Discovery of Small Molecules that Induce the Degradation of Huntingtin

Tomoshige, Shusuke; Nomura, Shōichiro; Ohgane, Kenji; Hashimoto, Yuichi; Ishikawa, Minoru

doi:10.1002/anie.201706529

Cited by 98 publications

(69 citation statements)

References 30 publications

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“…Proteolysis targeting chimera (PROTAC) can lower specific protein levels with small molecules PROTAC-based approaches utilise bifunctional molecules to simultaneously bind both the protein of interest and a ubiquitin E3 ligase to promote the ubiquitylation and degradation of the target molecule [132,133] by bringing the target protein and E3 ligase into proximity. Recently, a PROTAC-based series of molecules has been described for selective ubiquitylation and then degradation of mHTT via the UPS [134] . Hybrid molecules that link a ligand for cIAP1 (cellular inhibitor of apoptosis protein 1) E3 ligase to ligands for mHTT were shown to selectively reduce levels of mHTT through E3 ligase recruitment and proteasome degradation pathways in HD patientderived fibroblasts.…”

Section: Therapeutic Approaches In Hd Targeting Upsmentioning

confidence: 99%

Proteostasis in Huntington's disease: disease mechanisms and therapeutic opportunities

Harding

Tong

2018

Acta Pharmacol Sin

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Many neurodegenerative diseases are characterized 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 new 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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Section: Therapeutic Approaches In Hd Targeting Upsmentioning

confidence: 99%

Proteostasis in Huntington's disease: disease mechanisms and therapeutic opportunities

Harding

Tong

2018

Acta Pharmacol Sin

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“…Secondly, chemical protein knockdown may be applied to various proteins, including undruggable proteins, if their ligands are identified. In fact, chemical protein knockdown of targets such as CRABP, huntingtin, and Tau proteins, which are impossible to be modulated by inhibitors, agonists, antagonists, or PPI inhibitors, has already been successful ,,. Thus, this approach may extend the range of therapeutic targets.…”

Section: Discussionmentioning

confidence: 99%

Chemical Protein Degradation Approach and its Application to Epigenetic Targets

Itoh

2018

The Chemical Record

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In addition to traditional drugs, such as enzyme inhibitors, receptor agonists/antagonists, and protein-protein interaction inhibitors as well as genetic technology, such as RNA interference and the CRISPR/Cas9 system, protein knockdown approaches using proteolysis-targeting chimeras (PROTACs) have attracted much attention. PROTACs, which induce selective degradation of their target protein via the ubiquitin-proteasome system, are useful for the down-regulation of various proteins, including disease-related proteins and epigenetic proteins. Recent reports have shown that chemical protein knockdown is possible not only in cells, but also in vivo and this approach is expected to be used as the therapeutic strategy for several diseases. Thus, this approach may be a significant technique to complement traditional drugs and genetic ablation and will be more widely used for drug discovery and chemical biology studies in the future. In this personal account, a history of chemical protein knockdown is introduced, and its features, recent progress in the epigenetics field, and future outlooks are discussed.

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“…60,61) Since this methodology was successful, it has been widely used and applied to target several proteins. [62][63][64][65][66][67] In addition, not only IAP ligands but also other E3 ligands have been used for protein knockdown, [68][69][70][71] where some of them are especially adaptable to in vivo studies or to the clinical trial stages. 44,63,[72][73][74] Thus, our drug discovery studies on ubiquitination inducers have driven the establishment of protein degradation approach using small molecules.…”

Section: Ubiquitination Modulators and Their Applicationmentioning

confidence: 99%

Drug Discovery Researches on Modulators of Lysine-Modifying Enzymes Based on Strategic Chemistry Approaches

Itoh

2020

CHEMICAL & PHARMACEUTICAL BULLETIN

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Enzymatic and post-translational modifications (PTMs) such as ubiquitination, acetylation, and methylation occur at lysine residues. The PTMs play critical roles in the regulation of the protein functions, and thus, various cellular processes. In addition, aberrations of the PTMs are associated with various diseases, such as cancer and neurodegenerative disorders. Therefore, we hypothesized that modulation of the PTMs and normalization of the PTM abnormalities could be useful as methods to control various cellular mechanisms and as a therapeutic strategy, respectively. To modulate the PTMs, we have focused on lysine-modifying enzymes and have pursued drug discovery researches on ubiquitination inducers, lysine deacetylase (KDAC) inhibitors, and lysine demethylase (KDM) inhibitors. For the identification of the modulators, we have used not only conventional drug design, such as structure-based drug design (SBDD) and ligand-based drug design (LBDD), but also "strategic chemistry approaches," such as drug design based on enzyme catalytic mechanism. As a result, we have identified several modulators which have pharmacological effects in animal models or in cellular studies. In this review, focusing on the drug design based on enzyme catalytic mechanism, our drug discovery researches have been discussed.

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Discovery of Small Molecules that Induce the Degradation of Huntingtin

Cited by 98 publications

References 30 publications

Proteostasis in Huntington's disease: disease mechanisms and therapeutic opportunities

Proteostasis in Huntington's disease: disease mechanisms and therapeutic opportunities

Chemical Protein Degradation Approach and its Application to Epigenetic Targets

Drug Discovery Researches on Modulators of Lysine-Modifying Enzymes Based on Strategic Chemistry Approaches

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