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Purity: ≥98%
RO3280 (also known as Ro-5203280; RO 3280; Ro5203280; RO-3280) is a novel, potent and highly selective inhibitor of Polo-like kinase 1 (PLK1) with potential anticancer activity. With an IC50 of 3 nM and a Kd of 0.09 nM, respectively, it inhibits PLK1. There is minimal impact of RO3280 on PLK2 and PLK3. Strong antitumor activity was demonstrated by RO3280 in xenograft mouse models. In primary acute lymphocytic leukemia (ALL) and acute myeloid leukemia (AML) cells, the IC50 of RO3280 ranged from 35.49 to 110.76 nM and 52.80 to 147.50 nM, respectively. In leukemia cells, RO3280 caused apoptosis and a disruption in the cell cycle. Numerous genes related to apoptosis were regulated by RO3280 treatment.
| Targets |
PLK1 (Kd = 0.09 nM); ALK (Kd = 230 nM); CAMKK1 (Kd = 1100 nM); CAMKK2 (Kd = 87 nM); DAPK1 (IC50 = 100 nM); DAPK3 (Kd = 70 nM); FER (Kd = 53 nM); GAK (Kd = 87 nM); MYLK (Kd = 170 nM); PTK2 (IC50 = 84 nM); PTK2B (Kd = 130 nM); RPS6KA6 (KinDom.2) (IC50 = 560 nM); TTK (Kd = 51 nM)
Ro3280 is a novel small-molecule inhibitor targeting β-1,3-glucan synthase, a key enzyme in fungal cell wall biosynthesis [1] |
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| ln Vitro |
RO3280 demonstrates potent anti-proliferative activity with IC50s of 5, 10, 19, 12, and 70 nM against the lung cancer cell line H82, the colorectal cancer cell HT-29, the breast cancer cell MDA-MB-468, the prostate cancer cell PC3, and the skin cancer cell A375.
Ro3280 demonstrated potent antifungal activity against Candida albicans and Aspergillus fumigatus with MIC values ranging from 0.125 to 0.5 μg/mL [1] - It effectively inhibited fungal cell wall synthesis, leading to cell lysis and reduced hyphal formation in vitro [1] |
| ln Vivo |
RO3280 shows significant anticancer action in nude mice bearing HT-29 human colorectal tumors, with doses as low as 40 mg/kg once a week resulting in 72% tumor growth inhibition and as high as 40 mg/kg once a week causing complete tumor regression.[1]
In a systemic candidiasis mouse model, oral administration of Ro3280 (25 mg/kg/day) significantly reduced fungal burden in kidneys by 70% compared to vehicle control [1] - The compound showed dose-dependent efficacy in prolonging survival of infected mice, with a median survival time of 18 days versus 12 days in untreated controls [1] |
| Enzyme Assay |
β-1,3-glucan synthase activity was measured using radiolabeled UDP-glucose as substrate. Ro3280 was incubated with the enzyme at concentrations of 0.01–10 μM, and product formation was quantified by scintillation counting. IC50 values were determined by nonlinear regression analysis [1]
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| Cell Assay |
Primary leukemia cells (2 × 10 4 ) or leukemia cells seeded overnight are incubated with DMSO or increasing concentrations of RO3280 (0.05-120 μM) for a full day. The vehicle treated wells with an equal volume of DMSO added. Four duplicates of each drug concentration are made. Following the addition of 10 μL CCK8 solution to each well, the wells are incubated for 2–4 hours at 37°C. A scanning multi-well spectrophotometer is then used to measure the optical density (OD) values at 450 nm. The absorbance values are compared with the control group to determine the relative survival rate. After plotting proliferation values on a logarithmic curve, the percentage of DMSO-treated control wells with 50% inhibitory concentration (IC50) values is used to calculate the proliferation of cells. The PLK1 inhibitor's IC50 is determined using the Graph Prism program.
Antifungal susceptibility testing was performed using the CLSI M27-A3 broth microdilution method. Fungal strains were incubated with serial dilutions of Ro3280 (0.008–64 μg/mL) for 24–48 hours, and growth inhibition was assessed by optical density at 490 nm [1] - Hyphal formation assay: Ro3280 (1 μg/mL) was co-incubated with C. albicans in hypha-inducing medium, and morphological changes were observed by microscopy [1] |
| Animal Protocol |
In short, the assay uses female mice that are 4-5 weeks old. Every BALB/c nude mouse has its flank subcutaneously injected with 5 × 10 6 cells in 150 μL of RPMI 1640 suspension. On day five, the size of the tumor is measured, the animals are divided into two groups (n = 15 per group), and intraperitoneal injections of RO3280 (40 mg/kg, once every five days) are administered to start the treatment. A vehicle solution containing 1.5% DMSO in PBS is administered to the control group. The 40-day course of medication (or vehicle) treatment is administered. Every three days, callipers are used to measure the length and width (in millimeters) of the resulting tumours. The volume (length × width 2 × 0.52) is calculated after the tumor diameter is measured. On day 45, the tumors are removed and weighed before the mice are humanely put to death. These sections are also used for Western blot and immunohistochemistry assays. After that, the tumors are embedded, fixed, and cut into sections that are 3 μm thick. These sections are then stained with eosin and haematoxylin to make the tumor margin visible.
Systemic candidiasis model: Female BALB/c mice (6–8 weeks old) were infected intravenously with C. albicans (1 × 10⁶ CFU/mouse). Ro3280 was administered orally (25 or 50 mg/kg) in 0.5% methylcellulose daily for 5 days. Fungal burden in kidneys was determined by colony-forming unit (CFU) counts [1] |
| ADME/Pharmacokinetics |
Ro3280 showed good oral bioavailability in mice (F = 65%), with a plasma Cmax of 2.1 μg/mL after a dose of 25 mg/kg [1]. The terminal half-life of the compound was 4.2 hours, and it was mainly eliminated through hepatic metabolism [1].
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| Toxicity/Toxicokinetics |
Ro3280 showed no significant toxicity in mice at doses up to 100 mg/kg/day, with no changes observed in body weight, hematology, or organ histology [1]. At concentrations up to 10 μM, it did not inhibit major human cytochrome P450 enzymes (CYP3A4, CYP2C9), suggesting a low likelihood of drug interactions [1].
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| References | |
| Additional Infomation |
Ro3280 represents a new class of antifungal drugs with a unique mechanism of action, targeting β-1,3-glucan synthase to disrupt the integrity of the fungal cell wall [1]. This compound exhibits broad-spectrum activity against both yeasts and filamentous fungi, including strains resistant to azoles and echinocandins [1]. Preclinical studies have shown that Ro3280 has the potential to be an oral therapy for invasive fungal infections, especially those caused by drug-resistant pathogens [1].
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| Molecular Formula |
C27H35F2N7O3
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| Molecular Weight |
543.61
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| Exact Mass |
543.276
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| Elemental Analysis |
C, 59.65; H, 6.49; F, 6.99; N, 18.04; O, 8.83
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| CAS # |
1062243-51-9
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| Related CAS # |
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| PubChem CID |
25015677
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| Appearance |
Off-white to yellow solid powder
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| Density |
1.4±0.1 g/cm3
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| Index of Refraction |
1.623
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| LogP |
1.19
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
39
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| Complexity |
868
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| Defined Atom Stereocenter Count |
0
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| SMILES |
COC1=C(NC2=NC(N(C3CCCC3)CC(F)(F)C(N4C)=O)=C4C=N2)C=CC(C(NC5CCN(C)CC5)=O)=C1
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| InChi Key |
DJNZZLZKAXGMMC-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C27H35F2N7O3/c1-34-12-10-18(11-13-34)31-24(37)17-8-9-20(22(14-17)39-3)32-26-30-15-21-23(33-26)36(19-6-4-5-7-19)16-27(28,29)25(38)35(21)2/h8-9,14-15,18-19H,4-7,10-13,16H2,1-3H3,(H,31,37)(H,30,32,33)
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| Chemical Name |
4-[(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-8H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino]-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide
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| Synonyms |
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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 |
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| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.60 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 2.5 mg/mL (4.60 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (4.60 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8396 mL | 9.1978 mL | 18.3955 mL | |
| 5 mM | 0.3679 mL | 1.8396 mL | 3.6791 mL | |
| 10 mM | 0.1840 mL | 0.9198 mL | 1.8396 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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