OXFBD04
目录号 : GC39417OXFBD04 是一种有效的选择性 BRD4 抑制剂,IC50 为 166 nM。OXFBD04 是一种有效的 BET 溴结构域配体,对 CREBBP 溴结构域具有额外的适度亲和力。OXFBD04 具有抗癌活性。
Cas No.:2231747-03-6
Sample solution is provided at 25 µL, 10mM.
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OXFBD04 is a potent and selective BRD4 inhibitor with an IC50 of 166?nM. OXFBD04 is a potent BET bromodomain ligand with additional modest affinity for the CREBBP bromodomain. OXFBD04 has anti-cancer activity[1].
[1]. Jennings LE, et al. BET bromodomain ligands: Probing the WPF shelf to improve BRD4 bromodomain affinity and metabolic stability. Bioorg Med Chem. 2018 Jul 15;26(11):2937-2957.
Cas No. | 2231747-03-6 | SDF | |
Canonical SMILES | OC(C1=CC(O)=CC(C2=C(C)ON=C2C)=C1)C3=CC=CN=C3 | ||
分子式 | C17H16N2O3 | 分子量 | 296.32 |
溶解度 | DMSO: ≥ 250 mg/mL (843.68 mM) | 储存条件 | Store at -20°C |
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1 mM | 3.3747 mL | 16.8737 mL | 33.7473 mL |
5 mM | 0.6749 mL | 3.3747 mL | 6.7495 mL |
10 mM | 0.3375 mL | 1.6874 mL | 3.3747 mL |
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Bioactivation of Isoxazole-Containing Bromodomain and Extra-Terminal Domain (BET) Inhibitors
Metabolites 2021 Jun 15;11(6):390.PMID:34203690DOI:10.3390/metabo11060390.
The 3,5-dimethylisoxazole motif has become a useful and popular acetyl-lysine mimic employed in isoxazole-containing bromodomain and extra-terminal (BET) inhibitors but may introduce the potential for bioactivations into toxic reactive metabolites. As a test, we coupled deep neural models for quinone formation, metabolite structures, and biomolecule reactivity to predict bioactivation pathways for 32 BET inhibitors and validate the bioactivation of select inhibitors experimentally. Based on model predictions, inhibitors were more likely to undergo bioactivation than reported non-bioactivated molecules containing isoxazoles. The model outputs varied with substituents indicating the ability to scale their impact on bioactivation. We selected OXFBD02, OXFBD04, and I-BET151 for more in-depth analysis. OXFBD's bioactivations were evenly split between traditional quinones and novel extended quinone-methides involving the isoxazole yet strongly favored the latter quinones. Subsequent experimental studies confirmed the formation of both types of quinones for OXFBD molecules, yet traditional quinones were the dominant reactive metabolites. Modeled I-BET151 bioactivations led to extended quinone-methides, which were not verified experimentally. The differences in observed and predicted bioactivations reflected the need to improve overall bioactivation scaling. Nevertheless, our coupled modeling approach predicted BET inhibitor bioactivations including novel extended quinone methides, and we experimentally verified those pathways highlighting potential concerns for toxicity in the development of these new drug leads.
BET bromodomain ligands: Probing the WPF shelf to improve BRD4 bromodomain affinity and metabolic stability
Bioorg Med Chem 2018 Jul 15;26(11):2937-2957.PMID:29776834DOI:10.1016/j.bmc.2018.05.003.
Ligands for the bromodomain and extra-terminal domain (BET) family of bromodomains have shown promise as useful therapeutic agents for treating a range of cancers and inflammation. Here we report that our previously developed 3,5-dimethylisoxazole-based BET bromodomain ligand (OXFBD02) inhibits interactions of BRD4(1) with the RelA subunit of NF-κB, in addition to histone H4. This ligand shows a promising profile in a screen of the NCI-60 panel but was rapidly metabolised (t½ = 39.8 min). Structure-guided optimisation of compound properties led to the development of the 3-pyridyl-derived OXFBD04. Molecular dynamics simulations assisted our understanding of the role played by an internal hydrogen bond in altering the affinity of this series of molecules for BRD4(1). OXFBD04 shows improved BRD4(1) affinity (IC50 = 166 nM), optimised physicochemical properties (LE = 0.43; LLE = 5.74; SFI = 5.96), and greater metabolic stability (t½ = 388 min).