E3 ligase ligand chemistries: from building blocks to protein degraders

Sosič, Izidor; Bricelj, Aleša; Steinebach, Christian

doi:10.1039/d2cs00148a

Cited by 83 publications

(69 citation statements)

References 315 publications

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“…1B). 18,19 With the in-depth understanding of the mechanism of action of PROTAC and its great potential in biological research and disease treatment, more and more researchers have begun to pay attention to this field, and more and more targets have been proved to be capable of being used by PROTACs. According to the latest statistics in February 2022, PROTACs can induce the degradation of more than 130 target proteins, including cancer, immune disorders, viral infections, neurodegenerative diseases, etc.…”

Section: Introductionmentioning

confidence: 99%

Chemistries of bifunctional PROTAC degraders

et al. 2022

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Section: Introductionmentioning

confidence: 99%

Chemistries of bifunctional PROTAC degraders

et al. 2022

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“…Firstly, CRBN and VHL are widely and abundantly expressed in multiple tumor cells, which guarantees the degradation efficiencies of CRBN- and VHL-based PROTACs. Secondly, CRBN and VHL ligands are easy to synthesize, and their molecule weights are relatively low, exhibiting good drug-like properties [ 30 ]. Finally, the safety and biocompatibility of these two kinds of ligands have been extensively evaluated in vivo.…”

Section: Introductionmentioning

confidence: 99%

Small-Molecule PROTACs for Cancer Immunotherapy

Liu¹,

Zhang²,

Xiang³

et al. 2022

Molecules

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Unsatisfactory physicochemical properties of macromolecular drugs seriously hinder their application in tumor immunotherapy. However, these problems can be effectively solved by small-molecule compounds. In the promising field of small-molecule drug development, proteolysis targeting chimera (PROTAC) offers a Cancer Patients. Bosn. J. Basic novel mode of action in the interactions between small molecules and therapeutic targets (mainly proteins). This revolutionary technology has shown considerable impact on several proteins related to tumor survival but is rarely exploited in proteins associated with immuno-oncology up until now. This review attempts to comprehensively summarize the well-studied and less-developed immunological targets available for PROTAC technology, as well as some targets to be explored, aiming to provide more options and opportunities for the development of small-molecule-based tumor immunotherapy. In addition, some novel directions that can magnify and broaden the protein degradation efficiency are mentioned to improve PROTAC design in the future.

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“…This is especially true for transcription factors (TFs), which generally contain unstructured domains and lack obvious “ligandable” pockets ( 6, 7 ). Additionally, the development of PROTACs requires substantial synthetic efforts to test various combinations of recruited ubiquitin E3 ligases and linkers that are optimal for forming a ternary complex of the PROTAC, POI, and ubiquitin E3 ligase ( 8 ). Other elegant degradation platforms, including the degradation tag system ( 9 ) and transcription factor targeting chimeras (TRAFTACs) ( 10 ), have been developed for difficult protein targets.…”

Section: Main Textmentioning

confidence: 99%

A cell-permeant nanobody-based degrader that induces fetal hemoglobin

Shen

Setegne

et al. 2022

Preprint

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Proximity-based strategies to degrade proteins have enormous therapeutic potential in medicine, but the technologies are limited to proteins for which small molecule ligands exist. The identification of such ligands for therapeutically relevant but undruggable proteins remains challenging. Herein, we employed yeast surface display of synthetic nanobodies to identify a protein ligand selective for BCL11A, a critical repressor of fetal globin gene transcription. Fusion of the nanobody to a cell-permeant miniature protein and an E3 adaptor creates a degrader that depletes cellular BCL11A in erythroid precursor cells, thereby inducing the expression of fetal hemoglobin, a modifier of clinical severity of sickle cell disease and beta-thalassemia. This work establishes a new paradigm for the targeted degradation of previously intractable proteins using cell-permeant nanobody-based degraders.

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E3 ligase ligand chemistries: from building blocks to protein degraders

Abstract: This review comprehensively illustrates chemistries of E3 ligase ligands, which were used successfully in the development of PROTACs.

Cited by 83 publications

References 315 publications

Chemistries of bifunctional PROTAC degraders

Chemistries of bifunctional PROTAC degraders

Small-Molecule PROTACs for Cancer Immunotherapy

A cell-permeant nanobody-based degrader that induces fetal hemoglobin

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