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Review
. 2021;28(20):3892-3912.
doi: 10.2174/0929867327666200810135039.

Current Status of SUMOylation Inhibitors

Christopher M Brackett  1 , Brian S J Blagg  1
Affiliations
Review

Current Status of SUMOylation Inhibitors

Christopher M Brackett et al. Curr Med Chem. 2021.

Abstract

SUMOylation has emerged as an important post-translational modification that involves the covalent attachment of the Small Ubiquitin-like Modifier (SUMO) polypeptide to a lysine residue of a target protein. The enzymatic pathway of SUMOylation is very similar to ubiquitinylation and involves an activating enzyme, a conjugating enzyme, ligases, and deconjugating enzymes. SUMOylation modulates the function of a number of proteins associated with various pathways, and in fact, dysregulation of the SUMOylation pathway is observed in both cancer and neurological diseases. In many cancers, the SUMO enzymes are upregulated, and SUMO levels correlate directly with prognosis and disease progression. As a result, there has been an emphasis on the discovery and development of inhibitors of SUMOylation. In this review, the latest advances in SUMOylation inhibitors are described alongside the methods used to discover small molecule SUMOylation inhibitors, which include natural products, peptidomimetics, as well as synthetic derivatives identified via virtual screens.

Keywords: SUMO; cancer; enzyme inhibitors.; natural products; post-translational modifications; small-molecules; ubiquitin-like.

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Figures

Figure 1.
Figure 1.
SUMOylation catalytic cycle (Maturation). Immature SUMO has its C-terminal cap cleaved to reveal a diglycine motif by SENP1. (Activation) SUMO is then activated in an ATP-dependent reaction by heterodimeric SAE by forming a thioester between the active site cysteine and the C-terminus of SUMO. (Conjugation) SUMO is then transferred to the active site cysteine residue of the SUMO-conjugating protein, Ubc9. (Ligation) The substrate protein is then SUMOylated on the side chain amine of a lysine residue usually involving an E3 ligase. (De-modification) SUMOylation can be reversed through the action of SENPs.
Figure 2.
Figure 2.
Natural product E1 inhibitors. First identified SUMOylation inhibitors, ginkgolic acid (1), anacardic acid (2), and kerriamycin B (3), and polyphenolic SUMOylation inhibitors, davidiin (4), and tannic acid (5).
Figure 3.
Figure 3.
Semisynthetic SUMO adducts mimicking the acyl-adenylate intermediate, 6-7.
Figure 4.
Figure 4.
Synthetic SUMOylation inhibitors discovered from virtual screens, 8-12. Initial hit compound CID9549553 (13) and lead compound COH000 (14), and quinoxaline SAE inhibitor (15).
Figure 5.
Figure 5.
AMP mimic SAE inhibitors developed by Takeda, ML-792 (16) and TAK-981 (17).
Figure 6.
Figure 6.
First identified natural product inhibitors of SUMO-E2, spectomycin B (18), viomellein (19), and chaetochromin A (20). Compounds discovered from developed high throughput assays, 2-D08 (21) and 22.
Figure 7.
Figure 7.
Ubc9 inhibitors that can effectively compete against target proteins as substrates for SUMOylation.
Figure 8.
Figure 8.
Synthetic inhibitors of Ubc9 discovered from a virtual screen, 26 and 27.
Figure 9.
Figure 9.
Natural product SENP inhibitors, momordin Ic (28), streptonigrin (29), NSC76919 (30), NSC45384 (31), vialinin A (32), and atromentin (33).
Figure 10.
Figure 10.
Aza-epoxide SENP inhibitors 34 and 35, and second generation SENP inhibitors 36-38.
Figure 11.
Figure 11.
First synthetic small molecule inhibitors of SENPs, 39-41.
Figure 12.
Figure 12.
SENP inhibitors discovered through virtual screen studies 42-54.
Figure 13.
Figure 13.
Modulators of the SUMOylation pathway with novel mechanisms of action 55-63.
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