SZL P1-41 is a specific inhibitor of S phase kinase-associated protein 2 (Skp2)[1]. SZL P1-41 can prevent the assembly of Skp2-Skp1 complex and inhibit Skp2-mediated p27Kip1 and Akt ubiquitination[2]. SZL P1-41 has tumor growth inhibitory activity and has therapeutic effects on pulmonary fibrosis[3].
In vitro, SZL P1-41 (0-20μM) treatment of prostate cancer cell lines (PC-3 and LNCaP cells) for 3 days reduced the viability of cancer cells in a concentration-dependent manner, but had little effect on the viability of normal prostate epithelial PNT1A cells, and also induced the expression of endogenous p27 and p21 proteins in PC-3 cells[4]. SZL P1-41 (20μM) treatment of A549 and H1299 cells for 24 h significantly induced the expression of p27 protein[5].
In vivo, SZL P1-41 (80 mg/kg) was treated by intraperitoneal injection for 28 days in mice with renal cancer, which significantly inhibited tumor growth (reduced Ki-67, increased p21), induced cell apoptosis (increased C-Cas-3), and showed synergistic therapeutic effects when used in combination with MLN8237[6]. SZL P1-41 (80 mg/kg) was treated by intraperitoneal injection for 14 days in mice with bleomycin-induced pulmonary fibrosis, which significantly reduced the expression of COL1A1 and fibronectin in the lungs, attenuated the progression of pulmonary fibrosis, and restored body weight[7].
References:
[1] Jing J, Rui L, Junyuan S, et al. Small-molecule compounds inhibiting S-phase kinase-associated protein 2: a review[J]. Frontiers in Pharmacology, 2023, 14: 1122008.
[2]Wu J, Su H, Yu Z, et al. Skp2 modulates proliferation, senescence and tumorigenesis of glioma[J]. Cancer Cell International, 2020, 20: 1-11.
[3]Chuang H M, Shih T E, Lu K Y, et al. Mesenchymal stem cell therapy of pulmonary fibrosis: improvement with target combination[J]. Cell Transplantation, 2018, 27(11): 1581-1587.
[4]Chan C H, Morrow J K, Li C F, et al. Pharmacological inactivation of Skp2 SCF ubiquitin ligase restricts cancer stem cell traits and cancer progression[J]. Cell, 2013, 154(3): 556-568.
[5]Zhang S B, Hong M, Sun X Y, et al. Silybin has therapeutic efficacy against non-small cell lung cancer through targeting of skp2[J]. Acta Materia Medica, 2022, 1(3): 302-313.
[6]Li P, Chen T, Kuang P, et al. Aurora-A/FOXO3A/SKP2 axis promotes tumor progression in clear cell renal cell carcinoma and dual-targeting Aurora-A/SKP2 shows synthetic lethality[J]. Cell Death & Disease, 2022, 13(7): 606.
[7]Mikamo M, Kitagawa K, Sakai S, et al. Inhibiting Skp2 E3 ligase suppresses bleomycin-induced pulmonary fibrosis[J]. International journal of molecular sciences, 2018, 19(2): 474.
SZL P1-41是一种特异性S期激酶相关蛋白2（Skp2）抑制剂[1]。 SZL P1-41可阻止Skp2-Skp1复合物的组装，并抑制Skp2介导的p27 Kip1和Akt泛素化[2]。SZL P1-41具有肿瘤生长抑制活性，还有治疗肺纤维化的作用[3]。
在体外，SZL P1-41（0-20μM）处理前列腺癌细胞系（PC-3和LNCaP细胞）3 天，浓度依赖性地降低了癌细胞的活力，但对正常前列腺上皮PNT1A细胞的活力影响较小，还诱导了PC-3细胞中内源性p27和p21蛋白的表达[4]。SZL P1-41（20μM）处理A549和H1299细胞24 h，显著诱导了p27蛋白的表达[5]。
在体内，SZL P1-41（80 mg/kg）通过腹膜内注射治疗肾癌小鼠28天，显著抑制了肿瘤生长（Ki-67降低、p21升高），诱导了细胞凋亡（增加C-Cas-3），并与MLN8237联合使用表现出协同治疗作用[6]。SZL P1-41（80 mg/kg）通过腹膜内注射治疗博莱霉素诱导的肺纤维化小鼠14天，显著减少了肺的COL1A1和纤连蛋白的表达，减弱肺纤维化进展并恢复体重[7]。