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Review
. 2023 Sep 4;13(14):5017-5056.
doi: 10.7150/thno.78876. eCollection 2023.

Targeting cullin neddylation for cancer and fibrotic diseases

Zhang-Xu He  1   2 , Wei-Guang Yang  3 , Dan Zengyangzong  2 , Ge Gao  2 , Qian Zhang  2 , Hong-Min Liu  2 , Wen Zhao  2 , Li-Ying Ma  2   4   5
Affiliations
Review

Targeting cullin neddylation for cancer and fibrotic diseases

Zhang-Xu He et al. Theranostics. .

Abstract

Protein neddylation is a post-translational modification, and its best recognized substrates are cullin family proteins, which are the core component of Cullin-RING ligases (CRLs). Given that most neddylation pathway proteins are overactivated in different cancers and fibrotic diseases, targeting neddylation becomes an emerging approach for the treatment of these diseases. To date, numerous neddylation inhibitors have been developed, of which MLN4924 has entered phase I/II/III clinical trials for cancer treatment, such as acute myeloid leukemia, melanoma, lymphoma and solid tumors. Here, we systematically describe the structures and biological functions of the critical enzymes in neddylation, highlight the medicinal chemistry advances in the development of neddylation inhibitors and propose the perspectives concerning targeting neddylation for cancer and fibrotic diseases.

Keywords: Cancer; Cullin neddylation; Fibrotic diseases; Inhibitors.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Figure 1
Figure 1
The three-step enzymatic reaction for protein neddylation. N8, NEDD8 (neural precursor cell expressed, developmentally down-regulated 8).
Figure 2
Figure 2
(A) The overall structure of NEDD8. Reproduced with permission . Copyright 1998, American Society for Biochemistry and Molecular Biology. (B) The structure of the APPBP1-UBA3-NEDD8-ATP complex. (C) The interactions between catalytic cysteine domain of NAE and NEDD8's acidic surface. (D) The interactions between NEDD8's C-terminal tail and ATP of adenylation domain. Reproduced with permission . Copyright 2003, Cell Press.
Figure 3
Figure 3
(A) The domain structure of UBC12/UBE2F. (B) Overall structure of the APPBP1-UBA3~NEDD8(T)-NEDD8(A)-MgATP-UBC12(C111A) complex. Reproduced with permission . Copyright 2007, Nature Publishing Group. (C) Overall structure of NAEufd-UBE2Fcore compared to NAEufd-UBC12core. (D) The structural superposition of UBE2Fcore and UBC12core. (E) The interactions between NAEufd and UBE2Fcore, NAEufd and UBC12core separately. Reproduced with permission . Copyright 2009, Elsevier Inc.
Figure 4
Figure 4
(A) Ribbon representation of full-length S. cerevisiae DCN1. The PONY and UBA domains are shown in blue and red separately. Reproduced with permission . Copyright 2008, Elsevier Inc. (B) Close-up of UBC12's acetylated N terminus binding to DCN1 in cartoon. Reproduced with permission . Copyright 2011, the American Association for the Advancement of Science. (C) Overall structure of RBX1-UBC12~NEDD8-CUL1-DCN1 complex as cartoon. (D) The surface of RBX1-UBC12~NEDD8-CUL1-DCN1 complex. Reproduced with permission . Copyright 2014, Elsevier Inc.
Figure 5
Figure 5
(A) The chemical structure of MLN4924 . (B) The co-crystal structure of NAE (white), NEDD8 (green) and MLN4924 (yellow) (PDB: 3GZN) . Reproduced with permission . Copyright 2010, Elsevier Inc. (C) The chemical structure of molecule 2 .
Figure 6
Figure 6
(A) The predicted binding modes of compound 3 (green) with NAE (white) . Reproduced with permission . Copyright 2011, American Chemical Society. (B) The chemical structures of MLN4924 analogues 3-7 -.
Figure 7
Figure 7
(A) The chemical structures of sulfamoyl-substituted analogues 8-10. (B-D) The corresponding binding modes of compounds 8-10 with NAE, respectively . Reproduced with permission . Copyright 2014, American Chemical Society.
Figure 8
Figure 8
The chemical structures of natural products 11-15 -.
Figure 9
Figure 9
The chemical structures of metal-based NAE inhibitors 16-17 , .
Figure 10
Figure 10
(A) and (C) The chemical structures of FDA-approved drugs 18-19. (B) The binding modes of compound 18 (yellow) with NAE (green). Reproduced with permission . Copyright 2014, Elsevier Masson SAS. (D) The binding modes of compound 19 (yellow) with NAE (green) , . Reproduced with permission . Copyright 2018, Elsevier Masson SAS.
Figure 11
Figure 11
The chemical structures of FDA-approved drug 20 and its analogue 21 , .
Figure 12
Figure 12
The chemical structures and design strategy of chromen-based NAE inhibitors 22-24 -.
Figure 13
Figure 13
(A) The chemical structures of benzothiazole derivatives 25-26. (B) Docking modes of analogues 25 (B) and 26 (C) with NAE . Reproduced with permission . Copyright 2017, Elsevier Masson SAS.
Figure 14
Figure 14
(A) The chemical structures and design strategy of indole-based NAE inhibitors 27-28. (B) Docking modes of compound 28 with NAE. Reproduced with permission . Copyright 2020, Elsevier Ltd. (C) The chemical structure of indole-based NAE inhibitor 29. (D) Docking modes of compound 29 with NAE , . Reproduced with permission . Copyright 2020, Elsevier Inc.
Figure 15
Figure 15
(A) The chemical structure of urea derivative-based NAE inhibitor 30. (B) Docking modes of compound 30 with NAE . Reproduced with permission . Copyright 2021, Elsevier B.V.
Figure 16
Figure 16
The chemical structures of NAE activators 31-32 , .
Figure 17
Figure 17
(A) The crystal structure of DCN1 complexed with UBC12 peptide (PDB: 3TDU). (B) Hydrophobic hotspots (purple mesh) at the UBC12 peptide binding site. (C) The co-crystal structure of DCN1 complexed with DI-591 (PDB: 5UFI). (D) The chemical structures and design strategy of peptidomimetic compounds 33-35 . Reproduced with permission . Copyright 2017, Nature Publishing Group.
Figure 18
Figure 18
(A) Predicted binding modes of derivative 36 with DCN1. (B) The chemical structures of peptidomimetic compounds 36-37 . Reproduced with permission . Copyright 2018, American Chemical Society.
Figure 19
Figure 19
(A) The chemical structures and design strategy of covalent inhibitor 38. (B) and (C) The co-crystal structures of DCN1 complexed with peptidomimetic compounds 35 and 38 (PDB: 6XOO), respectively. (D) The covalent adduct of peptidomimetic compound 38 with DCN1 . Reproduced with permission . Copyright 2021, Nature Publishing Group.
Figure 20
Figure 20
The chemical structures and design strategy of piperidinyl urea derivatives 39-42. (A) The co-crystal structure overlay of 39 (orange) with DCN1 and UBC12NAc (magenta) with DCN1 (PDB: 5V83 and 3TDU), indicating the critical regions targeted for optimizations -. Reproduced with permission . Copyright 2018, American Chemical Society.
Figure 21
Figure 21
(A) The chemical structures and design strategy of pyrazolo-pyridone derivatives 43-45. (B) The co-crystal structure overlay of 43 (orange) with DCN1 and UBC12NAc (blue) with DCN1 (PDB: 6P5W and 3TDU). Reproduced with permission . Copyright 2019, American Chemical Society. (C) The co-crystal structure of 44 with DCN1 (PDB: 6P5V). Reproduced with permission . Copyright 2019, American Chemical Society. (D) The co-crystal structure of 45 with DCN1 (PDB: 7KWA) , . Reproduced with permission . Copyright 2021, American Chemical Society.
Figure 22
Figure 22
(A) The chemical structures and design strategy of triazolo[1,5-a]pyrimidine derivatives 46-47. (B) The predicted binding modes of compound 47 with DCN1 . Reproduced with permission . Copyright 2019, American Chemical Society.
Figure 23
Figure 23
(A and D) The chemical structures of DCN1 inhibitors 48-52. (B) The predicted binding modes of 5‑cyano-6-phenyl-pyrimidine derivative 49 (blue) with DCN1 protein (white) . Reproduced with permission . Copyright 2019, American Chemical Society. (C) The predicted binding modes of compound 50 (blue) with DCN1 protein (green) . Reproduced with permission . Copyright 2022, American Chemical Society. (E) The predicted binding modes of compound 52 (blue) with DCN1 protein (white) . Reproduced with permission . Copyright 2021, Elsevier Masson SAS.
Figure 24
Figure 24
The chemical structure of Cul1/5 inhibitor Gossypol .
Figure 25
Figure 25
The chemical structure of UBE2F inhibitor HA-9104 .
Figure 26
Figure 26
The chemical structure of UBC12 inhibitor arctigenin .
Figure 27
Figure 27
A summary of targeting neddylation through inhibiting various proteins of this pathway.
See this image and copyright information in PMC

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