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| 25mg |
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Purity: ≥98%
BAY-299 (BAY299) is a novel, highly potent, and selective dual inhibitor of BRD1 and TAF1 with important biological activity. It inhibits BRPF2 bromodomains (BD), TAF1 BD2 and TAF1L BD2 with IC50s of 67 nM, 8 nM, and 106 nM, respectively. Bromodomains (BD) are readers of lysine acetylation marks present in numerous proteins associated with chromatin. The substituted benzoisoquinolinedione series was identified by high-throughput screening, and subsequent structure-activity relationship optimization allowed generation of low nanomolar BRPF2 BD inhibitors with strong selectivity against BRPF1 and BRPF3 BDs. In addition, a strong inhibition of TAF1/TAF1L BD2 was measured for most derivatives. The best compound of the series was BAY-299, which is a very potent, dual inhibitor with an IC50 of 67 nM for BRPF2 BD, 8 nM for TAF1 BD2, and 106 nM for TAF1L BD2. Importantly, no activity was measured for BRD4 BDs. Furthermore, cellular activity was evidenced using a BRPF2- or TAF1-histone H3.3 or H4 interaction assay.
| ln Vitro |
BAY-299 functions as a dual inhibitor, targeting both the TATA box-binding protein-associated factors TAF1 and TAF1L as well as the bromodomain and PHD finger (BRPF) family member BRPF2. With an IC50 of 67 nM and a selectivity that is 47 and 83 times greater than that of BRPF1 and BRPF3 BD, respectively, the TR-FRET test demonstrated that BAY-299 is a strong inhibitor of BRPF2 BD. The AlphaScreen test provided additional confirmation of BAY-299's properties. An IC50 of 97 nM was found, suggesting 23- and 25-fold selectivity over BRPF1 and BRPF3 BD, respectively. With IC50 values of 575 and 825 nM, respectively, BAY-299 inhibits the interaction of BRPF2 BD with histones H4 and H3.3, according to NanoBRET studies. The IC50 values for TAF1 BD2 were 970 and 1400 nM, in that order. At doses up to 10 μM, BAY-299 showed no inhibitory effect on the interaction between BRPF1 or BRD4 and histone H4. The MOLM-13, MV4-11, 769-P, Jurkat, NCI-H526, CHL-1, and 5637 cell growth is inhibited by BAY-299, with corresponding GI50 values of 1060, 2630, 3210, 3900, 6860, 7400, and 7980 nM [1].
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| ln Vivo |
Research on the pharmacokinetic characteristics of BAY-299 in rats reveals that the drug has a large steady-state volume of distribution, a long to very long terminal half-life (t1/2=10 hours), a low blood clearance rate (about 17% of hepatic blood flow), and a high bioavailability (F=73%). Although in vivo blood clearance was less than anticipated based on hepatocyte data, it was in line with estimates based on rat liver microsomal values [1].
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| References |
[1]. Bouché L, et al. Benzoisoquinolinediones as Potent and Selective Inhibitors of BRPF2 and TAF1/TAF1L Bromodomains. J Med Chem. 2017 May 11;60(9):4002-4022
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| CAS # |
2080306-23-4
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| SMILES |
O=C1N(C2=C(C)C=C(N3C)C(N(C)C3=O)=C2)C(C4=CC=C(CCCO)C5=CC=CC1=C45)=O
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| InChi Key |
OFWWWKWUCDUISA-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C25H23N3O4/c1-14-12-20-21(27(3)25(32)26(20)2)13-19(14)28-23(30)17-8-4-7-16-15(6-5-11-29)9-10-18(22(16)17)24(28)31/h4,7-10,12-13,29H,5-6,11H2,1-3H3
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| Chemical Name |
6-(3-Hydroxypropyl)-2-(1,3,6-trimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-1H-benzo[de]isoquinoline-1,3(2H)-dione
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| Synonyms |
BAY299; BAY 299; BAY-299.
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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) |
DMSO : ~25 mg/mL (~58.21 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.82 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 (5.82 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
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.
omparison of5with previously described BRPF inhibitors.J Med Chem. 2017 May 11;60(9):4002-4022. |
Screening strategy for the discovery of6and identification of5.J Med Chem. 2017 May 11;60(9):4002-4022. |
Binding mode of7in BRPF2 BD and basis for selectivity. (A) Cartoon representation of BRPF2 BD domain (white) with key interacting side-chains shown in stick representation with C, N, and O atoms colored white, blue, and red, respectively.J Med Chem. 2017 May 11;60(9):4002-4022. |
Atropisomerism. (A) Atropisomers5aand5bof5.J Med Chem. 2017 May 11;60(9):4002-4022. |
Biophysical selectivity profile of5 |
Cellular activity of5and31in NanoBRET assays.J Med Chem. 2017 May 11;60(9):4002-4022. |
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