Development of target protein-selective degradation inducer for protein knockdown

Itoh, Yukihiro; Ishikawa, Minoru; Kitaguchi, Risa; Sato, Shinichi; Naito, Mikihiko; Hashimoto, Yuichi

doi:10.1016/j.bmc.2011.03.057

Cited by 75 publications

(60 citation statements)

References 35 publications

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“…However, the utility of SNIPER-based protein degradation is limited due to off-target binding of bestatin (Umezawa et al, 1976; Orning et al, 1991) and the induction of autoubiquitination and subsequent degradation of the cIAP1 E3 itself (Sekine et al, 2008). Ligand optimization of the cIAP1 recruiting moiety bestatin has reduced cIAP1 autoubiquitination (Itoh et al, 2011a), but their efficacy remained in the micromolar range. Thus far, SNIPERs have successfully degraded multiple cellular targets, e.g., Cellular Retinoic Acid-Binding Protein I (CRABPI) and CRABPII (Itoh et al, 2010; Itoh et al, 2012; Okuhira et al, 2017), ERα (Itoh et al, 2011b; Demizu et al, 2012; Okuhira et al, 2013), the spindle regulatory protein Transforming Acidic Coiled-Coil-3 (TACC3) (Ohoka et al, 2014), the Breakpoint Cluster Region-Abelson tyrosine kinase (BCR-ABL) (Demizu et al, 2016) and various HaloTag fusion proteins (Tomoshige et al, 2016).…”

Section: Targeted Proteasomal Degradationmentioning

confidence: 99%

Targeted Protein Degradation: from Chemical Biology to Drug Discovery

Cromm

Crews

2017

Cell Chemical Biology

297

256

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Traditional pharmaceutical drug discovery is almost exclusively focused on directly controlling protein activity to cure diseases. Modulators of protein activity, especially inhibitors, are developed and applied at high concentration to achieve maximal effects. Thereby, reduced bioavailability and off-target effects can hamper compound efficacy. Nucleic acid-based strategies that control protein function by affecting expression have emerged as an alternative. However, metabolic stability and broad bioavailability represent development hurdles that remain to be overcome for these approaches. More recently, utilizing the cell’s own protein destruction machinery for selective degradation of essential drivers of human disorders has opened up a new and exciting area of drug discovery. Small molecule-induced proteolysis of selected substrates offers the potential of reaching beyond the limitations of the current pharmaceutical paradigm to expand the druggable target space.

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Section: Targeted Proteasomal Degradationmentioning

confidence: 99%

Targeted Protein Degradation: from Chemical Biology to Drug Discovery

Cromm

Crews

2017

Cell Chemical Biology

297

256

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“…To avoid the concomitant autoubiquitination and degradation of cIAP promoted by bestatin ester derivatives, the amide-linked SNIPER cmpd 6 was developed to retain cIAP binding but abolish autodegradation [30]. SNIPER cmpd 6 promoted depletion of CRABP-II from 1 µM in cells with no effect on cIAP levels or apparent inhibition of cIAP endogenous function.…”

Section: Hijacking E3 Ligases For Specific Target Degradation Using Bmentioning

confidence: 99%

Chemical approaches to targeted protein degradation through modulation of the ubiquitin–proteasome pathway

Collins

Wang

Caldwell

et al. 2017

Biochemical Journal

125

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Manipulation of the ubiquitin–proteasome system to achieve targeted degradation of proteins within cells using chemical tools and drugs has the potential to transform pharmacological and therapeutic approaches in cancer and other diseases. An increased understanding of the molecular mechanism of thalidomide and its analogues following their clinical use has unlocked small-molecule modulation of the substrate specificity of the E3 ligase cereblon (CRBN), which in turn has resulted in the advancement of new immunomodulatory drugs (IMiDs) into the clinic. The degradation of multiple context-specific proteins by these pleiotropic small molecules provides a means to uncover new cell biology and to generate future drug molecules against currently undruggable targets. In parallel, the development of larger bifunctional molecules that bring together highly specific protein targets in complexes with CRBN, von Hippel–Lindau, or other E3 ligases to promote ubiquitin-dependent degradation has progressed to generate selective chemical compounds with potent effects in cells and in vivo models, providing valuable tools for biological target validation and with future potential for therapeutic use. In this review, we survey recent breakthroughs achieved in these two complementary methods and the discovery of new modes of direct and indirect engagement of target proteins with the proteasome. We discuss the experimental characterisation that validates the use of molecules that promote protein degradation as chemical tools, the preclinical and clinical examples disclosed to date, and the future prospects for this exciting area of chemical biology.

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“…It should also be noted that targeting cIAP1 targetting by using bestatin in PROTAC design has been highlighted as problematic due to bestatin causing the degradation of cIAP1 which can in turn trigger apoptosis. Switching the linker of bestatin in the PROTAC design from an ester to an amide, reduces cIAP1 degradation in some systems evaluated although this mechanism is currently not understood and the molecules showed similar affinity for cIAP1 130 . Numerous PROTAC examples illustrate the importance of exploring different linker designs to connect the two functional groups whilst maintaining the desired target protein degradation and further exploration is warranted for HTT-degrading PROTACs too 131,132 .…”

Section: Proteolysis Targeting Chimera (Protac)mentioning

confidence: 99%

Proteostasis in Huntington’s Disease: Disease Mechanisms and Therapeutic Opportunities

Harding

Tong

2018

Preprint

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Abstract:Many neurodegenerative diseases are characterised by impairment of protein quality control mechanisms in neuronal cells. Ineffective clearance of misfolded proteins by the proteasome, autophagy pathways and exocytosis leads to accumulation of toxic protein oligomers and aggregates in neurons.Toxic protein species affect various cellular functions resulting in the development of a spectrum of different neurodegenerative proteinopathies, including Huntington's disease (HD). Playing an integral role in proteostasis, dysfunction of the ubiquitylation system in HD is progressive and multi-faceted with numerous biochemical pathways affected, in particular the ubiquitin proteasome system and autophagy routes for protein aggregate degradation. Unravelling the molecular mechanisms involved in HD pathogenesis of proteostasis provides insight in disease progression in HD as well as possible therapeutic avenues. Recent developments of potential therapeutics are discussed in this review.

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Development of target protein-selective degradation inducer for protein knockdown

Cited by 75 publications

References 35 publications

Targeted Protein Degradation: from Chemical Biology to Drug Discovery

Targeted Protein Degradation: from Chemical Biology to Drug Discovery

Chemical approaches to targeted protein degradation through modulation of the ubiquitin–proteasome pathway

Proteostasis in Huntington’s Disease: Disease Mechanisms and Therapeutic Opportunities

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Development of target protein-selective degradation inducer for protein knockdown

Cited by 75 publications

References 35 publications

Targeted Protein Degradation: from Chemical Biology to Drug Discovery

Targeted Protein Degradation: from Chemical Biology to Drug Discovery

Chemical approaches to targeted protein degradation through modulation of the ubiquitin–proteasome pathway

Proteostasis in Huntington&rsquo;s Disease: Disease Mechanisms and Therapeutic Opportunities

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Product

Resources

About

Proteostasis in Huntington’s Disease: Disease Mechanisms and Therapeutic Opportunities