Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models

Silva, M. Catarina; Ferguson, Fleur M.; Cai, Quan; Donovan, Katherine A.; Nandi, Ghata; Patnaik, Debasis; Zhang, Tinghu; Huang, Hai‐Tsang; Lucente, Diane; Dickerson, Bradford C.; Mitchison, Timothy J.; Fischer, Eric S.; Gray, Nathanael S.; Haggarty, Stephen J.

doi:10.7554/elife.45457

Cited by 201 publications

(183 citation statements)

References 96 publications

Supporting

Mentioning

162

Contrasting

Unclassified

Order By: Relevance

“…Recently, an application of PROTAC combined with position emission tomography (PET) tracers, which are useful tools for the diagnosis of tauopathies, was reported [77]. The most clinically advanced tau PET tracer ( 18 F-T807 or 18 F-AV-1451) was coupled via linkers to pomalidomide.…”

Section: Tau-protacsmentioning

confidence: 99%

PROTACs– a game-changing technology

Konstantinidou

Zhang

et al. 2019

Expert Opinion on Drug Discovery

121

109

View full text Add to dashboard Cite

Introduction: Proteolysistargeting chimeras (PROTACs) have emerged as a new modality with the potential to revolutionize drug discovery. PROTACs are heterobifunctional molecules comprising of a ligand targeting a protein of interest, a ligand targeting an E3 ligase and a connecting linker. The aim is instead of inhibiting the target to induce its proteasomal degradation. Areas covered: PROTACs, due to their bifunctional design, possess properties that differentiate them from classical inhibitors. A structural analysis, based on published crystal aspects, kinetic features and aspects of selectivity are discussed. Specific types such as homoPROTACs, PROTACs targeting Tau protein and the first PROTACs recently entering clinical trials are examined. Expert opinion: PROTACs have shown remarkable biological responses in challenging targets, including an unprecedented selectivity over protein family members and even efficacy starting from weak or unspecific binders. Moreover, PROTACs are standing out from classical pharmacology by inducing the degradation of the target protein and not merely its inhibition. However, there are also challenges in the field, such as the rational structure optimization, the evolution of computational tools, limited structural data and the greatly anticipated clinical data. Despite the remaining hurdles, PROTACs are expected to soon become a new therapeutic category of drugs.

show abstract

Section: Tau-protacsmentioning

confidence: 99%

PROTACs– a game-changing technology

Konstantinidou

Zhang

et al. 2019

Expert Opinion on Drug Discovery

121

109

View full text Add to dashboard Cite

show abstract

“…CRBN or Cereblon ( FDR = 0.003) is known to play a role in memory and learning and it has been previously associated with mental retardation [72]. It is also used in ubiquitination/proteasomal degradation of Tau [58] which could be relevant for Alzheimer disease [23]. MYL6 only reaches significance by using our test (Bonferroni-corrected) while being under the significance threshold using Limma.…”

Section: Resultsmentioning

confidence: 99%

Finding associations in a heterogeneous setting: Statistical test for aberration enrichment

Mezlini

Das

Goldenberg

2020

Preprint

View full text Add to dashboard Cite

Most two-group statistical tests are implicitly looking for a broad pattern such as an overall shift in mean, median or variance between the two groups. Therefore, they operate best in settings where the effect of interest is uniformly affecting everyone in one group versus the other. In real-world applications, there are many scenarios where the effect of interest is heterogeneous. For example, a drug that works very well on only a proportion of patients and is equivalent to a placebo on the remaining patients, or a disease associated gene expression dysregulation that only occurs in a proportion of cases whereas the remaining cases have expression levels indistinguishable from the controls for the considered gene. In these examples with heterogeneous effect, we believe that using classical two-group statistical tests may not be the most powerful way to detect the signal. In this paper, we developed a statistical test targeting heterogeneous effects and demonstrated its power in a controlled simulation setting compared to existing methods. We focused on the problem of finding meaningful associations in complex genetic diseases using omics data such as gene expression, miRNA expression, and DNA methylation. In simulated and real data, we showed that our test is complementary to the traditionally used statistical tests and is able to detect disease-relevant genes with heterogeneous effects which would not be detectable with previous approaches.

show abstract

“…Heterobifunctional degraders have garnered attention recently due to potential advantages over traditional small molecule inhibitors, including their ability to target proteins deemed undruggable through the use of non-functional ligands (Farnaby et al, 2019;Silva et al, 2019) and to achieve selectivity with promiscuous ligands . However, one advantage of degraders that has not been fully investigated is their potential to exert long-lasting pharmacological effects.…”

Section: Discussionmentioning

confidence: 99%

Discovery of an AKT Degrader with Prolonged Inhibition of Downstream Signaling

You

Erickson

Donovan

et al. 2019

Preprint

View full text Add to dashboard Cite

The PI3K/AKT signaling cascade is one of the most commonly dysregulated pathways in cancer, with over half of tumors exhibiting aberrant AKT activation. Although potent small molecule AKT inhibitors have entered clinical trials, robust and durable therapeutic responses have not been observed. As an alternative strategy to target AKT, we report the development of INY-03-041, a pan-AKT degrader consisting of the ATP-competitive AKT inhibitor GDC-0068 conjugated to lenalidomide, a recruiter of the E3 ubiquitin ligase substrate adaptor Cereblon (CRBN). INY-03-041 induced potent degradation of all three AKT isoforms and displayed enhanced anti-proliferative effects relative to GDC-0068. Notably, INY-03-041 promoted sustained AKT degradation and inhibition of downstream signaling effects for up to 96 hours, even after compound washout. Our findings indicate that AKT degradation may confer prolonged pharmacological effects compared to inhibition, and highlight the potential advantages of AKT-targeted degradation.

show abstract

Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models

Cited by 201 publications

References 96 publications

PROTACs– a game-changing technology

PROTACs– a game-changing technology

Finding associations in a heterogeneous setting: Statistical test for aberration enrichment

Discovery of an AKT Degrader with Prolonged Inhibition of Downstream Signaling

Contact Info

Product

Resources

About