PHOTACs enable optical control of protein degradation

Reynders, Martin; Matsuura, Bryan S.; Bérouti, Marleen; Simoneschi, Daniele; Marzio, Antonio; Pagano, Michele; Trauner, Dirk

doi:10.1126/sciadv.aay5064

Cited by 207 publications

(179 citation statements)

References 69 publications

(89 reference statements)

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“…Studies on the cell viability of RS4;11 lymphoblast cells showed a significant difference in the activity of this protac upon irradiation with 390 nm light pulses for 72 h in comparison with incubations in the dark. These results were corroborated by a parallel light dependence degradation of the target BET proteins BRD2-4, as revealed by Western blot analysis [94].…”

Section: Photocontrolled Protacssupporting

confidence: 59%

The Potential of Proteolytic Chimeras as Pharmacological Tools and Therapeutic Agents

2020

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The induction of protein degradation in a highly selective and efficient way by means of druggable molecules is known as targeted protein degradation (TPD). TPD emerged in the literature as a revolutionary idea: a heterobifunctional chimera with the capacity of creating an interaction between a protein of interest (POI) and a E3 ubiquitin ligase will induce a process of events in the POI, including ubiquitination, targeting to the proteasome, proteolysis and functional silencing, acting as a sort of degradative knockdown. With this programmed protein degradation, toxic and disease-causing proteins could be depleted from cells with potentially effective low drug doses. The proof-of-principle validation of this hypothesis in many studies has made the TPD strategy become a new attractive paradigm for the development of therapies for the treatment of multiple unmet diseases. Indeed, since the initial protacs (Proteolysis targeting chimeras) were posited in the 2000s, the TPD field has expanded extraordinarily, developing innovative chemistry and exploiting multiple degradation approaches. In this article, we review the breakthroughs and recent novel concepts in this highly active discipline.

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Section: Photocontrolled Protacssupporting

confidence: 59%

The Potential of Proteolytic Chimeras as Pharmacological Tools and Therapeutic Agents

2020

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“…dBET6 [48], a linker optimized derivative of dBET1, showed more activities in BRD4 degradation and tumor growth inhibition in cells and mouse models of acute lymphoblastic leukemia. PROTAC-I-3 was derived from dBET1 with a light-switchable linker [49]. Upon irradiation, it robustly decreased BRD4 in leukemia RS4;11 cells and showed a potent anti-proliferation activity.…”

Section: Crbn-based Protacsmentioning

confidence: 99%

Proteolysis-targeting chimera (PROTAC) for targeted protein degradation and cancer therapy

2020

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Proteolysis-targeting chimera (PROTAC) has been developed to be a useful technology for targeted protein degradation. A bifunctional PROTAC molecule consists of a ligand (mostly small-molecule inhibitor) of the protein of interest (POI) and a covalently linked ligand of an E3 ubiquitin ligase (E3). Upon binding to the POI, the PROTAC can recruit E3 for POI ubiquitination, which is subjected to proteasome-mediated degradation. PROTAC complements nucleic acid-based gene knockdown/out technologies for targeted protein reduction and could mimic pharmacological protein inhibition. To date, PROTACs targeting~50 proteins, many of which are clinically validated drug targets, have been successfully developed with several in clinical trials for cancer therapy. This article reviews PROTAC-mediated degradation of critical oncoproteins in cancer, particularly those in hematological malignancies. Chemical structures, cellular and in vivo activities, pharmacokinetics, and pharmacodynamics of these PROTACs are summarized. In addition, potential advantages, challenges, and perspectives of PROTAC technology in cancer therapy are discussed.

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“…In addition, the Trauner group first developed a series of novel optical controlled PROTACs, named PHOTACs, for targeting FKBP12 with an azobenzene photoswitch, which inserted in the linker part of dFKBP-1 for proof of concept 338 (Fig. 48).…”

Section: Protacs For Treating Neurodegenerative Diseasementioning

confidence: 99%

PROTACs: great opportunities for academia and industry

Sun

Gao

Yang

et al. 2019

Sig Transduct Target Ther

431

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Although many kinds of therapies are applied in the clinic, drug-resistance is a major and unavoidable problem. Another disturbing statistic is the limited number of drug targets, which are presently only 20-25% of all protein targets that are currently being studied. Moreover, the focus of current explorations of targets are their enzymatic functions, which ignores the functions from their scaffold moiety. As a promising and appealing technology, PROteolysis TArgeting Chimeras (PROTACs) have attracted great attention both from academia and industry for finding available approaches to solve the above problems. PROTACs regulate protein function by degrading target proteins instead of inhibiting them, providing more sensitivity to drug-resistant targets and a greater chance to affect the nonenzymatic functions. PROTACs have been proven to show better selectivity compared to classic inhibitors. PROTACs can be described as a chemical knockdown approach with rapidity and reversibility, which presents new and different biology compared to other gene editing tools by avoiding misinterpretations that arise from potential genetic compensation and/or spontaneous mutations. PRTOACs have been widely explored throughout the world and have outperformed not only in cancer diseases, but also in immune disorders, viral infections and neurodegenerative diseases. Although PROTACs present a very promising and powerful approach for crossing the hurdles of present drug discovery and tool development in biology, more efforts are needed to gain to get deeper insight into the efficacy and safety of PROTACs in the clinic. More target binders and more E3 ligases applicable for developing PROTACs are waiting for exploration.

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PHOTACs enable optical control of protein degradation

Cited by 207 publications

References 69 publications

The Potential of Proteolytic Chimeras as Pharmacological Tools and Therapeutic Agents

The Potential of Proteolytic Chimeras as Pharmacological Tools and Therapeutic Agents

Proteolysis-targeting chimera (PROTAC) for targeted protein degradation and cancer therapy

PROTACs: great opportunities for academia and industry

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