Cysteine Alkylation in Enzymes and Transcription Factors: A Therapeutic Strategy for Cancer
Simple Summary
Abstract
1. Introduction
2. Enzyme and Transcriptional Regulation in Neoplastic Cells
2.1. Thioredoxin Reductase (TrxR) and Its Role in Cancer Cells
- TrxR and Trx are overexpressed in many aggressive tumours, managing the increased reactive oxygen species (ROS) levels due to their high metabolic rate [11].
- The system of TrxR, Trx and NADPH reduces oxidised proteins and maintains cellular redox homeostasis [12].
- By reducing ROS, TrxR helps cancer cells survive, proliferate, enhance growth tumours and optimise nutrient and oxygen supply [13].
- Reduced Trx can inhibit apoptosis by binding to apoptosis signalling kinase-1 (ASK-1). In contrast, oxidised Trx loses this ability, highlighting the importance of Trx’s redox state in regulating apoptotic pathways [14].
- Due to its role in protecting cancer cells, TrxR is a potential target for cancer therapy. Inhibiting TrxR can disrupt redox balance in cancer cells, making them more susceptible to oxidative damage and apoptosis [15].
2.2. Exportin-1 (CRM1/XPO1) and Its Role in Cancer Cells
2.3. Signal Transducer and Activator of Transcription 3 (STAT3) and Its Role in Cancer Cells
2.4. Nuclear Factor NF-κB, IKKβ Kinase and Their Role in Cancer Cells
- Cytokines and chemokines, such as IL-1β (a pro-inflammatory cytokine involved in acute and chronic inflammation), TNF-α (a potent pro-inflammatory cytokine), IL-6 (a cytokine involved in inflammation and immune response), IL-8 (a chemokine that attracts neutrophils to sites of inflammation) and MCP-1 (monocyte chemoattractant protein-1, a chemokine that attracts monocytes and macrophages) [59];
- Cell survival and proliferation genes, such as Bcl-2 (an anti-apoptotic protein that inhibits cell death), c-myc (a proto-oncogene involved in cell proliferation), cyclins and CDKs (proteins involved in cell cycle regulation) [70];
- Inhibitors of apoptosis proteins such as c-IAP1 and c-IAP2 [71] and other genes, such as ICAM-1 (intercellular adhesion molecule-1, involved in cell adhesion) [72], VCAM-1 (vascular cell adhesion molecule-1, involved in cell adhesion) [73], COX-2 (cyclooxygenase-2, an enzyme involved in inflammation and pain) [74], iNOS (inducible nitric oxide synthase, an enzyme that produces nitric oxide) [75] and MMPs (matrix metalloproteinases, involved in extracellular matrix degradation) [59].
2.5. Hypoxia-Inducible Factor 1 (HIF-1) and Its Role in Cancer Cells
3. Synthetic and Natural Products as Alkylating Agents for Cysteine Residues
- Afatinib, Neratinib, Sunitinib, Osimertinib and Ibrutinib, as Tyrosine Kinase inhibitors (TKIs). TK plays a crucial role in the signalling pathways that regulate cell division and survival, and TKIs can help control the growth of cancer cells [95].
- Palbociclib, Ribociclib, Trilaciclib and Dalpiciclib as Cyclin-Dependent Kinases (CDKs) inhibitors. CDKs play a crucial role in regulating the cell cycle by interacting with cyclins and inhibitors halt cell division and proliferation [96].
- Nitro Fatty Acids (NO2-FAs), which have broader biological effects and inhibit the activity of NF-κB, are bioactive lipids formed by the reaction of unsaturated fatty acids (UFAs) with reactive nitrogen species like NO and nitrite anions. NO2-FAs possess a nitroalkene moiety, which is a potent Michael acceptor, allowing them to undergo nucleophilic attacks on thiol groups of biologically relevant proteins [97].
- Selective Inhibitors of Nuclear Export (SINEs) as inhibitors of XPO1. Several compounds have been developed, such as Verdinexor, Selinexor and Eltanexor. By inhibiting XPO1, these drugs help keep tumour suppressor proteins inside the nucleus, which can induce cancer cell death [98].
- MA-based covalent inhibitors represent a critical class of targeted cancer therapies, particularly for hard-to-drug proteins like KRAS G12C. Sotorasib and Adagrasib are small-molecule inhibitors designed to target the KRAS G12C mutation, a common oncogenic driver in non-small cell lung cancer (NSCLC) and other cancers. This mutation results in a permanently active K-Ras protein that drives cancer cell proliferation. Sotorasib is the first approved KRAS G12C inhibitor. It binds irreversibly to the mutant KRAS G12C protein, locking it in an inactive GDP-bound state, thereby inhibiting downstream signalling pathways such as MAPK/ERK. Adagrasib is another KRAS G12C inhibitor, with similar mechanisms, developed to overcome limitations of resistance or suboptimal responses seen in some Sotorasib-treated patients. It has shown promise in both monotherapy and combination regimens.
- SHP2 (Src homology region 2-containing protein tyrosine phosphatase 2) is indeed a key cancer-related protein and a promising target for covalent inhibition, especially via Michael acceptor-based strategies. Mutations or overactivation of SHP2 is associated with leukemias, solid tumours and RASopathies. Cys459 (in the PTP domain) is the nucleophilic cysteine required for enzymatic dephosphorylation. Although directly targeting this site poses a risk of off-target effects due to high conservation among PTPs, it remains a feasible option.
4. Structures and Location of Cys Residues
5. Local Docking of Michael Acceptor Compounds on Reactive Cysteines
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Enzyme or Transcription Factor | Cys or Sec Residues |
---|---|
TrxR | Cys497 and Sec498 |
XPO1 | Cys528 |
STAT3 | Cys259 |
NF-kB | Cys38 |
IKKβ | Cys179 |
HIF-1 | Cys255 |
TRXR Sec 498 |
TRXR Cys 497 | XPO1 | STAT3 | NF-KB | IKKß | HIF-1 | |
---|---|---|---|---|---|---|---|
Curcumin | −3.8 | −4.0 | −7.6 | −5.5 | −6.0 | −5.4 | −2.9 |
Cinnamaldehyde | −1.1 | −0.9 | −3.6 | −1.8 | −3.1 | −3.5 | −2.5 |
Zerumbone | −2.1 | −2.2 | −5.5 | −4.7 | −4.3 | −3.8 | +5.0 |
Helenalin | −3.8 | −3.0 | −6.1 | −4.4 | −5.9 | −4.4 | −4.4 |
Umbelliferone | −0.5 | −2.0 | −5.0 | −3.9 | −3.4 | −3.4 | −1.2 |
Stat3-In-1 | −4.4 | −3.7 | −8.7 | −6.0 | −7.7 | −5.4 | −1.6 |
Cddo-Me | −4.2 | −4.4 | −9.3 | −5.1 | −6.2 | +2.0 | +40.4 |
Sunitinib | −2.7 | −2.8 | −7.2 | −4.0 | −4.7 | −4.4 | +4.1 |
Palbociclib | −5.4 | −4.4 | −7.6 | −6.6 | −6.1 | −2.0 | +15.8 |
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Andrés, C.M.C.; Lobo, F.; Pérez de la Lastra, J.M.; Munguira, E.B.; Juan, C.A.; Pérez-Lebeña, E. Cysteine Alkylation in Enzymes and Transcription Factors: A Therapeutic Strategy for Cancer. Cancers 2025, 17, 1876. https://doi.org/10.3390/cancers17111876
Andrés CMC, Lobo F, Pérez de la Lastra JM, Munguira EB, Juan CA, Pérez-Lebeña E. Cysteine Alkylation in Enzymes and Transcription Factors: A Therapeutic Strategy for Cancer. Cancers. 2025; 17(11):1876. https://doi.org/10.3390/cancers17111876
Chicago/Turabian StyleAndrés, Celia María Curieses, Fernando Lobo, José Manuel Pérez de la Lastra, Elena Bustamante Munguira, Celia Andrés Juan, and Eduardo Pérez-Lebeña. 2025. "Cysteine Alkylation in Enzymes and Transcription Factors: A Therapeutic Strategy for Cancer" Cancers 17, no. 11: 1876. https://doi.org/10.3390/cancers17111876
APA StyleAndrés, C. M. C., Lobo, F., Pérez de la Lastra, J. M., Munguira, E. B., Juan, C. A., & Pérez-Lebeña, E. (2025). Cysteine Alkylation in Enzymes and Transcription Factors: A Therapeutic Strategy for Cancer. Cancers, 17(11), 1876. https://doi.org/10.3390/cancers17111876