NSC232003 is a small molecule inhibitor targeting UHRF1 [1]. NSC232003 binds to the 5-methylcytosine recognition pocket of the SRA domain of UHRF1, thereby interfering with the interaction between UHRF1 and DNMT1, leading to a decrease in intracellular DNA methylation levels [2-3]. NSC232003 is primarily focused on tumor and epigenetic interventions [4].
In NRK-49F cells, NSC232003 (50μM; 1h) significantly reduced TGF-β1-induced KLF15 hypermethylation, while also decreasing the expression of α-SMA and fibronectin [5]. In fibroblasts, NSC232003 (5μM; 4h) exerts a significant anti-fibrotic effect by inhibiting the protein expression of fibrosis markers [6].
In KYSE450 cells xenograft mouse model, NSC232003 (5 mg/kg; ip; 3 weeks) significantly inhibited UHRF1 activity, and its combination with the DNMT inhibitor SGI-1027 more effectively suppressed NKX2-5/LHX1 expression and tumor growth by disrupting the UHRF1-DNMT positive feedback loop [7].
References:
[1]. Myrianthopoulos V, Cartron P F, Liutkevičiūtė Z, et al. Tandem virtual screening targeting the SRA domain of UHRF1 identifies a novel chemical tool modulating DNA methylation[J]. European journal of medicinal chemistry, 2016, 114: 390-396.
[2]. Patnaik D, Estève P O, Pradhan S. Targeting the SET and RING-associated (SRA) domain of ubiquitin-like, PHD and ring finger–containing 1 (UHRF1) for anti-cancer drug development[J]. Oncotarget, 2018, 9(40): 26243.
[3]. Song Y, Liu H, Xian Q, et al. Mechanistic insights into UHRF1‑mediated DNA methylation by structure‑based functional clarification of UHRF1 domains[J]. Oncology Letters, 2023, 26(6): 542.
[4]. Kim A, Benavente C A. Oncogenic roles of UHRF1 in cancer[J]. Epigenomes, 2024, 8(3): 26.
[5]. Gu Y, Lv S, Huang X, et al. Inhibition of epigenetic regulator UHRF1 attenuates renal fibrosis and retains transcription factor Krüppel-like factor 15 expression[J]. Cell Death Discovery, 2025, 11(1): 270.
[6]. Cheng D, Wang Y, Li Z, et al. Liposomal UHRF1 siRNA shows lung fibrosis treatment potential through regulation of fibroblast activation[J]. JCI insight, 2022, 7(22): e162831.
[7]. Li X, Fan D, Li Y, et al. NKX2‐5/LHX1 and UHRF1 Establishing a Positive Feedback Regulatory Circuitry Drives Esophageal Squamous Cell Carcinoma through Epigenetic Dysregulation[J]. Advanced Science, 2025, 12(20): 2413508.
NSC232003是一种靶向UHRF1的小分子抑制剂 [1]。NSC232003与UHRF1 SRA结构域的5-甲基胞嘧啶识别口袋结合，从而干扰UHRF1与DNMT1的相互作用，导致细胞内DNA甲基化水平降低 [2-3]。NSC232003主要应用于肿瘤和表观遗传干预 [4]。
在NRK-49F细胞中，NSC232003（50μM；1h）显著降低了TGF-β1诱导的KLF15高甲基化，同时降低了α-SMA和纤连蛋白的表达 [5]。在成纤维细胞中，NSC232003（5μM；4h）通过抑制纤维化标志物的蛋白表达发挥显著的抗纤维化作用 [6]。
在KYSE450细胞异种移植小鼠模型中，NSC232003（5 mg/kg；ip；3周）显著抑制了UHRF1活性，并且它与DNMT抑制剂SGI-1027的组合通过破坏UHRF1-DNMT正反馈环路更有效地抑制了NKX2-5/LHX1表达和肿瘤生长 [7]。