PCNA-I1
目录号 : GC44577
An inhibitor of PCNA
Cas No.:444930-42-1
Sample solution is provided at 25 µL, 10mM.
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- Purity: >98.00%
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PCNA-I1 is an inhibitor of proliferating cell nuclear antigen (PCNA) that binds to PCNA trimers (Kd = 0.41 µM) and dose-dependently reduces the level of PCNA associated with chromatin in PC3 cells. It preferentially inhibits growth of a variety of human and mouse cancer cell lines (IC50s = 0.05-0.3 µM) over non-transformed cells (IC50s = 0.99-2 µM). PCNA-I1 leads to an accumulation of cells in the G1 phase during the first 24 hours of incubation and halts the cell cycle in the S and G2/M phases by 72 hours following treatment. It also reduces tumor growth in an LNCaP prostate cancer mouse xenograft model when administered at a dose of 10 mg/kg, five days per week, for two weeks.
| Cas No. | 444930-42-1 | SDF | |
| Canonical SMILES | OC1=C(/C=N/NC(C2=C(C)C=CS2)=O)C=CC3=CC=CC=C31 | ||
| 分子式 | C17H14N2O2S | 分子量 | 310.4 |
| 溶解度 | DMF: 10 mg/ml,DMSO: 10 mg/ml,DMSO:PBS(pH 7.2) (1:3): 0.25 mg/ml | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 3.2216 mL | 16.1082 mL | 32.2165 mL |
| 5 mM | 0.6443 mL | 3.2216 mL | 6.4433 mL |
| 10 mM | 0.3222 mL | 1.6108 mL | 3.2216 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Target validation and structure-activity analysis of a series of novel PCNA inhibitors
Pharmacol Res Perspect 2015 Mar;3(2):e00115.PMID:25729582DOI:10.1002/prp2.115.
Proliferating cell nuclear antigen (PCNA) plays an essential role in DNA replication and repair. Tumor cells express high levels of PCNA, identifying it as a potentially ideal target for cancer therapy. Previously, we identified nine compounds termed PCNA inhibitors (PCNA-Is) that bind directly to PCNA, stabilize PCNA trimer structure, reduce chromatin-associated PCNA, and selectively inhibit tumor cell growth. Of these compounds, PCNA-I1 was most potent. The purpose of this study is to further establish targeting of PCNA by PCNA-I1 and to identify PCNA-I1 analogs with superior potencies. We found that PCNA-I1 does not affect the level of chromatin-associated PCNA harboring point mutations at the predicted binding site of PCNA-I1. Forty-six PCNA-I1 analogs with structures of 1-hydrazonomethyl-2-hydroxy (scaffold A), 2-hydrazonomethyl-1-hydroxy (scaffold B), 2-hydrazonomethyl-3-hydroxy (scaffold C), and 4-pyridyl hydrazine (scaffold D) were analyzed for their effects on cell growth in four tumor cell lines and PCNA trimer stabilization. Compounds in scaffold group A and group B showed the highest trimer stabilization and the most potent cell growth inhibitory activities with a significant potency advantage observed in the Z isomers of scaffold A. The absence of trimer stabilization and growth inhibitory effects in compounds of scaffold group D confirms the essentiality of the hydroxynaphthyl substructure. Compounds structure-activity relationship (SAR)-6 and SAR-24 were analyzed for their effects on and found to reduce chromatin-associated PCNA in tumor cells. This study led to the identification of SAR-24, a compound with superior potencies and potentially improved solubility, which will be used for future development of PCNA-targeting cancer therapies.
Antitumor effects of a novel small molecule targeting PCNA chromatin association in prostate cancer
Mol Cancer Ther 2014 Dec;13(12):2817-26.PMID:25253786DOI:10.1158/1535-7163.MCT-14-0522.
Proliferating cell nuclear antigen (PCNA) plays an essential role in DNA replication and repair. Tumor cells express high levels of PCNA, identifying it as a potentially ideal target for cancer therapy. Previously, we identified nine compounds termed PCNA inhibitors (PCNA-Is) that bind directly to PCNA, stabilize PCNA trimer structure, reduce chromatin-associated PCNA, and selectively inhibit tumor cell growth. Of these compounds, PCNA-I1 is most potent. The purposes of this study were to further investigate the effects of targeting PCNA chromatin association on DNA damage and cytotoxicity and to evaluate the therapeutic potential of PCNA-I1 against tumors in mice. Given the important roles of tumor suppressor p53 in regulating sensitivity of tumor cells to chemotherapeutics, we performed studies in two human prostate cancer cell lines differing in p53 expression: LNCaP cells (wild-type p53) and PC-3 cells (p53-null). PCNA-I1 induced DNA damage and apoptosis in both LNCaP and PC-3 cells and enhanced DNA damage and apoptosis triggered by cisplatin. PCNA-I1 also induced autophagy in PC-3 cells. A short-term pretreatment with PCNA-I1 reduced colony formation by 50% in both cell lines. These data suggest that, unlike many other cytotoxic drugs, the effects of PCNA-I1 on tumor cells do not depend on expression of p53. Intravenous administrations of PCNA-I1 significantly retarded growth of LNCaP tumors of in nude mice without causing detectable effects on mouse body weight and hematology profiles. These data provide proof of concept that targeting PCNA chromatin association could be a novel and effective therapeutic approach for treatment of cancer.
Heat-Shock protein A12A is a novel PCNA-binding protein and promotes hepatocellular carcinoma growth
FEBS J 2020 Dec;287(24):5464-5477.PMID:32128976DOI:10.1111/febs.15276.
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death. Proliferating cell nuclear antigen (PCNA) plays a pivotal role in cancer development and progression. However, the long-term dismal prognosis of HCC mandates more investigation to identify novel regulators in HCC pathogenesis. Heat-shock protein A12A (HSPA12A) encodes a novel member of the HSP70 family. Here, we report that HCC cells showed increased HSPA12A expression, and overexpression of HSPA12A promoted HCC growth and angiogenesis in mice. Gain- and loss-of-functional studies demonstrated that the proliferation of HCC HepG2 cells, as well as β-catenin expression and nuclear translocation, was promoted by HSPA12A overexpression, but in turn suppressed by HSPA12A knockdown. HSPA12A did not impact PCNA expression; however, mass spectrometry and co-immunoprecipitation immunoblotting analysis revealed that HSPA12A directly binds to PCNA and promotes its trimerization, which is an essential functional conformation of PCNA for carcinogenesis. Importantly, PCNA inhibition by PCNA-I1 reversed the HSPA12A-mediated HepG2 cell differentiation. These findings indicate that HSPA12A is a novel regulator of HCC cell proliferation and tumor growth through binding to PCNA for its trimerization. HSPA12A inhibition might represent a viable strategy for the management of HCC in humans.
Small-molecule targeting of proliferating cell nuclear antigen chromatin association inhibits tumor cell growth
Mol Pharmacol 2012 Jun;81(6):811-9.PMID:22399488DOI:10.1124/mol.112.077735.
Proliferating cell nuclear antigen (PCNA), a potential anticancer target, forms a homotrimer and is required for DNA replication and numerous other cellular processes. The purpose of this study was to identify novel small molecules that modulate PCNA activity to affect tumor cell proliferation. An in silico screen of a compound library against a crystal structure of PCNA and a subsequent structural similarity search of the ZINC chemical database were carried out to derive relevant docking partners. Nine compounds, termed PCNA inhibitors (PCNA-Is), were selected for further characterization. PCNA-I1 selectively bound to PCNA trimers with a dissociation constant (K(d)) of ~0.2 to 0.4 μM. PCNA-Is promoted the formation of SDS-refractory PCNA trimers. PCNA-I1 dose- and time-dependently reduced the chromatin-associated PCNA in cells. Consistent with its effects on PCNA trimer stabilization, PCNA-I1 inhibited the growth of tumor cells of various tissue types with an IC(50) of ~0.2 μM, whereas it affected the growth of nontransformed cells at significantly higher concentrations (IC(50), ~1.6 μM). Moreover, uptake of BrdU was dose-dependently reduced in cells treated with PCNA-I1. Mechanistically the PCNA-Is mimicked the effect of PCNA knockdown by siRNA, inducing cancer cell arrest at both the S and G(2)/M phases. Thus, we have identified a class of compounds that can directly bind to PCNA, stabilize PCNA trimers, reduce PCNA association with chromatin, and inhibit tumor cell growth by inducing a cell cycle arrest. They are valuable tools in studying PCNA function and may be useful for future PCNA-targeted cancer therapy.
Potential New Therapeutic Approaches for Cisplatin-Resistant Testicular Germ Cell Tumors
Front Biosci (Landmark Ed) 2022 Aug 16;27(8):245.PMID:36042160DOI:10.31083/j.fbl2708245.
Background: Testicular germ cell tumors (TGCTs), a group of heterogeneous neoplasms, are the most frequent tumors of teenagers and young men, with the incidence rising worldwide. High cure rates can be achieved through cisplatin (CDDP)-based treatment, but approximately 10% of patients present refractory disease and virtually no treatment alternatives. Here, we explored new strategies to treat CDDP-resistant. Methods: In vitro TGCT CDDP-resistance model was established and differential mRNA expression profiles were evaluated using NanoString technology. Then, TGCT cell lines were treated with four potential drugs (PCNA-I1, ML323, T2AA, and MG-132) to overcome CDDP-resistance. Results: We found several differentially expressed genes related to DNA repair and cell cycle regulation on CDDP-resistant cell line (NTERA-2R) compared to parental cell line (NTERA-2P), and the proteasome inhibitor MG-132 demonstrated cytotoxic activity in all cell lines evaluated, even at a nanomolar range. MG-132 also enhanced cell lines' sensitivity to CDDP, increasing apoptosis in both NTERA-2P and NTERA-2R. Conclusions: MG-132 emerges as a potential new drug to treat CDDP-resistant TGCT. Targeted therapy based on molecular mechanism insights may contribute to overcome acquired chemotherapy CDDP-resistance.