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Targeting Cullin-RING Ubiquitin Ligases and the Applications in PROTACs

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Cullin-RING Ligases and Protein Neddylation

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1217))

Abstract

Cullin-RING ligases (CRLs), the largest family of E3 ubiquitin ligases, have become an attractive target for drug discovery, primarily due to their ability to regulate the degradation of numerous functionally and structurally diverse proteins, thereby controlling a myriad of biological processes. As the abnormal expressions of CRLs and their substrate proteins are associated with human diseases, elucidating their roles in these physiological and pathological processes will facilitate CRL-targeting drug development for the treatment of these diseases. Notably, these studies are also providing new concepts for the design of potential small-molecule therapeutics targeting CRLs and for the use of CRLs to degrade “undruggable” proteins. In this chapter, we systematically review the development of small molecules that target CRLs and especially emphasize the applications of CRLs in a chemical chimera for protein degradation, termed proteolysis-targeting chimeras (PROTACs).

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Abbreviations

A3G:

APOBEC3G

AD:

Alzheimer’s disease

AML:

Acute myeloid leukemia

AR:

Androgen receptor

BTK:

Bruton’s tyrosine kinase

BTZ:

Bortezomib

CAND1:

Cullin-associated and neddylation-dissociated-1

CDK9:

Cyclin-dependent kinase 9

COI1:

Coronatine-insensitive protein 1

CRBN:

Cereblon

CRL:

Cullin-RING ligase

CRPC:

Castration-resistant prostate cancer

DHT:

Dihydrotestosterone

E2:

Ubiquitin-conjugating enzyme

E3:

Ubiquitin ligase

ER:

Estrogen receptor

ERRα:

Estrogen-related receptor alpha

GCN5:

General control nonderepressible 5

HBV:

Hepatitis B virus

HBX:

X protein of HBV

HDAC:

Histone deacetylase

HIF1α:

Hypoxia-inducible factor 1α

KEAP1:

Kelch-like ECH-associated protein 1

NAE:

NEDD8 activating enzyme

NEDD8:

Neural precursor cell expressed, developmentally downregulated 8

NHL:

Non-Hodgkin’s lymphoma

PCAF:

P300/CBP-associated factor

POI:

Protein of interest

PPI:

Protein-protein interaction

PROTAC:

Proteolysis-targeting chimeric molecule

SAR:

Structure-activity relationship

SCF:

Skp1-CUL1-F-box

SMER:

Small-molecule enhancer of rapamycin

Ub:

Ubiquitin

UPS:

Ubiquitin proteasome system

VHL:

von Hippel-Lindau protein

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Funding

This work was supported by the National Key R&D Program of China (2016YFA0501800 to Y.Z. and X.X.), the National Natural Science Foundation of China (81672728, 81972591, and 81721091 to Y.Z. and 81572708 and 81974429 to X.X.), and the Natural Science Foundation of Zhejiang Province (LR16C050001 to Y.Z.).

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Authors and Affiliations

  1. Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Longyuan Gong, Danrui Cui & Yongchao Zhao

  2. Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China

    Longyuan Gong, Danrui Cui, Xiufang Xiong & Yongchao Zhao

  3. Cancer Institute of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Xiufang Xiong

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  1. Longyuan Gong
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  2. Danrui Cui
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  3. Xiufang Xiong
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  4. Yongchao Zhao
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Correspondence to Xiufang Xiong or Yongchao Zhao .

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Editors and Affiliations

  1. Radiation Oncology, University of Michigan, Ann Arbor, MI, USA

    Yi Sun

  2. Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Wenyi Wei

  3. Life Science Institute, Zhejiang University, Hangzhou, China

    Jianping Jin

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Gong, L., Cui, D., Xiong, X., Zhao, Y. (2020). Targeting Cullin-RING Ubiquitin Ligases and the Applications in PROTACs. In: Sun, Y., Wei, W., Jin, J. (eds) Cullin-RING Ligases and Protein Neddylation. Advances in Experimental Medicine and Biology, vol 1217. Springer, Singapore. https://doi.org/10.1007/978-981-15-1025-0_19

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