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Purity: ≥98%
INCB054329 is a novel potent and selective inhibitor of Bromodomain and extra-terminal (BET) protein. It that targets Bromodomains 1 (BD1) and BD2 of BRD2, BRD3 and BRD4. INCB054329 inhibited binding of BRD2, BRD3 and BRD4 to an acetylated histone H4 peptide with low nanomolar potency. In myeloma cell lines, treatment with INCB054329 inhibited expression of c-MYC and induced HEXIM1. The majority of myeloma, AML, and lymphoma cell lines tested were growth inhibited by INCB054329 with potencies less than 200 nM. Selectivity was seen when compared with nontransformed cells as the potency for growth inhibition of IL-2 stimulated T-cells from normal donors was greater than 1300 nM. Cell cycle analysis revealed treatment-induced G1 arrest. Furthermore in both AML and lymphoma cell lines, INCB054329 induced apoptosis consistent with increased expression of pro-apoptotic regulators. In vivo, oral administration of INCB054329 inhibited tumor growth in several models of hematologic cancers. In the MM1.S multiple myeloma xenograft model, inhibition of tumor growth was correlated with reduction of c-MYC levels. PK-PD analysis showed c-MYC suppression was associated with an IC50 value of less than 100 nM in vivo. In summary these studies demonstrate that INCB054329 is a potent inhibitor of BET transcriptional regulators in models of hematologic malignancies in vitro and in vivo and support its clinical development for the treatment of cancer.
| Targets |
Bromodomain and Extra-Terminal (BET) family proteins including BRD2, BRD3, and BRD4; it inhibited the binding of these proteins to an acetylated histone H4 peptide with low nanomolar potency [2]
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| ln Vitro |
INCB054329 is a bromodomain and extra-terminal motif (BET) inhibitor[1]. INCB054329 inhibits binding of BRD2, BRD3 and BRD4 to an acetylated histone H4 peptide with low nanomolar efficacy. In myeloma cell lines, treatment with INCB054329 inhibited expression of c- MYC and activated HEXIM1. The majority of myeloma, AML, and lymphoma cell lines studied are growth suppressed by INCB054329 with potencies less than 200 nM. Selectivity is demonstrated when compared with nontransformed cells since the potency for growth inhibition of IL-2 activated T- cells from normal donors is greater than 1300 nM. Cell cycle analysis demonstrates treatment-induced G1 arrest. Furthermore in both AML and lymphoma cell lines, INCB054329 promotes apoptosis commensurate with elevated expression of pro-apoptotic regulators[2].
In myeloma cell lines, treatment with INCB054329 led to the inhibition of c-MYC expression and the induction of HEXIM1 expression [2] - The majority of tested myeloma, acute myeloid leukemia (AML), and lymphoma cell lines showed growth inhibition when treated with INCB054329, with potencies (growth inhibition) less than 200 nM [2] - When compared with nontransformed cells, INCB054329 exhibited selectivity: the potency for growth inhibition of IL-2 stimulated T-cells from normal donors was greater than 1300 nM [2] - Cell cycle analysis revealed that treatment with INCB054329 induced G1 phase arrest in the tested cell lines [2] - In both AML and lymphoma cell lines, INCB054329 induced apoptosis, which was consistent with the increased expression of pro-apoptotic regulators [2] |
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| ln Vivo |
In a number of hematologic cancer models, oral treatment of INCB054329 reduces the growth of tumors. Reduction of c-MYC levels is linked with prevention of tumor growth in the MM1.S multiple myeloma xenograft model. According to PK-PD study, in vivo c-MYC suppression is linked to an IC50 value of less than 100 nM[2].
Oral administration of INCB054329 inhibited tumor growth in several models of hematologic cancers [2] - In the MM1.S multiple myeloma xenograft model, the inhibition of tumor growth by INCB054329 was correlated with a reduction in c-MYC levels [2] - Pharmacokinetic-pharmacodynamic (PK-PD) analysis showed that the suppression of c-MYC by INCB054329 was associated with an IC₅₀ value of less than 100 nM in vivo [2] |
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| Enzyme Assay |
Assay for evaluating the binding inhibition of BET proteins to acetylated histone H4 peptide: The assay was designed to measure the ability of INCB054329 to inhibit the interaction between BRD2, BRD3, BRD4 (members of the BET family) and an acetylated histone H4 peptide. The experiment was conducted to detect the binding activity, and the result showed that INCB054329 inhibited the binding with low nanomolar potency, though specific numerical values for the binding inhibition potency (such as IC50) were not provided [2]
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| Cell Assay |
Cell growth inhibition assay for myeloma, AML, and lymphoma cell lines: The cell lines (myeloma, AML, lymphoma) were treated with different concentrations of INCB054329. After a certain incubation period, the growth status of the cells was evaluated to determine the potency of the drug in inhibiting cell growth. The majority of the tested cell lines showed growth inhibition with potencies less than 200 nM [2]
- Cell growth inhibition assay for IL-2 stimulated T-cells: IL-2 stimulated T-cells from normal donors were treated with INCB054329 at various concentrations. After incubation, the growth inhibition effect of the drug on these T-cells was assessed, and the potency for growth inhibition was found to be greater than 1300 nM [2] - Cell cycle analysis assay: The tested cell lines were treated with INCB054329. After treatment, the cells were processed to analyze their cell cycle distribution (e.g., using flow cytometry-based methods). The analysis revealed that the drug induced G1 phase arrest in the cells [2] - Apoptosis detection assay in AML and lymphoma cell lines: AML and lymphoma cell lines were treated with INCB054329. After treatment, the cells were examined to detect apoptosis (e.g., through methods that assess apoptotic markers or cell morphological changes). The assay showed that the drug induced apoptosis, and this was accompanied by increased expression of pro-apoptotic regulators [2] - Western blot or similar assay for c-MYC and HEXIM1 expression in myeloma cell lines: Myeloma cell lines were treated with INCB054329. After treatment, the cells were lysed, and the expression levels of c-MYC and HEXIM1 proteins were detected (likely using western blot). The results indicated that the drug inhibited c-MYC expression and induced HEXIM1 expression [2] |
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| References | |||
| Additional Infomation |
INCB054329 is a novel BET inhibitor[2]
- BET protein plays an important role in transcriptional regulation by interacting with complexes such as Mediator and p-TEFb on gene promoter and enhancer elements[2] - Studies using gene knockdown and small molecule inhibitors have shown that targeting BET protein has therapeutic effects in cancer and acute inflammation models, which provides a theoretical basis for developing INCB054329 as a potential anticancer drug[2] - INCB054329 has shown strong inhibitory effects on BET transcriptional regulators in both in vitro and in vivo hematologic malignancy models, supporting its clinical development in cancer treatment[2] - INCB054329 is listed as a BET bromine domain inhibitor and is currently in the clinical trial stage (as of the time of publication[1]), and its structure has not yet been disclosed[1] |
| Molecular Formula |
C19H16N4O3
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|---|---|
| Molecular Weight |
348.3553
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| Exact Mass |
348.122
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| CAS # |
1628607-64-6
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| Related CAS # |
(R)-INCB054329;1628607-63-5;INCB054329 Racemate;1628607-62-4
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| PubChem CID |
90410660
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
1.9
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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 |
2
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| Heavy Atom Count |
26
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| Complexity |
561
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| Defined Atom Stereocenter Count |
1
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| SMILES |
O1C2=C(C3C(C)=NOC=3C)C=CC3=C2N(C(N3)=O)[C@@]([H])(C2=CC=CC=N2)C1
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| InChi Key |
XYLPKCDRAAYATL-OAHLLOKOSA-N
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| InChi Code |
InChI=1S/C19H16N4O3/c1-10-16(11(2)26-22-10)12-6-7-14-17-18(12)25-9-15(23(17)19(24)21-14)13-5-3-4-8-20-13/h3-8,15H,9H2,1-2H3,(H,21,24)/t15-/m1/s1
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| Chemical Name |
(11S)-7-(3,5-dimethyl-1,2-oxazol-4-yl)-11-pyridin-2-yl-9-oxa-1,3-diazatricyclo[6.3.1.04,12]dodeca-4(12),5,7-trien-2-one
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| Synonyms |
INCB54329; INCB 54329; INCB-54329; INCB054329; INCB-054329; INCB 054329
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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 |
| 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 (7.18 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 (7.18 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 (7.18 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 | 2.8706 mL | 14.3530 mL | 28.7059 mL | |
| 5 mM | 0.5741 mL | 2.8706 mL | 5.7412 mL | |
| 10 mM | 0.2871 mL | 1.4353 mL | 2.8706 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.
 Overview of bromodomain inhibition. Bromodomains recognize acetylation marks in histone tails and recruit transcriptional machinery promoting target gene transcription, such as in the case ofc-MYC. Bromodomain inhibitors prevent interaction between the bromodomain and the acetyl group, causing the downregulation of certain genes. Bromodomains play a key role in gene transcription regulation.Epigenetics. 2017; 12(5): 323–339. |
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 Structure-based phylogeny of the human bromodomains and their inhibitors. There are 61 bromodomains in 46 bromodomain-containing proteins. Roman numerals indicate the eight major structural classes.Epigenetics. 2017; 12(5): 323–339. |
 BET bromodomain inhibitor molecules. Non-BET bromodomain inhibitor molecules.Epigenetics. 2017; 12(5): 323–339. |
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