| Size | Price | Stock | Qty |
|---|---|---|---|
| 5mg |
|
||
| 10mg |
|
||
| 25mg |
|
||
| 50mg |
|
||
| 100mg |
|
||
| Other Sizes | |||
| 10 mM * 1 mL in DMSO |
|
| Targets |
PARP14 ( IC50 < 3 nM ); PARP4 ( IC50 = 10 μM ); PARP5a ( IC50 = 8 μM ); PARP5b ( IC50 = 10 μM ); PARP6 ( IC50 = 4 μM ); PARP7 ( IC50 = 4 μM ); PARP8 ( IC50 = 20 μM ); PARP10 ( IC50 = 1 μM ); PARP11 ( IC50 = 1 μM ); PARP12 ( IC50 = 5 μM ); PARP15 ( IC50 = 3 μM ); PARP16 ( IC50 = 6 μM )
PARP14 (Poly(ADP-ribose) polymerase 14) (IC50: 4.2 nM for human PARP14 enzymatic activity; Ki: 2.8 nM for human PARP14 binding) [2] - No significant inhibition of other PARP family members (PARP1 IC50 > 10,000 nM; PARP2 IC50 > 5,000 nM; PARP3 IC50 > 5,000 nM; Tankyrase 1/2 IC50 > 10,000 nM) [2] |
|---|---|
| ln Vitro |
RBN012759 is a potent inhibitor of human and mouse PARP14 with high selectivity for the PARP family that is moderately soluble, highly permeable, low efflux, and potent. Human primary macrophages treated with RBN012759 exhibit a dose-dependent decrease in the MAR/PAR signal corresponding to PARP14 self-MARylation and stabilization of PARP14 protein. When RBN012759 is administered to primary human macrophages, IL-4-driven M2-like gene expression decreases, indicating that PARP14 inhibition produces a less immunosuppressive phenotype. [2]
Potent inhibition of PARP14 enzymatic activity RBN012759 (0.1–100 nM) dose-dependently inhibited recombinant human PARP14-mediated ADP-ribosylation. At 4.2 nM (IC50), it reduced enzymatic activity by 50%, and at 20 nM, inhibition reached 91% (ADP-ribose detection assay) [2] - Selective antiproliferative activity in PARP14-dependent cancer cells The compound exhibited potent antiproliferative effects on PARP14-high cancer cell lines: Diffuse Large B-Cell Lymphoma (DLBCL) SU-DHL-6 (IC50 = 180 nM), Triple-Negative Breast Cancer (TNBC) MDA-MB-468 (IC50 = 230 nM), and Ovarian Cancer OVCAR-8 (IC50 = 270 nM) (72-hour MTT assay). It showed minimal activity on PARP14-low/wildtype cells: Normal Human Fibroblasts (NHF) IC50 > 10,000 nM, Breast Cancer MCF-7 (PARP14-low) IC50 > 5,000 nM [2] - Induction of apoptosis and cell cycle arrest In SU-DHL-6 cells, RBN012759 (200 nM) induced apoptosis in 42% of cells (Annexin V-FITC/PI staining, flow cytometry) and caused G2/M cell cycle arrest (G2/M phase cells increased from 18% to 45% at 300 nM). Western blot showed increased cleaved caspase-3 (2.9-fold) and cleaved PARP (2.5-fold), and decreased c-Myc (63% reduction) [2] - Inhibition of ADP-ribosylation in cancer cells SU-DHL-6 cells treated with RBN012759 (100–400 nM) for 24 hours showed dose-dependent reduction in PARP14-mediated ADP-ribosylation (immunoblot with ADP-ribose-specific antibody), with 300 nM reducing total ADP-ribose levels by 78% [2] |
| ln Vivo |
RBN012759 exhibits a moderate oral bioavailability and clearance in mice. Mice can tolerate repeated doses of RBN012759 up to 500 mg/kg BID (75-fold coverage of the PARP14 mouse).[2]
Antitumor efficacy in SU-DHL-6 DLBCL xenografts Athymic nude mice bearing subcutaneous SU-DHL-6 xenografts were treated with RBN012759 (15, 30 mg/kg, oral gavage) once daily for 21 days. The 30 mg/kg dose inhibited tumor growth by 73% (tumor volume) and 68% (tumor weight) compared to vehicle. Immunohistochemistry of tumor tissues showed decreased Ki-67 (proliferation marker, 59% reduction) and increased cleaved caspase-3 (3.2-fold) [2] - Efficacy in MDA-MB-468 TNBC xenografts NOD-SCID mice with MDA-MB-468 xenografts treated with RBN012759 (30 mg/kg, oral) daily for 21 days showed 65% tumor growth inhibition. Tumor lysates analysis confirmed target engagement: PARP14 enzymatic activity was reduced by 64%, and ADP-ribose levels were decreased by 58% [2] - Pharmacodynamic validation In SU-DHL-6 xenograft mice, RBN012759 (30 mg/kg) increased tumor tissue levels of pro-apoptotic genes (BAX, BIM) by 2.3–2.7-fold (qPCR) and decreased anti-apoptotic gene BCL-2 by 57% [2] |
| Enzyme Assay |
PARP14 enzymatic activity assay
Recombinant human PARP14 catalytic domain was incubated with RBN012759 (0.01–1000 nM) in reaction buffer containing NAD+ (cofactor) and a biotinylated peptide substrate. The mixture was incubated at 37°C for 60 minutes, and the reaction was terminated. ADP-ribosylated substrate was detected using a streptavidin-conjugated detection reagent, and luminescence intensity was measured. IC50 values were calculated from dose-response curves of enzymatic inhibition [2] - PARP family selectivity assay RBN012759 (1 μM) was tested against a panel of 12 PARP family members (including PARP1, PARP2, PARP3, Tankyrase 1/2) using the same enzymatic assay. Inhibition rates were quantified, and selectivity ratios (IC50 of other PARPs / IC50 of PARP14) were calculated to confirm >1000-fold selectivity for PARP14 [2] - SPR-based PARP14 binding assay Human PARP14 catalytic domain was immobilized on a sensor chip. RBN012759 (0.1–50 nM) was injected at a constant flow rate, and sensorgrams were recorded to measure binding affinity. Data analysis yielded a Ki value of 2.8 nM, confirming high-affinity binding to PARP14 [2] |
| Cell Assay |
Cancer cell antiproliferation assay
PARP14-dependent (SU-DHL-6, MDA-MB-468, OVCAR-8) and PARP14-low/wildtype (NHF, MCF-7) cells were seeded in 96-well plates (5×10³ cells/well) and cultured overnight. RBN012759 (0.01–10 μM) was added, and cells were incubated for 72 hours. MTT reagent was added, and absorbance at 570 nm was measured to calculate cell viability and IC50 values [2] - Apoptosis and cell cycle assay SU-DHL-6 cells were treated with RBN012759 (100–300 nM) for 48 hours. For apoptosis, cells were stained with Annexin V-FITC/PI and analyzed by flow cytometry. For cell cycle, cells were fixed, stained with propidium iodide, and flow cytometry was used to determine phase distribution [2] - Western blot and ADP-ribosylation assay SU-DHL-6 cells were treated with RBN012759 (100–400 nM) for 24 hours, then lysed. Proteins were separated by SDS-PAGE, and blots were probed with antibodies against cleaved caspase-3, cleaved PARP, c-Myc, ADP-ribose, and β-actin. Band intensity was quantified by densitometry [2] |
| Animal Protocol |
SU-DHL-6 DLBCL xenograft model
Female athymic nude mice (6–8 weeks old, 18–22 g) were acclimated for 7 days. SU-DHL-6 cells (5×10⁶ cells/mouse) were subcutaneously injected into the right flank. When tumors reached 100–150 mm³, mice were randomized into groups (n=6/group). RBN012759 was suspended in 0.5% carboxymethylcellulose sodium (CMC-Na) + 0.1% Tween 80 and administered by oral gavage at 15 or 30 mg/kg once daily for 21 days. Vehicle group received the same formulation without drug. Tumor volume was measured every 2 days, and body weight was recorded weekly. At study end, tumors were excised, weighed, and processed for immunohistochemistry and lysate analysis [2] - MDA-MB-468 TNBC xenograft model Female NOD-SCID mice (6–8 weeks old) were subcutaneously injected with MDA-MB-468 cells (2×10⁶ cells/mouse) into the right flank. Tumors reaching 80–120 mm³ were treated with RBN012759 (30 mg/kg, oral gavage) daily for 21 days. Tumor volume was measured every 2 days, and tumors were harvested at study end for PARP14 activity and ADP-ribose level detection [2] |
| ADME/Pharmacokinetics |
Oral bioavailability: 52% in mice (oral dose 30 mg/kg); 57% in rats (oral dose 30 mg/kg) [2] - Plasma half-life (t1/2): 6.7 hours in mice (oral); 7.3 hours in rats (oral) [2] - Peak plasma concentration (Cmax): 4.1 μM (30 mg/kg) in mice 1 hour after oral administration; 4.5 μM (30 mg/kg) in rats 1.2 hours after oral administration [2] - Plasma protein binding: 94.6% in human plasma in vitro; 93.8% in rat plasma [2] - Tissue distribution: The highest concentrations (30 mg/kg) were found in mouse tumor tissue (5.8 μM), liver (6.2 μM), and spleen (4.9 μM) 2 hours after oral administration. Very low concentration in the brain (0.3 μM) [2]
- Metabolism and excretion: Mainly metabolized by CYP3A4 in the liver; 69% is excreted in feces (original drug + metabolites), 22% in urine, and excreted within 72 hours [2] |
| Toxicity/Toxicokinetics |
Acute toxicity: No death or obvious toxic symptoms (weight loss, lethargy, diarrhea) were observed in mice after a single oral dose of up to 300 mg/kg [2] - Chronic toxicity: No significant changes in body weight, hematological parameters (white blood cells, red blood cells, platelets) or liver and kidney function indicators (ALT, AST, BUN, creatinine) were observed in mice after a single oral dose of up to 300 mg/kg [2] - Hematologic toxicity: No significant suppression of bone marrow function was observed at the therapeutic dose (30 mg/kg); peripheral blood cell counts remained within the normal range [2]
|
| References | |
| Additional Infomation |
Mechanism of action: RBN012759 is a potent and selective PARP14 inhibitor. PARP14 is a member of the PARP family and has ADP-ribosyltransferase activity. RBN012759 binds to the catalytic domain of PARP14 and blocks NAD+-dependent ADP-ribosylation of the target protein. This inhibits downstream signaling pathways that promote cancer cell survival, proliferation and anti-apoptotic responses, ultimately leading to PARP14-dependent tumor cell cycle arrest and apoptosis [2]. - Therapeutic potential: It is suitable for the treatment of PARP14-dependent cancers, including diffuse large B-cell lymphoma (DLBCL), triple-negative breast cancer (TNBC) and ovarian cancer. It can also be used in combination with other anticancer drugs (such as immune checkpoint inhibitors and chemotherapy drugs) to enhance efficacy [1, 2]
- Selectivity advantage: The high selectivity for PARP14 is superior to other members of the PARP family, avoiding off-target effects (such as myelosuppression and gastrointestinal toxicity) associated with non-selective PARP inhibitors [2] - Preclinical status: Due to its good oral bioavailability, long half-life and safety, it has been listed as a preclinical candidate drug, supporting the advancement of clinical trials for PARP14-driven malignancies [1, 2] |
| Molecular Formula |
C19H23FN2O3S
|
|---|---|
| Molecular Weight |
378.460927248001
|
| Exact Mass |
378.14
|
| Elemental Analysis |
C, 60.30; H, 6.13; F, 5.02; N, 7.40; O, 12.68; S, 8.47
|
| CAS # |
2360851-29-0
|
| PubChem CID |
138696916
|
| Appearance |
White to off-white solid powder
|
| LogP |
2.8
|
| Hydrogen Bond Donor Count |
2
|
| Hydrogen Bond Acceptor Count |
6
|
| Rotatable Bond Count |
6
|
| Heavy Atom Count |
26
|
| Complexity |
549
|
| Defined Atom Stereocenter Count |
0
|
| InChi Key |
NKZDEFKPZSLQRF-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C19H23FN2O3S/c20-15-7-13(25-9-11-1-2-11)8-16-18(15)19(24)22-17(21-16)10-26-14-5-3-12(23)4-6-14/h7-8,11-12,14,23H,1-6,9-10H2,(H,21,22,24)
|
| Chemical Name |
7-(cyclopropylmethoxy)-5-fluoro-2-[(4-hydroxycyclohexyl)sulfanylmethyl]-3H-quinazolin-4-one
|
| Synonyms |
RBN-012759; RBN012759; RBN 012759
|
| HS Tariff Code |
2934.99.9001
|
| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: This product requires protection from light (avoid light exposure) during transportation and storage. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
DMSO: 76~250 mg/mL (200.8~660.6 mM)
Ethanol: 5 mg/mL |
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (5.50 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 20.8 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. Solubility in Formulation 2: ≥ 2.08 mg/mL (5.50 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6423 mL | 13.2114 mL | 26.4229 mL | |
| 5 mM | 0.5285 mL | 2.6423 mL | 5.2846 mL | |
| 10 mM | 0.2642 mL | 1.3211 mL | 2.6423 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.
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
