Homo-PROTACs for the Chemical Knockdown of Cereblon

Steinebach, Christian; Lindner, Stefanie; Udeshi, Namrata D.; Mani, Deepak; Kehm, Hannes; Köpff, Simon; Carr, Steven A.; Gütschow, Michael; Krönke, Jan

doi:10.1021/acschembio.8b00693

Cited by 123 publications

(130 citation statements)

References 69 publications

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“…In 2018, homobifunctional PROTACs that utilize cereblon (CRBN) as the hijacked degrader and at the same time, as the protein targeted for degradation, were described, aiming at the chemical-induced CRBN degradation [71]. Two pomalidomide moieties were conjugated via linear linkers with varying length, varying hydrophobicity, and different attachment positions.…”

Section: Homo-protacsmentioning

confidence: 99%

PROTACs– a game-changing technology

Konstantinidou

Zhang

et al. 2019

Expert Opinion on Drug Discovery

121

109

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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.

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Section: Homo-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

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“…Since 2015, more and more PROTACs have been synthesized to target a broad number of cellular proteins and most of them were studied in cultured cells or animal models [57][58][59][60][61][62][63][64][65][66]. ARV-110 is an oral PROTAC that can target androgen receptor (AR) and induce AR degradation.…”

Section: Protac: the Ubiquitin-proteasome Systemmediated Degradation mentioning

confidence: 99%

Novel immunomodulatory drugs and neo-substrates

2020

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Thalidomide, lenalidomide and pomalidomide are immunomodulatory drugs (IMiDs) effective in the treatment of multiple myeloma, myelodysplastic syndrome (MDS) with deletion of chromosome 5q and other hematological malignancies. Recent studies showed that IMiDs bind to CRBN, a substrate receptor of CRL4 E3 ligase, to induce the ubiquitination and degradation of IKZF1 and IKZF3 in multiple myeloma cells, contributing to their anti-myeloma activity. Similarly, lenalidomide exerts therapeutic efficacy via inducing ubiquitination and degradation of CK1α in MDS with deletion of chromosome 5q. Recently, novel thalidomide analogs have been designed for better clinical efficacy, including CC-122, CC-220 and CC-885. Moreover, a number of neo-substrates of IMiDs have been discovered. Proteolysis-targeting chimeras (PROTACs) as a class of bi-functional molecules are increasingly used as a strategy to target otherwise intractable cellular protein. PROTACs appear to have broad implications for novel therapeutics. In this review, we summarized new generation of immunomodulatory compounds, their potential neo-substrates, and new strategies for the design of novel PROTAC drugs.

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“…Like CM11, another CRBN-based homo-PROTAC was reported, which had the potent effect of antagonism with pomalidomide. 78…”

Section: Homo-protacsmentioning

confidence: 99%