (Xue et al, 2019) (10) New WDR5 targeting PROTACS were designed based on existing WDR5 ligands (Poso 2021), and folate based PROTACs were released to specifically deliver PROTACs in a controllable manner to degrade the POI, thus eliminating potential unwanted toxicity to normal tissues (Liu et al, 2021c).…”

Section: Introductionmentioning

confidence: 99%

Options to Improve the Action of PROTACs in Cancer: Development of Controlled Delivery Nanoparticles

Juan¹,

Noblejas-López

Arenas-Moreira³

et al. 2022

Front. Cell Dev. Biol.

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Classical targeting in cancer focuses on the development of chemical structures able to bind to protein pockets with enzymatic activity. Some of these molecules are designed to bind the ATP side of the kinase domain avoiding protein activation and the subsequent oncogenic activity. A further improvement of these agents relies on the generation of non-allosteric inhibitors that once bound are able to limit the kinase function by producing a conformational change at the protein and, therefore, augmenting the antitumoural potency. Unfortunately, not all oncogenic proteins have enzymatic activity and cannot be chemically targeted with these types of molecular entities. Very recently, exploiting the protein degradation pathway through the ubiquitination and subsequent proteasomal degradation of key target proteins has gained momentum. With this approach, non-enzymatic proteins such as Transcription Factors can be degraded. In this regard, we provide an overview of current applications of the PROteolysis TArgeting Chimeras (PROTACs) compounds for the treatment of solid tumours and ways to overcome their limitations for clinical development. Among the different constraints for their development, improvements in bioavailability and safety, due to an optimized delivery, seem to be relevant. In this context, it is anticipated that those targeting pan-essential genes will have a narrow therapeutic index. In this article, we review the advantages and disadvantages of the potential use of drug delivery systems to improve the activity and safety of PROTACs.

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“…In order to reduce cell toxicity as the off-target effect caused by PROTACs, various strategies allowing the localized activation of these drugs have been devised. The spatiotemporal regulation of PROTAC’s activity can be obtained by the use of photocage or photo-switch technologies aimed at creating molecules with light-dependent activation [ 44 ]. This is the case of photocaged PROTACs (pc-PROTACs), drugs owning photocaged groups that, on the one hand, prevent the formation of the ternary complex and, on the other hand, can be removed by the irradiation with light of a suitable wavelength.…”

Section: Introductionmentioning

confidence: 99%

“…This is the case of photocaged PROTACs (pc-PROTACs), drugs owning photocaged groups that, on the one hand, prevent the formation of the ternary complex and, on the other hand, can be removed by the irradiation with light of a suitable wavelength. These PROTACs are thus rapidly activated to degrade POIs upon irradiation with UV light [ 44 ]. In this regard, Xue et al designed a pc-PROTAC, called pc-PROTAC1, which aimed to enhance the degradation of the BET protein BRD4 through the release of dBET1 upon irradiation with light at 365 nm of wavelength [ 45 ].…”

Section: Introductionmentioning

confidence: 99%

“…One of the major issues of the described technology is the irreversible activation of PROTACs upon light irradiation, with the process of protein degradation ending upon the drug’s clearance. As a possible solution, various groups have developed PROTAC molecules combined with photo-switches that can be reversibly activated and inactivated by light exposure [ 44 ]. Examples of this approach are photo-PROTACs, molecules featured by photo-switchable activation by the insertion of an azobenzene group in the linker structure.…”

Section: Introductionmentioning

confidence: 99%

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Proteolysis Targeting Chimeric Molecules: Tuning Molecular Strategies for a Clinically Sound Listening

Pedrucci

Pappalardo

Marzaro

et al. 2022

IJMS

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From seminal evidence in the early 2000s, the opportunity to drive the specific knockdown of a protein of interest (POI) through pharmacological entities called Proteolysis Targeting Chimeric molecules, or PROTACs, has become a possible therapeutic option with the involvement of these compounds in clinical trials for cancers and autoimmune diseases. The fulcrum of PROTACs pharmacodynamics is to favor the juxtaposition between an E3 ligase activity and the POI, followed by the ubiquitination of the latter and its degradation by the proteasome system. In the face of an apparently modular design of these drugs, being constituted by an E3 ligase binding moiety and a POI-binding moiety connected by a linker, the final structure of an efficient PROTAC degradation enhancer often goes beyond the molecular descriptors known to influence the biological activity, specificity, and pharmacokinetics, requiring a rational improvement through appropriate molecular strategies. Starting from the description of the basic principles underlying the activity of the PROTACs to the evaluation of the strategies for the improvement of pharmacodynamics and pharmacokinetics and rational design, this review examines the molecular elements that have been shown to be effective in allowing the evolution of these compounds from interesting proof of concepts to potential aids of clinical interest.

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Light-Controllable PROTACs for Temporospatial Control of Protein Degradation

Cited by 22 publications

References 178 publications

Targeting Oncoproteins for Degradation by Small Molecule-Based Proteolysis-Targeting Chimeras (PROTACs) in Sex Hormone-Dependent Cancers

Targeting Oncoproteins for Degradation by Small Molecule-Based Proteolysis-Targeting Chimeras (PROTACs) in Sex Hormone-Dependent Cancers

Options to Improve the Action of PROTACs in Cancer: Development of Controlled Delivery Nanoparticles

Proteolysis Targeting Chimeric Molecules: Tuning Molecular Strategies for a Clinically Sound Listening

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