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Purity: ≥98%
CPI-203 (RO6870810, JQ-2, TEN010, RG6146) is a novel, selective, cell permeable and orally bioavailable BET bromodomain inhibitor with anticancer activity. It inhibits BRD4 with an IC50 of 37 nM in a BRD4 α-screen assay. CPI 203 shows potent in vitro antiproliferative activity and high in vivo antitumor efficacy. CPI203 can enhance the antiproliferative effects of rapamycin on human neuroendocrine tumors. CPI203 can downregulate Myc expression, causes G1 cell cycle arrest and attenuate cell proliferation in human pancreatic neuroendocrine tumors. CPI203 arrests the growth of T cell acute lymphoblastic leukemia cells in vitro (EC50 = 91.2 nM).
| Targets |
Bromodomain and Extra-Terminal (BET) family proteins, primarily BRD4, with additional activity against BRD2 and BRD3. For CPI-203 (RO-6870810, TEN-010, JQ2, RG-6146), the Ki values were 0.3 nM (BRD4 BD1), 0.4 nM (BRD4 BD2), 0.6 nM (BRD2 BD1), 0.8 nM (BRD2 BD2), 0.5 nM (BRD3 BD1), and 0.7 nM (BRD3 BD2) [2]
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| ln Vitro |
CPI-203 inhibits BRD4 in vitro and in cells, but does not influence BRD4 kinase activity in vitro [1]. CPI -203 had cytostatic effects in all 9 MCL cell lines with GI50 ranging from 0.06 to 0.71 μM and had little cytotoxicity against normal PBMC from healthy volunteers. In addition, CPI -203 can effectively initiate the cell death pathway in MCL cells [2].
In bortezomib-resistant mantle cell lymphoma (MCL) cell lines (Jeko-1/BtzR, Mino/BtzR), CPI-203 single-agent treatment dose-dependently inhibited cell proliferation. The IC50 values were 0.4 μM (Jeko-1/BtzR) and 0.5 μM (Mino/BtzR) after 72-hour incubation [2] - Combined treatment with CPI-203 (0.1–0.5 μM) and lenalidomide (1–5 μM) showed synergistic antiproliferative effects in Jeko-1/BtzR and Mino/BtzR cells, with Combination Index (CI) values <0.8 (indicating synergy). This synergy was associated with enhanced caspase-3/7 activation (2.5–3.0-fold increase vs. single agents) and increased apoptotic cell death (flow cytometry: ~40% apoptotic cells vs. ~15% with single agents) [2] - Western blot analysis revealed that CPI-203 (0.5 μM, 24 hours) downregulated the expression of BET target genes, including c-Myc (60% reduction), BCL2 (50% reduction), and cyclin D1 (45% reduction), in Jeko-1/BtzR cells. qRT-PCR confirmed a 3.0–3.5-fold decrease in c-Myc and BCL2 mRNA levels [2] |
| ln Vivo |
Lenalidomide and CPI-203 (2.5 mg/kg, i.p.) together improved the anticancer effects of each individual drug by causing apoptosis in nREC-1 tumor-bearing mice and mutating MYC and IRF4 expression. [2].
In nude mice bearing bortezomib-resistant Jeko-1/BtzR xenografts, oral administration of CPI-203 (30 mg/kg, once daily for 21 days) significantly inhibited tumor growth, reducing tumor volume by ~35% and tumor weight by ~30% compared to vehicle control (0.5% methylcellulose + 0.1% Tween 80) [2] - Combined treatment with CPI-203 (30 mg/kg, oral, once daily) and lenalidomide (10 mg/kg, intraperitoneal, once daily) for 21 days showed superior efficacy: tumor volume was reduced by ~65% and tumor weight by ~60% vs. vehicle, with no significant increase in toxicity vs. single agents [2] - Immunohistochemistry of tumor tissues from CPI-203-treated mice showed a 55% reduction in c-Myc protein levels and a 45% reduction in Ki-67 (a proliferation marker) compared to vehicle, confirming in vivo target inhibition [2] |
| Enzyme Assay |
Homogeneous Time-Resolved Fluorescence (HTRF) BET Binding Assay: Recombinant BET bromodomain proteins (BRD2 BD1/BD2, BRD3 BD1/BD2, BRD4 BD1/BD2) were incubated with a fluorescently labeled acetylated histone H4 peptide and serial dilutions of CPI-203 (0.01 nM–1 μM). The assay measured the displacement of the labeled peptide by CPI-203, and Ki values were calculated using a competitive binding model [2]
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| Cell Assay |
MCL Cell Proliferation Assay: Bortezomib-resistant MCL cells (Jeko-1/BtzR, Mino/BtzR) were seeded in 96-well plates at 5×10³ cells/well and allowed to attach overnight. Cells were treated with serial dilutions of CPI-203 (0.05–2 μM) alone or in combination with lenalidomide (0.5–10 μM) for 72 hours. Cell viability was measured using a colorimetric MTT assay, and IC50/CI values were calculated via CalcuSyn software [2]
- Apoptosis Assay: Jeko-1/BtzR cells were treated with CPI-203 (0.5 μM) + lenalidomide (5 μM) for 48 hours. Cells were stained with annexin V-FITC and propidium iodide, then analyzed by flow cytometry to quantify apoptotic (annexin V-positive) cells [2] - Western Blot and qRT-PCR Assays: Jeko-1/BtzR cells were treated with CPI-203 (0.5 μM) for 24 hours. For Western blot, cells were lysed, proteins separated by SDS-PAGE, and probed with antibodies against c-Myc, BCL2, cyclin D1, and GAPDH (loading control). For qRT-PCR, total RNA was isolated, reverse-transcribed to cDNA, and amplified with primers for c-Myc and BCL2 (normalized to GAPDH) [2] |
| Animal Protocol |
2.5 mg/kg i.p. Treatment with JQ1 derivative CPI203 inhibits BRD4 phosphorylation of CTD Ser2 in vivo. HeLa cells were transfected as above and treated with increasing concentrations of CPI203.
Bortezomib-Resistant MCL Xenograft Study: Female nude mice (6–8 weeks old) were subcutaneously implanted with 2×10⁶ Jeko-1/BtzR cells in the right flank. When tumors reached ~150 mm³, mice were randomized into 4 groups (n=6 per group): vehicle control, CPI-203 alone, lenalidomide alone, and CPI-203 + lenalidomide [2] - Drug Formulation and Administration: CPI-203 was formulated in 0.5% methylcellulose + 0.1% Tween 80 in water and administered orally via gavage at 30 mg/kg once daily. Lenalidomide was dissolved in PBS and administered via intraperitoneal injection at 10 mg/kg once daily. All treatments lasted for 21 days [2] - Tumor and Toxicity Monitoring: Tumor volume was measured every 3 days using calipers (volume = length × width² / 2). Body weight was recorded weekly to assess toxicity. At study end, mice were euthanized, tumors were excised and weighed, and tumor tissues were fixed in formalin for immunohistochemistry [2] |
| Toxicity/Toxicokinetics |
In a 21-day xenotransplantation study, neither CPI-203 alone (30 mg/kg, orally) nor in combination with lenalidomide (10 mg/kg, intraperitoneally) caused significant changes in mouse body weight (weight loss of no more than 5% compared to the vector group) nor did it cause any toxic clinical symptoms (e.g., lethargy, decreased appetite) [2]
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| References |
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| Additional Infomation |
CPI-203 (also known as RO-6870810, TEN-010, JQ2, RG-6146) is a potent and selective BET bromodomain inhibitor designed to block the interaction between BET proteins and chromatin by binding to the acetylated lysine pocket in BRD2/3/4 [2]
- The synergistic effect of CPI-203 with lenalidomide in bortezomib-resistant mantle cell lymphoma (MCL) suggests its potential for treating relapsed/refractory MCL in which BET target genes (e.g., c-Myc) are often overexpressed [2] |
| Molecular Formula |
C19H18CLN5OS
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| Molecular Weight |
399.90
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| Exact Mass |
399.092
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| CAS # |
1446144-04-2
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| Related CAS # |
(Rac)-CPI-203;202591-23-9
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| PubChem CID |
71291068
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| Appearance |
Light yellow to yellow solid powder
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| Density |
1.5±0.1 g/cm3
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| Boiling Point |
690.5±65.0 °C at 760 mmHg
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| Flash Point |
371.4±34.3 °C
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| Vapour Pressure |
0.0±2.2 mmHg at 25°C
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| Index of Refraction |
1.749
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| LogP |
1.85
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
27
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| Complexity |
611
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| Defined Atom Stereocenter Count |
1
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| SMILES |
CC1=C(SC2=C1C(=N[C@H](C3=NN=C(N32)C)CC(=O)N)C4=CC=C(C=C4)Cl)C
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| InChi Key |
QECMENZMDBOLDR-AWEZNQCLSA-N
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| InChi Code |
InChI=1S/C19H18ClN5OS/c1-9-10(2)27-19-16(9)17(12-4-6-13(20)7-5-12)22-14(8-15(21)26)18-24-23-11(3)25(18)19/h4-7,14H,8H2,1-3H3,(H2,21,26)/t14-/m0/s1
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| Chemical Name |
2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamide
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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 (6.25 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 (6.25 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 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 (6.25 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 | 2.5006 mL | 12.5031 mL | 25.0063 mL | |
| 5 mM | 0.5001 mL | 2.5006 mL | 5.0013 mL | |
| 10 mM | 0.2501 mL | 1.2503 mL | 2.5006 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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