Uridine cytidine kinase 2's function in tumors and the ongoing research on its inhibitors

doi:10.12092/j.issn.1009-2501.2026.03.008

Abstract

Abstract:

Uridine cytidine kinase 2 (UCK2) is the rate-limiting enzyme in the pyrimidine salvage synthesis pathway. Recent studies have shown that UCK2 is overexpressed in a variety of tumors and is associated with poor prognosis. In addition to its catalytic function as a kinase, UCK2 also plays a non-catalytic role in cellular signal transduction. UCK2 can not only support the rapid proliferation of tumor cells by catalyzing nucleotide synthesis, but also regulate various signaling pathways, thereby affecting the occurrence and development of tumors. Therefore, UCK2 is a promising target for cancer therapy, and it is of great clinical significance to explore its role in tumorigenesis and development and the development of related inhibitors. Now, the UCK2 inhibitors mainly include two categories: one is based on nucleotide analogs, which are competitive inhibitors of this enzyme’s catalytic function, and the other is based on non-competitive inhibitors that target the catalytic function of signal transduction. In addition, based on the database and molecular docking, we explore the molecules that may interact with UCK2 and their binding ability with UCK2. In conclusion, this review summarizes the roles and mechanisms of UCK2 in cancer, and the progress in the development of compounds that inhibit the biological functions of UCK2 and the mechanisms.

Key words: UCK2, cancer treatment targets, nucleotide synthesis, biomarkers, UCK2 inhibitor

CLC Number:

Jiawei ZHANG, Xuehan MA, Enhao XIAO, Simiao FAN, Danyang LIU. Uridine cytidine kinase 2's function in tumors and the ongoing research on its inhibitors[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2026, 31(3): 362-371.

Figures/Tables 6

Fig.1 Structure of UCK2 (taking chain A as an example)

Fig.2 UCK2 expression levels in normal tissues and tumor tissues blue represents normal samples, red represents tumor samples.

Fig.3 Structural formulas of small-molecule inhibitors of UCK2

Fig.4 Structural formulas of small molecules that may bind to UCK2 (predicted by databases)

Table 1 Docking energies between seven compounds and UCK2 (PDB ID: 1xrj)

Compound	Energy (kcal/mol)
Ara-CTP	?135.352
Poly-C	?135.248
Uridylate	?132.318
MgADP	?125.766
Citric acid	?123.328
Uridine	?114.914
Cytidine	?111.85

Fig.5 Molecular docking results between UCK2 (PDB ID: 1xrj) and seven compounds

References 44

1	Yi F, Wei XD, Guo LT, et al. The metabolic and non-metabolic roles of UCK2 in tumor progression[J]. Front Oncol, 2022, 12, 904887. doi: 10.3389/fonc.2022.904887
2	Appleby TC, Larson G, Cheney IW, et al. Structure of human uridine-cytidine kinase 2 determined by SIRAS using a rotating-anode X-ray generator and a single samarium derivative [J]. Acta Crystallogr D Biol Crystallogr, 2005, 61 (Pt 3): 278-284.
3	Kawai Y, Tsuchiya D, Takagi M, et al. Crystal structure of human uridine-cytidine kinase 2 in complex with ADP and cytidine monophosphate[J]. Biochemistry, 2023, 62 (22): 3245- 3254.
4	薛孟恩, 朱孝仁, 刘娜, 等. 尿苷-胞苷激酶在肿瘤生物学中的作用及其研究进展[J]. 山西医科大学学报, 2024, 55 (9): 1243- 1250.
5	Cui Y, Liu H, Zhang L, et al. Fructose drives colorectal cancer progression by regulating crosstalk between cancer-associated fibroblasts and tumour cells [J]. Gut, 2025, Sep 11: gutjnl-2025-335014.
6	Hoxhaj G, Tran D, Kesavan R, et al. De novo and salvage purine synthesis pathways across tissues and tumors [J]. Cell, 2024, 187 (14): 3602-3618. e20.
7	Cai J, Sun X, Guo H, et al. Non-metabolic role of UCK2 links EGFR-AKT pathway activation to metastasis enhancement in hepatocellular carcinoma[J]. Oncogenesis, 2020, 9 (12): 103. doi: 10.1038/s41389-020-00287-7
8	Zhang Q, Cheng Q, Xia M, et al. Hypoxia-induced lncRNA-NEAT1 sustains the growth of hepatocellular carcinoma via regulation of miR-199a-3p/UCK2[J]. Front Oncol, 2020, 10, 998. doi: 10.3389/fonc.2020.00998
9	Tian J, Li Y, Tong Y, et al. Uridine-cytidine kinase 2 is correlated with immune, DNA damage repair and promotion of cancer stemness in pan-cancer[J]. Front Oncol, 2025, 15, 1503300. doi: 10.3389/fonc.2025.1503300
10	Yu S, Li X, Guo X, et al. UCK2 upregulation might serve as an indicator of unfavorable prognosis of hepatocellular carcinoma[J]. IUBMB Life, 2019, 71 (1): 105- 112. doi: 10.1002/iub.1941
11	Huang S, Li J, Tam NL, et al. Uridine-cytidine kinase 2 upregulation predicts poor prognosis of hepatocellular carcinoma and is associated with cancer aggressiveness[J]. Mol Carcinog, 2019, 58 (4): 603- 615. doi: 10.1002/mc.22954
12	Gao C, Wang W, Liu T, et al. Annual review of EGFR inhibitors in 2024[J]. Eur J Med Chem, 2025, 292, 117677. doi: 10.1016/j.ejmech.2025.117677
13	Zhou F, Guo H, Xia Y, et al. The changing treatment landscape of EGFR-mutant non-small-cell lung cancer[J]. Nat Rev Clin Oncol, 2025, 22 (2): 95- 116. doi: 10.1038/s41571-024-00971-2
14	Zhou Q, Jiang H, Zhang J, et al. Uridine-cytidine kinase 2 promotes metastasis of hepatocellular carcinoma cells via the Stat3 pathway[J]. Cancer Manag Res, 2018, 10, 6339- 6355. doi: 10.2147/CMAR.S182859
15	Wu D, Zhang C, Liao G, et al. Targeting uridine-cytidine kinase 2 induced cell cycle arrest through dual mechanism and could improve the immune response of hepatocellular carcinoma[J]. Cell Mol Biol Lett, 2022, 27 (1): 105. doi: 10.1186/s11658-022-00403-y
16	Wu Y, Jamal M, Xie T, et al. Uridine-cytidine kinase 2 (UCK2): A potential diagnostic and prognostic biomarker for lung cancer[J]. Cancer Sci, 2019, 110 (9): 2734- 2747.
17	许杨, 刘黎, 王李杰, 等. 尿苷胞苷激酶2调控肺腺癌发生发展的机制研究[J]. 解放军医学院学报, 2022 (8): 880- 886.
18	Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours[J]. Nature, 2012, 490 (7418): 61- 70. doi: 10.1038/nature11412
19	Shen G, He P, Mao Y, et al. Overexpression of uridine-cytidine kinase 2 correlates with breast cancer progression and poor prognosis[J]. J Breast Cancer, 2017, 20 (2): 132- 141. doi: 10.4048/jbc.2017.20.2.132
20	Wu H, Xu H, Jia D, et al. METTL3-induced UCK2 m (6) A hypermethylation promotes melanoma cancer cell metastasis via the WNT/β-catenin pathway[J]. Ann Transl Med, 2021, 9 (14): 1155. doi: 10.21037/atm-21-2906
21	Liu J, Yue Y, Han D, et al. A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation[J]. Nat Chem Biol, 2014, 10 (2): 93- 95. doi: 10.1038/nchembio.1432
22	Roundtree IA, Luo GZ, Zhang Z, et al. YTHDC1 mediates nuclear export of N6-methyladenosine methylated mRNAs[J]. Elife, 2017, 6, e31311. doi: 10.7554/eLife.31311
23	刘宇, 王莉, 陈炳芳, 等. 胰液分子生物标志物在诊断胰腺癌中的研究进展[J]. 实用医学杂志, 2024, 40 (21): 3101- 3106.
24	El Hassouni B, Infante J, Mantini G, et al. Uridine cytidine kinase 2 as a potential biomarker for treatment with RX-3117 in pancreatic cancer[J]. Anticancer Res, 2019, 39 (7): 3609- 3614. doi: 10.21873/anticanres.13508
25	Richiardi L, Huncharek M, Kupelian V, et al. Increasing incidence of testicular cancer in the United States and Europe between 1992 and 2009[J]. Cancer Causes Control, 2024, 35 (6): 567- 576. doi: 10.1007/s00345-014-1361-y
26	Schumacher FR, Wang Z, Skotheim RI, et al. Testicular germ cell tumor susceptibility associated with the UCK2 locus on chromosome 1q23[J]. Hum Mol Genet, 2013, 22 (13): 2748- 2753. doi: 10.1093/hmg/ddt109
27	朱世春, 唐汝泽. 高危神经母细胞瘤放射治疗预后分析[J]. 实用临床医药杂志, 2023, 27 (13): 16- 19+25.
28	Van Kuilenburg AB, Meinsma R. The pivotal role of uridine-cytidine kinases in pyrimidine metabolism and activation of cytotoxic nucleoside analogues in neuroblastoma[J]. Biochim Biophys Acta, 2016, 1862 (9): 1504- 1512. doi: 10.1016/j.bbadis.2016.05.012
29	中华人民共和国国家卫生健康委员会. 中国结直肠癌诊疗规范(2023 版)[J]. 中国临床实用医学, 2023, 14 (5): 321- 335.
30	Okesli-Armlovich A, Gupta A, Jimenez M, et al. Discovery of small molecule inhibitors of human uridine-cytidine kinase 2 by high-throughput screening[J]. Bioorg Med Chem Lett, 2019, 29 (18): 2559- 2564. doi: 10.1016/j.bmcl.2019.08.010
31	Shimamoto Y, Koizumi K, Okabe H, et al. Sensitivity of human cancer cells to the new anticancer ribo-nucleoside TAS-106 is correlated with expression of uridine-cytidine kinase 2[J]. Jpn J Cancer Res, 2002, 93 (7): 825- 833. doi: 10.1111/j.1349-7006.2002.tb01325.x
32	Przybyła T, Sakowicz-Burkiewicz M, Maciejewska I, et al. Suppression of ID1 expression in colon cancer cells increases sensitivity to 5-fluorouracil[J]. Acta Biochim Pol, 2017, 64 (2): 315- 322. doi: 10.18388/abp.2016_1421
33	Balboni B, El Hassouni B, Honeywell RJ, et al. RX-3117 (fluorocyclopentenyl cytosine): a novel specific antimetabolite for selective cancer treatment[J]. Expert Opin Investig Drugs, 2019, 28 (4): 311- 322. doi: 10.1080/13543784.2019.1583742
34	Mahrou V, Vahabi G, Xu G, Sarkisjan D, et al. Unraveling resistance mechanisms to the novel nucleoside analog RX-3117 in lung cancer: insights into DNA repair, cell cycle dysregulation and targeting PKMYT1 for improved therapy[J]. J Exp Clin Cancer Res, 2025, 44, 217. doi: 10.1186/s13046-025-03470-z
35	Rasco D, Peterson C, Mazhari R, et al. RX-3117, an oral antimetabolite to treat advanced solid tumors (ST): phase 1 and ongoing phase 2a results [J]. Ann Oncol, 2016, 27 (Supplement 6): vi114-vi135.
36	Babiker HM. A phase I/II study of RX-3117, an oral antimetabolite nucleoside, in combination with nab-paclitaxel (nab-pac) as first-line treatment of metastatic pancreatic cancer (met-PC): preliminary results[J]. J Clin Oncol, 2019, 37, 420. doi: 10.1200/jco.2019.37.4_suppl.420
37	Bensaad K, Tsuruta A, Selak MA, et al. TIGAR, a p53-inducible regulator of glycolysis and apoptosis[J]. Cell, 2006, 126 (1): 107- 120. doi: 10.1016/j.cell.2006.05.036
38	Harris SL, Levine AJ. The p53 pathway: positive and negative feedback loops[J]. Oncogene, 2005, 24 (17): 2899- 2908. doi: 10.1038/sj.onc.1208615
39	Robledo S, Idol RA, Crimmins DL, et al. The role of human ribosomal proteins in the maturation of rRNA and ribosome production[J]. RNA, 2008, 14 (9): 1918- 1929. doi: 10.1261/rna.1132008
40	Lindstrom MS, Deisenroth C, Zhang Y. Putting a finger on growth surveillance: insight into MDM2 zinc finger-ribosomal protein interactions[J]. Cell Cycle, 2007, 6 (4): 434- 437. doi: 10.4161/cc.6.4.3861
41	Malami I, Alhassan AM, Adamu AA, et al. Cytotoxic flavokawain B inhibits the growth and metastasis of hepatocellular carcinoma through UCK2 modulation of the STAT3/Hif-1α/VEGF signalling pathway[J]. Curr Drug Targets, 2023, 24 (11): 919- 928. doi: 10.2174/1389450124666230803153750
42	Malami I, Abdul AB, Abdullah R, et al. Crude Extracts, Flavokawain B and Alpinetin Compounds from the Rhizome of Alpinia mutica Induce Cell Death via UCK2 Enzyme Inhibition and in Turn Reduce 18S rRNA Biosynthesis in HT-29 Cells[J]. PLoS One, 2017, 12 (1): e0170233. doi: 10.1371/journal.pone.0170233
43	Wu Y, Zhang F, Yang K, et al. SymMap: an integrative database of traditional Chinese medicine enhanced by symptom mapping[J]. Nucleic Acids Res, 2019, 47 (D1): D1110- D1117. doi: 10.1093/nar/gky1021
44	Szklarczyk D, Santos A, von Mering C, et al. STITCH 5: augmenting protein-chemical interaction networks with tissue and affinity data[J]. Nucleic Acids Res, 2016, 44 (D1): D380- D384. doi: 10.1093/nar/gkv1277

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