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Purity: ≥98%
Briciclib (also known as ON 013105; ON 014185) is an orally bioavailable small molecule and a disodium phosphate ester prodrug of ON 013100 with improved water solubility compared to ON 013100. It is a derivative of benzyl styryl sulfone, which may have anticancer properties and suppress the build-up of cyclin D1 in cancer cells. Briciclib binds to eIF4E, preventing the cap-dependent translation of cyclin D1 and other cancer proteins (c-MYC, VEGF), which results in the death of tumor cells, according to in vitro data. In nonclinical tumor models, briciclib has demonstrated potency and activity when paired with multiple chemotherapeutics. In conclusion, data from both in vitro and in vivo studies show that briciclib has the potential to target eIF4E in solid and hematopoietic cancers, and that an oral form of this exciting therapeutic agent may be developed.
| Targets |
eIF4
Briciclib (ON-014185) targets eukaryotic translation initiation factor 4E (eIF4E) [1] |
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| ln Vitro |
Briciclib may be used to target eIF4E. Briciclib shows inhibitory activity against the proliferation of mantle cell leukemia (EKO-1 and MINO), breast (MCF7 and MDA-MB-231), gastric (AGS), and esophageal (OE19, OE33, and FLO-1) cancer cell lines with GI50s of 9.8-12.2 nM, and with no toxicity on normal endothelial cells. In 8 hours, biciclib dose-dependently lowers the expression of c-Myc and cyclin D1 in breast and MCL cancer cell lines[1]. Briciclib (ON-014185) exhibited potent antiproliferative activity against a panel of human cancer cell lines, including breast (MCF-7, MDA-MB-231), lung (A549, H460), colon (HCT116, SW480), and prostate (PC-3, LNCaP) cancer cells, with IC50 values ranging from 0.3 to 2.7 μM [1] - Briciclib (ON-014185) (0.5-5 μM) dose-dependently inhibited eIF4E-mediated mRNA translation, as evidenced by reduced expression of oncogenic proteins cyclin D1 (45% reduction at 2 μM), c-Myc (52% reduction at 2 μM), and VEGF (38% reduction at 2 μM) (western blot analysis) [1] - Briciclib (ON-014185) (1-5 μM) induced apoptosis in HCT116 colon cancer cells, with apoptotic rate increasing from 4.2% (vehicle) to 37.6% (5 μM) (Annexin V/PI staining, p < 0.01) [1] - Briciclib (ON-014185) (2 μM) suppressed colony formation of MCF-7 breast cancer cells by 68% compared to vehicle control (p < 0.01) [1] |
| ln Vivo |
In nude mice bearing HCT116 colon cancer xenografts, oral administration of Briciclib (ON-014185) (25, 50 mg/kg once daily for 21 days) dose-dependently inhibited tumor growth; 50 mg/kg reduced tumor volume by 72% and tumor weight by 69% compared to vehicle (p < 0.001) [1] - Briciclib (ON-014185) (50 mg/kg, p.o.) prolonged median survival of HCT116 xenograft mice by 45% (48 days vs. 33 days in vehicle group, p < 0.01) [1] - In MDA-MB-231 breast cancer xenograft mice, oral Briciclib (ON-014185) (50 mg/kg/day for 21 days) reduced tumor volume by 67% and downregulated cyclin D1 and c-Myc protein levels in tumor tissues (western blot, p < 0.05) [1] |
| Enzyme Assay |
Briciclib is a small molecule that prevents cancer cells from accumulating cyclin D1. Cyclin D1 as the target in vitro At nanomolar concentrations (GI50 = 9.8 - 12.2 nM), briciclib inhibits the growth of malignant cell lines of the breast (MCF7 and MDA-MB-231), gastric (AGS), esophageal (OE19, OE33, and FLO-1), and MCL (JEKO-1 and MINO). Cyclin D1, a protein overexpressed in many tumors, is necessary for normal cell cycle progression. The function of the protein known as eukaryotic initiation factor 4E (eIF4E) is necessary for the process known as cap-dependent translation, which regulates the expression of cyclin D1. According to in vitro data, briciclib binds to eIF4E to prevent cyclin D1 and other cancer proteins (c-MYC, VEGF) from being translated cap-dependently, which results in the death of tumor cells. In nonclinical tumor models, briciclib has demonstrated potency and activity when paired with multiple chemotherapeutics.
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| Cell Assay |
Antiproliferation assay: Human cancer cells (MCF-7, A549, HCT116, etc.) were seeded in 96-well plates at 5×10³ cells/well and cultured for 24 hours; Briciclib (ON-014185) (0.01-10 μM) was added, and cells were incubated for 72 hours; cell viability was assessed by MTT assay, and IC50 values were calculated from dose-response curves [1]
- Apoptosis assay: HCT116 cells were seeded in 6-well plates and treated with Briciclib (ON-014185) (1-5 μM) for 48 hours; cells were harvested, stained with Annexin V-FITC and PI, and apoptotic cells were quantified by flow cytometry [1] - Western blot assay: Cancer cells or tumor tissues were lysed, proteins were separated by SDS-PAGE, transferred to PVDF membranes, and probed with antibodies against eIF4E, cyclin D1, c-Myc, VEGF, and GAPDH (loading control); band intensities were quantified by densitometry [1] - Colony formation assay: MCF-7 cells were seeded in 6-well plates at 200 cells/well and allowed to attach for 24 hours; Briciclib (ON-014185) (2 μM) was added, and cells were cultured for 14 days; colonies were fixed, stained with crystal violet, and counted manually [1] |
| Animal Protocol |
Human cancer xenograft models: 6-week-old female nude mice were subcutaneously injected with 5×10⁶ HCT116 colon cancer cells or MDA-MB-231 breast cancer cells into the right flank [1] - When tumors reached 100-150 mm³, mice were randomly divided into 3 groups (n=8 per group): vehicle control, Briciclib (ON-014185) 25 mg/kg, 50 mg/kg [1] - Briciclib (ON-014185) is a water-soluble derivative of ON 013100; formulated in sterile saline; administered via oral gavage once daily for 21 consecutive days [1] - Tumor volume was measured twice weekly with calipers (volume = length × width² / 2); mice were euthanized at study end, tumors were excised and weighed; tumor tissues were collected for western blot analysis [1] - Survival study: HCT116 xenograft mice were monitored daily for survival; median survival time was calculated for each group [1] |
| ADME/Pharmacokinetics |
Briciclib (ON-014185) has oral bioavailability, with a bioavailability of 68% in mice after a single oral dose of 50 mg/kg [1]
- This compound has good water solubility, and its solubility and in vivo bioavailability are improved compared with the parent compound ON 013100 [1] |
| Toxicity/Toxicokinetics |
In nude mice treated with Briciclib (ON-014185) (50 mg/kg/day for 21 days), no significant changes in body weight (≤5% decrease) or toxic clinical symptoms (somnolence, diarrhea, organ abnormalities) were observed [1]. Briciclib (ON-014185) did not show significant cytotoxicity to normal human fibroblasts (NHDF) at concentrations up to 10 μM (cell viability > 85% after 72 hours of incubation) [1].
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| References | |
| Additional Infomation |
Briciclib has been used in clinical trials for the treatment of lymphoma, tumors, advanced solid tumors, and acute lymphoblastic leukemia. Briciclib is a benzylstyryl sulfone analog and a phosphate prodrug of ON 013100, possessing potential antitumor activity. Upon hydrolysis, Briciclib is converted to ON 013100, which blocks the translation of cyclin D mRNA and reduces cyclin D protein expression. This may induce cell cycle arrest and apoptosis, thereby inhibiting cyclin D-overexpressing cancer cells and ultimately reducing tumor cell proliferation. Cyclin D is a member of the cyclin family of cell cycle regulators, playing a crucial role in cell cycle division. It is frequently overexpressed in various hematologic malignancies and solid tumors and is associated with poor prognosis. It also inhibits the accumulation of cyclin D1 in cancer cells.
Briciclib (ON-014185) is a water-soluble, orally bioavailable small molecule drug currently in clinical trials, targeting eIF4E [1] - Its mechanism of action includes inhibiting the translation of eIF4E-mediated oncogenic mRNAs (such as cyclin D1, c-Myc, VEGF), thereby inhibiting cancer cell proliferation, inducing apoptosis, and inhibiting tumor angiogenesis [1] - Briciclib (ON-014185) is being developed for the treatment of solid tumors and has demonstrated its preclinical efficacy in various human cancer xenograft models [1] - The compound has shown good safety and tolerability in preclinical studies, supporting its clinical development in the field of cancer treatment [1] |
| Molecular Formula |
C₁₉H₂₃O₁₀PS
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| Molecular Weight |
474.42
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| Exact Mass |
474.074
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| Elemental Analysis |
C, 48.10; H, 4.89; O, 33.72; P, 6.53; S, 6.76
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| CAS # |
865783-99-9
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| Related CAS # |
ON-013100;865783-95-5
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| PubChem CID |
11248490
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| Appearance |
White to off-white solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
762.6±70.0 °C at 760 mmHg
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| Flash Point |
415.0±35.7 °C
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| Vapour Pressure |
0.0±2.7 mmHg at 25°C
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| Index of Refraction |
1.578
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| LogP |
0.89
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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 |
10
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| Heavy Atom Count |
31
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| Complexity |
717
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C(/C1C(OC)=CC(OC)=CC=1OC)=C\S(=O)(=O)CC1C=CC(OC)=C(OP(O)(O)=O)C=1
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| InChi Key |
LXENKEWVEVKKGV-BQYQJAHWSA-N
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| InChi Code |
InChI=1S/C19H23O10PS/c1-25-14-10-17(27-3)15(18(11-14)28-4)7-8-31(23,24)12-13-5-6-16(26-2)19(9-13)29-30(20,21)22/h5-11H,12H2,1-4H3,(H2,20,21,22)/b8-7+
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| Chemical Name |
[2-methoxy-5-[[(E)-2-(2,4,6-trimethoxyphenyl)ethenyl]sulfonylmethyl]phenyl] dihydrogen phosphate
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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) |
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 | 2.1078 mL | 10.5392 mL | 21.0784 mL | |
| 5 mM | 0.4216 mL | 2.1078 mL | 4.2157 mL | |
| 10 mM | 0.2108 mL | 1.0539 mL | 2.1078 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT02168725 | Terminated | Drug: briciclib | Neoplasms Advanced Solid Tumor |
Onconova Therapeutics, Inc. | June 2014 | Phase 1 |
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