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| Targets |
PCNA (proliferating cell nuclear antigen) trimers. PCNA-I1 directly binds to PCNA trimers with a dissociation constant (Kd) of approximately 0.2 to 0.41 μM. PCNA is a DNA sliding clamp that serves as a critical scaffold for numerous proteins involved in DNA replication, DNA repair, chromatin remodeling, and cell cycle regulation. By targeting PCNA, PCNA-I1 disrupts the protein-protein interactions mediated by PCNA, particularly its chromatin association, without directly inhibiting its enzymatic activity. This mechanism of action is distinct from traditional DNA-damaging agents or kinase inhibitors, as it targets the structural platform rather than catalytic functions. The compound's selectivity for PCNA trimers over other cellular proteins contributes to its specificity and reduced off-target effects. PCNA-I1 induces S and G2/M phase cell cycle arrest in tumor cells, consistent with the role of PCNA in DNA replication and checkpoint control. The compound's ability to reduce the level of PCNA associated with chromatin in PC3 prostate cancer cells has been demonstrated, confirming its target engagement. PCNA-I1 represents a promising approach to target the "undruggable" PCNA scaffold, validating PCNA as a potential anticancer target.
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| ln Vitro |
PCNA-I1 demonstrates potent anti-proliferative activity across a range of tumor cell lines of various tissue types. The compound inhibits the growth of cancer cells with an IC50 of approximately 0.2 μM. In prostate cancer cells, PCNA-I1 induces DNA damage and apoptosis in both androgen-sensitive LNCaP and androgen-independent PC-3 cells. The compound also induces autophagy in PC-3 cells, indicating multiple modes of cell death induction. PCNA-I1 induces S and G2/M phase cell cycle arrest in tumor cells with greater efficacy than in non-transformed cells, suggesting a degree of cancer cell selectivity. The compound enhances DNA damage and apoptosis triggered by cisplatin, indicating potential for combination therapy with conventional chemotherapeutics. PCNA-I1 dose-dependently reduces the level of PCNA associated with chromatin in PC3 cells, confirming target engagement and functional activity. The compound's potency and efficacy are supported by its ability to disrupt PCNA-mediated protein-protein interactions, which are essential for DNA replication and repair in rapidly dividing cancer cells. PCNA-I1 shows no significant effect on non-transformed cells at concentrations that are effective against cancer cells, supporting its therapeutic window.
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| ln Vivo |
PCNA-I1 displays anti-tumor effects in vivo, as demonstrated in preclinical models. The compound inhibits tumor growth in xenograft models, consistent with its in vitro anti-proliferative and pro-apoptotic activities. PCNA-I1 has been evaluated in prostate cancer models, where it targets PCNA chromatin association. The compound's ability to induce DNA damage, apoptosis, and autophagy translates to tumor growth inhibition in vivo. PCNA-I1 has been shown to enhance the anti-tumor efficacy of cisplatin in vivo, supporting its potential as a combination therapy partner. The compound's mechanism of action, targeting the PCNA scaffold, is expected to be effective across a range of tumor types that are dependent on PCNA function. Detailed in vivo pharmacokinetic and pharmacodynamic data are limited in publicly available sources, but the compound's anti-tumor activity has been validated in several preclinical studies. PCNA-I1 represents a promising lead compound for further development as a targeted anticancer therapy.
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| Enzyme Assay |
PCNA-I1 binding to PCNA trimers is assessed using surface plasmon resonance (SPR) or isothermal titration calorimetry (ITC) to determine the dissociation constant (Kd). The assay involves immobilizing recombinant PCNA trimers on a sensor chip and flowing PCNA-I1 at varying concentrations over the surface to measure binding kinetics. Alternatively, fluorescence polarization or fluorescence resonance energy transfer (FRET) assays can be used to measure the displacement of a labeled PCNA-binding peptide by PCNA-I1. The Kd value for PCNA-I1 binding to PCNA trimers is approximately 0.2 to 0.41 μM. These cell-free assays confirm the direct interaction between PCNA-I1 and PCNA trimers, validating the compound's mechanism of action. The assays are typically performed in buffer systems at physiological pH and ionic strength, with controls to ensure specificity and reproducibility.
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| Cell Assay |
PCNA-I1's cellular activity is evaluated in a panel of cancer cell lines, including prostate cancer cells (LNCaP, PC-3) and other tumor types. Cells are cultured in appropriate media (e.g., RPMI-1640 with 10% FBS) at 37°C with 5% CO₂ and treated with PCNA-I1 at concentrations ranging from 0.1 to 10 μM for 24-72 hours. Cell viability and proliferation are assessed using MTT, CCK-8, or CellTiter-Glo assays to determine IC50 values. DNA damage is evaluated by measuring γ-H2AX foci formation via immunofluorescence or Western blotting. Apoptosis is assessed by Annexin V/PI staining, caspase-3/7 activity assays, and PARP cleavage Western blotting. Autophagy is evaluated by LC3-II/I conversion, p62 degradation, and GFP-LC3 puncta formation. Cell cycle distribution is analyzed by propidium iodide staining and flow cytometry. PCNA chromatin association is measured by chromatin fractionation followed by Western blotting for PCNA. Each experiment includes vehicle controls (DMSO) and appropriate positive controls (e.g., cisplatin for DNA damage) to validate the assay systems.
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| Animal Protocol |
In vivo efficacy of PCNA-I1 is evaluated in mouse xenograft models using human cancer cell lines, particularly prostate cancer cells such as PC-3 or LNCaP. Tumor cells are implanted subcutaneously in immunodeficient mice (e.g., nude mice or NSG mice). When tumors reach a predetermined size (typically 100-200 mm³), mice are randomized into treatment and control groups. PCNA-I1 is administered via intraperitoneal injection or oral gavage at doses determined by preclinical studies. The compound is formulated as a clear solution using 1% DMSO, 40% PEG300, 5% Tween 80, and 54% ddH₂O, or as a homogeneous suspension in CMC-Na. Tumor growth is monitored by caliper measurements, and tumor volume is calculated using the formula (length × width²)/2. Body weight and clinical signs are monitored throughout the study to assess tolerability. At study endpoint, tumors are harvested for histopathological analysis, immunohistochemistry (Ki67 for proliferation, cleaved caspase-3 for apoptosis), and biochemical assays (PCNA chromatin association, DNA damage markers). Sample sizes typically range from 6-10 animals per group.
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| ADME/Pharmacokinetics |
Molecular Weight: 310.37. Formula: C17H14N2O2S. CAS No.: 444930-42-1. Appearance: Light yellow to yellow solid powder. Density: 1.3±0.1 g/cm³. LogP: 5.3. Solubility: DMSO: 62 mg/mL (199.76 mM). In vivo formulation: Clear solution (1% DMSO, 40% PEG300, 5% Tween 80, 54% ddH₂O) or homogeneous suspension in CMC-Na (≥5 mg/mL). Storage: Powder at -20°C for 3 years; 4°C for 2 years; In solvent at -80°C for 6 months; -20°C for 1 month. Shipping: Room temperature. Purity: ≥98%. PCNA-I1 is cell-permeable and demonstrates potent anti-tumor activity with a favorable safety profile in preclinical models.
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| Toxicity/Toxicokinetics |
No comprehensive toxicology data are publicly available for PCNA-I1. The compound is intended for research use only and has not undergone full preclinical toxicology evaluation required for clinical development. In cell-based assays, PCNA-I1 shows no significant cytotoxicity in non-transformed cells at concentrations that are effective against cancer cells, suggesting a degree of selectivity. In animal studies, PCNA-I1 is generally well-tolerated at the tested doses, with no significant body weight loss or overt signs of toxicity reported. Standard toxicity studies would include acute toxicity assessment in rodents, repeated dose toxicity studies (14-day and 28-day), and genotoxicity screening (Ames test, micronucleus assay). The compound's mechanism of action, targeting PCNA, suggests potential toxicities may be limited to proliferating tissues such as bone marrow, gastrointestinal epithelium, and skin. However, the cancer cell selectivity observed in vitro may translate to a favorable therapeutic window in vivo.
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| References | |
| Additional Infomation |
PCNA-I1 is also known as PCNA inhibitor 1. Its chemical name is N'-[(1E)-(1-hydroxynaphthalen-2-yl)methylidene]-3-methylthiophene-2-carbohydrazide. PubChem CID: 135533619. PCNA-I1 is a first-in-class small-molecule inhibitor targeting the PCNA trimer, representing a novel approach to anticancer therapy. PCNA-I1 induces DNA damage, apoptosis, and autophagy in cancer cells. The compound has been cited in high-impact journals including Nature Medicine for its quality and research relevance. PCNA-I1 is a valuable tool for studying PCNA biology and validating PCNA as a therapeutic target. No clinical trials have been reported for this compound. PCNA-I1 is strictly for research use only and not for human use.
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| Molecular Formula |
C17H14N2O2S
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| Molecular Weight |
310.37
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| Exact Mass |
310.077
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| CAS # |
444930-42-1
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| PubChem CID |
135533619
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| Appearance |
Light yellow to yellow solid powder
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| Density |
1.3±0.1 g/cm3
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| Index of Refraction |
1.667
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| LogP |
5.3
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
22
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| Complexity |
429
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CC1=C(SC=C1)C(=O)N/N=C/C2=C(C3=CC=CC=C3C=C2)O
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| InChi Key |
NZWTWRNHYZNWNW-VCHYOVAHSA-N
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| InChi Code |
InChI=1S/C17H14N2O2S/c1-11-8-9-22-16(11)17(21)19-18-10-13-7-6-12-4-2-3-5-14(12)15(13)20/h2-10,20H,1H3,(H,19,21)/b18-10+
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| Chemical Name |
N-[(E)-(1-hydroxynaphthalen-2-yl)methylideneamino]-3-methylthiophene-2-carboxamide
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~100 mg/mL (~322.20 mM)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.2220 mL | 16.1098 mL | 32.2196 mL | |
| 5 mM | 0.6444 mL | 3.2220 mL | 6.4439 mL | |
| 10 mM | 0.3222 mL | 1.6110 mL | 3.2220 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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