A synthetic KLHL20 ligand to validate CUL3KLHL20 as a potent E3 ligase for targeted protein degradation

Farrell, Brian M, Gerth, Fabian, Yang, Cheng-Hao R, Yeh, Johannes T-H (September 2022) A synthetic KLHL20 ligand to validate CUL3KLHL20 as a potent E3 ligase for targeted protein degradation. Genes and Development, 36 (17-18). pp. 1031-1042. ISSN 0890-9369

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Abstract

Targeted protein degradation (TPD) has risen as a promising therapeutic modality. Leveraging the catalytic nature of the ubiquitin-proteasome enzymatic machinery, TPD exhibits higher potency to eliminate disease-causing target proteins such as oncogenic transcription factors that may otherwise be difficult to abrogate by conventional inhibitors. However, there are challenges that remain. Currently, nearly all degraders engage CUL4CRBN or CUL2VHL as the E3 ligase for target ubiquitination. While their immediate efficacies are evident, the narrowed E3 ligase options make TPD vulnerable to potential drug resistance. In addition, E3 ligases show differential tissue expression and have intrinsic limitations in accessing varying types of disease-relevant targets. As the success of TPD is closely associated with the ability of E3 ligases to efficiently polyubiquitinate the target of interest, the long-term outlook of TPD drug development will depend on whether E3 ligases such as CUL4CRBN and CUL2VHL are accessible to the targets of interest. To overcome these potential caveats, a broad collection of actionable E3 ligases is required. Here, we designed a macrocyclic degrader engaging CUL3KLHL20 for targeting BET proteins and validated CUL3KLHL20 as an E3 ligase system suitable for TPD. This work thus contributes to the expansion of usable E3 ligases for potential drug development.

Item Type:	Paper
Subjects:	bioinformatics bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification bioinformatics > genomics and proteomics > small molecules > cofactors bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes bioinformatics > genomics and proteomics > small molecules > cofactors > ligands bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein ubiquitination bioinformatics > genomics and proteomics > small molecules bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > ubiquitin ligase
CSHL Authors:	Yeh, Johannes Farrell, Brian Yang Cheng Hao Gerth Fabian
Communities:	CSHL labs > Yeh Lab CSHL Cancer Center Program CSHL Cancer Center Program > Cellular Communication in Cancer Program CSHL Cancer Center Shared Resources > Antibody and Phage Display Service CSHL Cancer Center Shared Resources > Mass Spectrometry Service CSHL Cancer Center Shared Resources > Proteomics Service
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	1 September 2022
Date Deposited:	09 Nov 2022 21:38
Last Modified:	09 Feb 2024 18:42
PMCID:	PMC9732910
URI:	https://repository.cshl.edu/id/eprint/40753

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