Chemically induced degradation of CK2 by proteolysis targeting chimeras based on a ubiquitin–proteasome pathway

Chen, Hong; Chen, Feihong; Liu, Nannan; Wang, Xinyi; Gou, Shaohua

doi:10.1016/j.bioorg.2018.09.005

Cited by 40 publications

(25 citation statements)

References 33 publications

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“…78 In 2018, Zhang reported their design of a PROTAC against ALK by using ALK inhibitors. 80 To date, PROTACs targeting RAR, 54 PI3K, 82 91 and TBK1 92 are also reported. They showed that the PROTACs significantly decreased cellular levels of ALK fusion proteins in different cell lines including SU-DHL-1 (lymphoma) and NCI-H2228 (lung cancer).…”

Section: Targeting Protein Kinasesmentioning

confidence: 99%

“…73 The designed PROTAC against ALL also promoted the degradation of other kinase such as PTK2, Aurora A, FER, and RPS6KA1. 80 To date, PROTACs targeting RAR, 54 PI3K, 82 CRABPI/II, 53,55 ALK4, 83 Smad3, 84 CDK9, 50,85 HDAC6, 86 Sirt2, 87 BTK, 88-90 CK2 casein kinase 2, 91 and TBK1 92 are also reported. 93 Most of the proteins are cellular located or nuclear located.…”

Section: Targeting Protein Kinasesmentioning

confidence: 99%

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The PROTAC technology in drug development

Zou

Wang

2019

Cell Biochemistry & Function

194

135

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Currently, a new technology termed PROTAC, proteolysis targeting chimera, has been developed for inducing the protein degradation by a targeting molecule. This technology takes advantage of a moiety of targeted protein and a moiety of recognizing E3 ubiquitin ligase and produces a hybrid molecule to specifically knock down a targeted protein. During the first decade, three pedigreed groups worked on the development of this technology. To date, this technology has been extended by different groups, aiming to develop new drugs against different diseases including cancers. This review summarizes the contributions of the groups for the development of PROTAC. Significance of the study This review summarized the development of the PROTAC technology for readers and also presented the author's opinions on the application of the technology in tumor therapy.

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Section: Targeting Protein Kinasesmentioning

confidence: 99%

Section: Targeting Protein Kinasesmentioning

confidence: 99%

The PROTAC technology in drug development

Zou

Wang

2019

Cell Biochemistry & Function

194

135

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“… CRBN (pomalidomide) CK2 Most promising results for n = 2. Degradation of CK2 in a dose and time-dependent manner resulting in downstream reduced phosphorylation of Akt Chen [ 107 ] 20. VHL ( 9 ) ALK n = 1 displayed the best properties.…”

Section: Overview Of Published Protac Moleculesmentioning

confidence: 99%

Bivalent Ligands for Protein Degradation in Drug Discovery

Scheepstra¹,

Hekking²,

Hijfte³

et al. 2019

Computational and Structural Biotechnology Journal

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Targeting the “undruggable” proteome remains one of the big challenges in drug discovery. Recent innovations in the field of targeted protein degradation and manipulation of the ubiquitin-proteasome system open up new therapeutic approaches for disorders that cannot be targeted with conventional inhibitor paradigms. Proteolysis targeting chimeras (PROTACs) are bivalent ligands in which a compound that binds to the protein target of interest is connected to a second molecule that binds an E3 ligase via a linker. The E3 protein is usually either Cereblon or Von Hippel-Lindau. Several examples of selective PROTAC molecules with potent effect in cells and in vivo models have been reported. The degradation of specific proteins via these bivalent molecules is already allowing for the study of biochemical pathways and cell biology with more specificity than was possible with inhibitor compounds. In this review, we provide a comprehensive overview of recent developments in the field of small molecule mediated protein degradation, including transcription factors, kinases and nuclear receptors. We discuss the potential benefits of protein degradation over inhibition as well as the challenges that need to be overcome.

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“…194 Overexpression of CK2 is relevant to occurrence of cancers. 195 In 2018, Gou and coworkers reported PROTACs targeting CK2 by conjugating a CK2 inhibitor (CX-4945) and pomalidomide 196 ( Fig. 17).…”

Section: Ck2mentioning

confidence: 99%

PROTACs: great opportunities for academia and industry

Sun

Gao

Yang

et al. 2019

Sig Transduct Target Ther

431

414

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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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Chemically induced degradation of CK2 by proteolysis targeting chimeras based on a ubiquitin–proteasome pathway

Cited by 40 publications

References 33 publications

The PROTAC technology in drug development

The PROTAC technology in drug development

Bivalent Ligands for Protein Degradation in Drug Discovery

PROTACs: great opportunities for academia and industry

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