A Cell-Based Target Engagement Assay for the Identification of Cereblon E3 Ubiquitin Ligase Ligands and Their Application in HDAC6 Degraders

Yang, Kuo‐Ho; Zhao, Yu; Nie, Xueqing; Wu, Hao; Wang, Bo; Almodovar-Rivera, Chelsi M.; Xie, Haibo; Tang, Weiping

doi:10.1016/j.chembiol.2020.04.008

Cited by 64 publications

(57 citation statements)

References 44 publications

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“…Despite their wide use, one limitation of IMiD-based PROTACs is their ability to induce off-target degradation via neo-substrate recruitment to CRBN (Chamberlain and Hamann, 2019;Ishoey et al, 2018). However, the development of thalidomide analogues that are incapable of inducing neo-substrate degradation will be an interesting avenue to explore in refining CRBN-based PROTAC selectivity (Yang et al, 2020). IAP The E3 ligase cellular IAPs (cIAPs) were recruited to cellular retinoic acid-binding proteins I (CRABPI) and CRABPII and induced their proteasomal degradation by a PROTAC composed of bestatin esters and all-trans-retinoic acid (Itoh et al, 2010;Naito et al, 2019).…”

Section: Expanding the Scope Of Chemically Tractable E3 Ligasesmentioning

confidence: 99%

PROTACs: An Emerging Therapeutic Modality in Precision Medicine

Nalawansha

Crews

2020

Cell Chemical Biology

290

217

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Targeted protein degradation (TPD) has emerged as an exciting new era in chemical biology and drug discovery. PROteolysis TArgeting Chimera (PROTAC) technology targets cellular proteins for degradation by co-opting the ubiquitin-proteasome system. Over the last 5 years, numerous studies have expanded our understanding of the unique mode of action and advantages of PROTACs, which has in turn spurred interest in both academia and industry to explore PROTACs as a novel therapeutic strategy. In this review, we first highlight the key advantages of PROTACs and then discuss the spatiotemporal regulation of protein degradation. Next, we explore current chemically tractable E3 ligases focusing on expanding the existing repertoire with novel E3 ligases to uncover the full potential of TPD. Collectively, these studies are guiding the development of the PROTAC technology as it emerges as a new modality in precision medicine. ll

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Section: Expanding the Scope Of Chemically Tractable E3 Ligasesmentioning

confidence: 99%

PROTACs: An Emerging Therapeutic Modality in Precision Medicine

Nalawansha

Crews

2020

Cell Chemical Biology

290

217

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“…While dHDAC6 demonstrated efficient degradation of HDAC6 in MCF-7 breast cancer cells, the multiple myeloma cell line MM.1S was more sensitive to dHDAC6 in regard to degradation of HDAC6 [278,279]. Since the initial report by Yang et al, several other HDAC degraders have been disclosed, including selective HDAC6 PROTACs [256,[279][280][281][282][283], class I-selective PRO-TACs [284][285][286] and HDAC3-selective degraders [287]. Although most work has focused on hematological cancers so far, there are some encouraging results indicating that HDAC PROTACs could be an innovative new option for the treatment of solid cancers.…”

Section: Protacsmentioning

confidence: 99%

Anticancer Therapy with HDAC Inhibitors: Mechanism-Based Combination Strategies and Future Perspectives

Jenke

Reßing

Hansen

et al. 2021

Cancers

117

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The increasing knowledge of molecular drivers of tumorigenesis has fueled targeted cancer therapies based on specific inhibitors. Beyond “classic” oncogene inhibitors, epigenetic therapy is an emerging field. Epigenetic alterations can occur at any time during cancer progression, altering the structure of the chromatin, the accessibility for transcription factors and thus the transcription of genes. They rely on post-translational histone modifications, particularly the acetylation of histone lysine residues, and are determined by the inverse action of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Importantly, HDACs are often aberrantly overexpressed, predominantly leading to the transcriptional repression of tumor suppressor genes. Thus, histone deacetylase inhibitors (HDACis) are powerful drugs, with some already approved for certain hematological cancers. Albeit HDACis show activity in solid tumors as well, further refinement and the development of novel drugs are needed. This review describes the capability of HDACis to influence various pathways and, based on this knowledge, gives a comprehensive overview of various preclinical and clinical studies on solid tumors. A particular focus is placed on strategies for achieving higher efficacy by combination therapies, including phosphoinositide 3-kinase (PI3K)-EGFR inhibitors and hormone- or immunotherapy. This also includes new bifunctional inhibitors as well as novel approaches for HDAC degradation via PROteolysis-TArgeting Chimeras (PROTACs).

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“…The CRBN component of this complex targets proteins for degradation via a ubiquitin-proteasome pathway, ultimately decreasing neuronal excitotoxicity and metabolic dysfunction when used to target dysfunctional proteins in the neural environment ( Shi and Chen, 2017 ). IMiDs are known to recruit several neo-substrates of CRBN to the E3 ubiquitin ligase complex, and this results in the diverse biological and pharmacological actions of IMiDs ( Lu et al, 2015 ; Winter et al, 2015 ; Donoghue et al, 2020 ; Yang et al, 2020 ; Figure 1 ). In particular, this CRBN-binding capability underlies the actions of IMiDs in the treatment of multiple myeloma.…”

Section: Immunomodulatory Imide Drugs (Imids)mentioning

confidence: 99%

Repurposing Immunomodulatory Imide Drugs (IMiDs) in Neuropsychiatric and Neurodegenerative Disorders

et al. 2021

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Neuroinflammation represents a common trait in the pathology and progression of the major psychiatric and neurodegenerative disorders. Neuropsychiatric disorders have emerged as a global crisis, affecting 1 in 4 people, while neurological disorders are the second leading cause of death in the elderly population worldwide (WHO, 2001; GBD 2016 Neurology Collaborators, 2019). However, there remains an immense deficit in availability of effective drug treatments for most neurological disorders. In fact, for disorders such as depression, placebos and behavioral therapies have equal effectiveness as antidepressants. For neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease, drugs that can prevent, slow, or cure the disease have yet to be found. Several non-traditional avenues of drug target identification have emerged with ongoing neurological disease research to meet the need for novel and efficacious treatments. Of these novel avenues is that of neuroinflammation, which has been found to be involved in the progression and pathology of many of the leading neurological disorders. Neuroinflammation is characterized by glial inflammatory factors in certain stages of neurological disorders. Although the meta-analyses have provided evidence of genetic/proteomic upregulation of inflammatory factors in certain stages of neurological disorders. Although the mechanisms underpinning the connections between neuroinflammation and neurological disorders are unclear, and meta-analysis results have shown high sensitivity to factors such as disorder severity and sample type, there is significant evidence of neuroinflammation associations across neurological disorders. In this review, we summarize the role of neuroinflammation in psychiatric disorders such as major depressive disorder, generalized anxiety disorder, post-traumatic stress disorder, and bipolar disorder, as well as in neurodegenerative disorders, such as Parkinson’s disease and Alzheimer’s disease, and introduce current research on the potential of immunomodulatory imide drugs (IMiDs) as a new treatment strategy for these disorders.

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A Cell-Based Target Engagement Assay for the Identification of Cereblon E3 Ubiquitin Ligase Ligands and Their Application in HDAC6 Degraders

Cited by 64 publications

References 44 publications

PROTACs: An Emerging Therapeutic Modality in Precision Medicine

PROTACs: An Emerging Therapeutic Modality in Precision Medicine

Anticancer Therapy with HDAC Inhibitors: Mechanism-Based Combination Strategies and Future Perspectives

Repurposing Immunomodulatory Imide Drugs (IMiDs) in Neuropsychiatric and Neurodegenerative Disorders

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