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.

Physicochemical Properties

Molecular Formula	C₁₉H₂₃O₁₀PS
Molecular Weight	474.42
Exact Mass	474.074
Elemental Analysis	C, 48.10; H, 4.89; O, 33.72; P, 6.53; S, 6.76
CAS #	865783-99-9
Related CAS #	ON-013100;865783-95-5
PubChem CID	11248490
Appearance	White to off-white solid powder
Density	1.4±0.1 g/cm3
Boiling Point	762.6±70.0 °C at 760 mmHg
Flash Point	415.0±35.7 °C
Vapour Pressure	0.0±2.7 mmHg at 25°C
Index of Refraction	1.578
LogP	0.89
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	10
Rotatable Bond Count	10
Heavy Atom Count	31
Complexity	717
Defined Atom Stereocenter Count	0
SMILES	C(/C1C(OC)=CC(OC)=CC=1OC)=C\S(=O)(=O)CC1C=CC(OC)=C(OP(O)(O)=O)C=1
InChi Key	LXENKEWVEVKKGV-BQYQJAHWSA-N
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+
Chemical Name	[2-methoxy-5-[[(E)-2-(2,4,6-trimethoxyphenyl)ethenyl]sulfonylmethyl]phenyl] dihydrogen phosphate
Synonyms	Briciclib.; ON-013105; ON014185; ON-014185; ON013105; ON 013105; ON 014185; ON-013105 sodium
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
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

Targets	eIF4
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].
ln Vivo
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.
Animal Protocol
References	[1]. Abstract 1649: Potent anticancer activity of an orally bioavailable small molecule, ON 013100, and its water soluble derivative, briciclib, a clinical-stage eIF4E-targeted agent. Cancer Research. August 2015, Volume 75, Issue 15.
Additional Infomation	Briciclib has been used in trials studying the treatment of Lymphoma, Neoplasms, Advanced Solid Tumor, and Acute Lymphocytic Leukemia. Briciclib is a benzyl styryl sulfone analog, and a phosphate ester prodrug of ON 013100, with potential antineoplastic activity. Upon hydrolysis, briciclib is converted to ON 013100, which blocks cyclin D mRNA translation and decreases protein expression of cyclin D. This may induce cell cycle arrest and apoptosis in cancer cells overexpressing cyclin D and eventually decrease tumor cell proliferation. Cyclin D, a member of the cyclin family of cell cycle regulators, plays a key role in cell cycle division and is often overexpressed in a variety of hematologic and solid tumors and is correlated with poor prognosis. suppresses cyclin D1 accumulation in cancer cells.

Solubility Data

Solubility (In Vitro)

DMSO: ≥ 30 mg/mL Water: N/A Ethanol: N/A

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 (e.g. IP/IV/IM/SC) Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline) *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). 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)] *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. Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline) Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline) Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline) Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil) Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL 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). Oral Formulation 3: Dissolved in PEG400 Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose Oral Formulation 6: Mixing with food powders Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.  (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.