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I-BET762 carboxylic acid (Molibresib carboxylic acid) is an I-BET762-based warhead ligand for conjugation reactions of PROTAC targeting on BET. I-BET762 carboxylic acid (Molibresib carboxylic acid) is a BRD4 inhibitor with a pIC50 of 5.1.
| Targets |
BRD4 (pIC50 = 5.1)
BET family bromodomains (BRD2, BRD3, BRD4)[1] |
|---|---|
| ln Vitro |
I-BET762 carboxylic acid (Molibresib carboxylic acid) (compound 27) blocks peripheral blood mononuclear cells (PBMC) with a pIC50 of less than 4 [1].
I-BET762 inhibits IL-6 production in LPS-challenged human peripheral blood mononuclear cells (PBMC) with a pIC₅₀ of 6.8 for compound 7, the precursor of I-BET762. In the same assay, compound 1 (I-BET762) showed a pIC₅₀ of 6.5.[1] I-BET762 exhibits high passive permeability (167 nm/sec) and good solubility in physiologically relevant media (>3 mg/mL in simulated gastric fluid, fasted state simulated intestinal fluid, and fed state simulated intestinal fluid).[1] I-BET762 showed no significant inhibition of major human CYP isoforms (CYP1A2, 2C9, 2C19, 2D6, 3A4; IC₅₀ ≥ 33 μM) and no time-dependent inhibition of CYP2D6 or CYP3A4.[1] I-BET762 had low in vitro clearance in human liver microsomes and hepatocytes (CLᵢ ≤ 1.7 mL/min/g liver).[1] I-BET762 was not mutagenic in the Ames test with or without S9-mix.[1] I-BET762 showed no appreciable activity (pIC₅₀/pEC₅₀ ≤ 4.8) in a panel of 38 safety-related assays and no significant inhibition (<30% at 10 μM) in an external panel of 50 selectivity assays.[1] I-BET762 did not interact with other bromodomain-containing proteins (BAZ2B, SP140, ATAD2, CREBBP, PCAF).[1] |
| ln Vivo |
I-BET762 demonstrated efficacy in a range of oncology and immunoinflammatory models.[1]
In a rat delayed-type hypersensitivity (DTH) model, I-BET762 dose-dependently inhibited ear swelling at 24 hours post-KLH challenge, comparable to the positive control rapamycin.[1] |
| Enzyme Assay |
Fluorescence polarization (FP) assay was used to measure binding affinity of benzodiazepine compounds to BET bromodomains (BRD2, BRD3, BRD4). The assay tracks ApoA1 upregulation in HepG2 cells, which correlates well with in vitro binding to BET proteins.[1]
Compound 7 (precursor) showed pIC₅₀ values of 5.9, 6.2, and 6.3 for BRD2, BRD3, and BRD4, respectively, in the FP assay.[1] I-BET762 (compound 1) showed a pIC₅₀ of 6.2 for BRD4 in the FP assay.[1] |
| Cell Assay |
ApoA1 upregulation assay: A stable human HepG2 hepatocyte cell line containing an ApoA1 luciferase reporter was used to screen compounds for their ability to upregulate ApoA1 expression. Compound 7 showed an EC₁₇₀ of 0.22 μM.[1]
IL-6 inhibition assay in PBMCs: Peripheral blood mononuclear cells were challenged with LPS, and IL-6 production was measured to assess anti-inflammatory activity of compounds.[1] GABA receptor binding assay: Compounds were tested for their ability to inhibit diazepam binding to the central GABA receptor to assess selectivity over CNS targets.[1] |
| Animal Protocol |
Pharmacokinetic studies were conducted in mouse, rat, dog, and primate. I-BET762 was administered intravenously as a 1-hour infusion in DMSO/Kleptose HPB/saline vehicle, and orally as a suspension in methylcellulose or HPMC/TWEEN80.[1]
In the rat delayed-type hypersensitivity model, I-BET762 was administered to evaluate its effect on ear swelling after KLH challenge. Results were analyzed by ANOVA followed by Tukey's post-hoc test.[1] |
| ADME/Pharmacokinetics |
I-BET762 exhibits high passive permeability (167 nm/sec) and good solubility in physiologically relevant media (>3 mg/mL) [1]. The free fraction (fᵤ) in blood is approximately 0.2 in different species [1]. In vitro metabolic stability is low in both hepatic microsomes and hepatocytes in different species (including humans) [1]. In vivo blood clearance is low in dogs and primates (≤30% hepatic blood flow) and moderate in mice and rats (≤70% hepatic blood flow) [1]. Volume of distribution is moderate in rats, dogs, and primates (~1.8 L/kg), but high in mice (~6.5 L/kg) [1]. Terminal half-life is short in rats (~0.5 h) and long in mice, dogs, and primates (~1.5–5.9 h) [1].
Oral bioavailability was moderate (~27%) in rats and high (44–61%) in mice, dogs, and primates. [1] |
| Toxicity/Toxicokinetics |
I-BET762 showed no mutagenicity in the Ames assay, with or without the addition of the S9 mixture. [1]
No significant activity was observed in 38 safety-related assays (pIC₅₀/pEC₅₀ ≤ 4.8) or 50 selectivity assays (inhibition rate <30% at 10 μM). [1] No significant inhibitory effect on major human CYP isoenzymes was observed. [1] |
| References | |
| Additional Infomation |
The bromine domain and additional C-terminal domain (BET) family are involved in the binding of histone epigenetic markers, more specifically, the binding of acetylated lysine residues. This article describes the discovery of potent benzodiazepine inhibitors and their structure-activity relationship (SAR) that disrupt the function of the bromine domains (BRD2, BRD3, and BRD4) of the BET family. This study yielded a highly potent and selective compound, I-BET762, which is currently undergoing Phase I/II clinical trials for nucleoprotein (NUT) midline carcinoma and other cancers. [1]
I-BET762 is a highly potent and selective small molecule BET bromine domain inhibitor that is currently undergoing clinical development for NUT midline carcinoma and other cancers. [1] This compound was optimized through a structure-activity relationship study of a benzodiazepine lead compound (compound 7) to improve its potency, selectivity, and acid stability. [1] X-ray crystallography analysis showed that the binding mechanism of I-BET762 to BRD4 was similar to that of acetylated lysine, in which water-bridge interactions replaced the direct hydrogen bonds observed in earlier compounds. [1] |
| Molecular Formula |
C20H17CLN4O3
|
|---|---|
| Molecular Weight |
396.826983213425
|
| Exact Mass |
396.098
|
| CAS # |
1300019-38-8
|
| Related CAS # |
Molibresib;1260907-17-2
|
| PubChem CID |
67173666
|
| Appearance |
Typically exists as Light yellow to yellow solids at room temperature
|
| LogP |
1.6
|
| Hydrogen Bond Donor Count |
1
|
| Hydrogen Bond Acceptor Count |
6
|
| Rotatable Bond Count |
4
|
| Heavy Atom Count |
28
|
| Complexity |
610
|
| Defined Atom Stereocenter Count |
1
|
| SMILES |
CC1=NN=C2N1C3=C(C=C(C=C3)OC)C(=N[C@H]2CC(=O)O)C4=CC=C(C=C4)Cl
|
| InChi Key |
VEIZLTSJCDOIBH-INIZCTEOSA-N
|
| InChi Code |
InChI=1S/C20H17ClN4O3/c1-11-23-24-20-16(10-18(26)27)22-19(12-3-5-13(21)6-4-12)15-9-14(28-2)7-8-17(15)25(11)20/h3-9,16H,10H2,1-2H3,(H,26,27)/t16-/m0/s1
|
| Chemical Name |
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]acetic acid
|
| Synonyms |
I-BET762 carboxylic acid; 1300019-38-8; Target Protein-binding moiety 4; CHEMBL2430881; (S)-2-(6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetic acid; 2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]acetic acid; Molibresib carboxylic acid; SCHEMBL1820357;
|
| 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)
|
| Solubility (In Vitro) |
DMSO : ~7.14 mg/mL (~17.99 mM)
|
|---|---|
| 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 | 2.5200 mL | 12.5999 mL | 25.1997 mL | |
| 5 mM | 0.5040 mL | 2.5200 mL | 5.0399 mL | |
| 10 mM | 0.2520 mL | 1.2600 mL | 2.5200 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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