(R)-BAY1238097 is the R-isomer of BAY-1238097 with lower activity than BAY1238097. BAY1238097 is a novel, potent and selective inhibitor of BET (bromodomain and extra-terminal) binding to histones and targeting the NFKB/TLR/JAK/STAT signalling pathways, MYC and E2F1-regulated genes, cell cycle regulation and chromatin structure. It has strong anti-proliferative activity in different AML (acute myeloid leukemia) and MM (multiple myeloma) models through down-regulation of c-Myc levels and its downstream transcriptome (IC50 <100 nM in a TR-FRET assay). In vitro, BAY 1238097 showed strong inhibitory activity (IC50 < 100 nM) in a TR-FRET assay using BET BRD4 bromodomain 1 and an acetylated peptide derived from histone H4. In the NanoBRET assay, the interaction between BRD4, BRD3 or BRD2 and H4 was inhibited with IC50 values of 63 nM, 609 nM and 2430 nM, showing selectivity of the compound for BRD4. A strong reduction of c-Myc transcript and protein levels was observed in treated MOLM-13 (AML) and MOLP-8 (MM) cell lines. ChIP experiments performed in these models additionally revealed that BAY 1238097 prevented binding of BRD4 to c-Myc regulatory regions. In vivo, BAY 1238097 showed strong efficacy in the AML models THP-1, MOLM-13 and KG-1, with T/C between 13 and 20%. Overall, the compound was well tolerated at MTD, with body weight losses of 5-9% at nadir. BAY 1238097 was also active in MM models. Efficacy was observed against a human IGH-cyclin D1 translocated MOLP-8 model with a T/C of 3%, whereas the standard-of-care agents bortezomib and lenalidomide were inactive or poorly active. In this model, BAY 1238097 was well tolerated at 10 mg/kg applied over 14 days, with no body weight loss measured. BAY 1238097 was also active against the FGFR/MMSET translocated model NCIH929, with 19% T/C versus 49% T/C for the standard-of-care lenalidomide. The compound was well tolerated applied at 12 mg/kg for 9 days (maximum body weight loss 6%).

Physicochemical Properties

Molecular Formula	C25H33N5O3
Molecular Weight	451.56
Exact Mass	451.258
CAS #	1564269-85-7
Related CAS #	BAY1238097;1564268-08-1
PubChem CID	90041345
Appearance	Light yellow to yellow solid powder
LogP	2.4
Hydrogen Bond Donor Count	1
Hydrogen Bond Acceptor Count	6
Rotatable Bond Count	4
Heavy Atom Count	33
Complexity	688
Defined Atom Stereocenter Count	1
SMILES	C1CN(C)CCN1C1=CC=C(C=C1)C1=NN(C(=O)NC)[C@@H](CC2C1=CC(=C(C=2)OC)OC)C
InChi Key	CJIPEACKIJJYED-KRWDZBQOSA-N
InChi Code	InChI=1R/C25H33N5O3/c1-17-14-19-15-22(32-4)23(33-5)16-21(19)24(27-30(17)25(31)26-2)18-6-8-20(9-7-18)29-12-10-28(3)11-13-29/h6-9,15-17H,10-14H2,1-5H3,(H,26,31)/t17-/m0/s1
Chemical Name	(R)-7,8-dimethoxy-N,4-dimethyl-1-(4-(4-methylpiperazin-1-yl)phenyl)-4,5-dihydro-3H-benzo[d][1,2]diazepine-3-carboxamide
Synonyms	R-isomer of BAY-1238097; BAY1238097; BAY-1238097; BAY 1238097; BAY 12-38097; BAY 123; BAY-123; BAY12-38097; BAY-12-38097
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 Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture.
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

ln Vitro	In vitro, BAY 1238097 showed strong inhibitory activity (IC50 < 100 nM) in a TR-FRET assay using BET BRD4 bromodomain 1 and an acetylated peptide derived from histone H4. In the NanoBRET assay, the interaction between BRD4, BRD3 or BRD2 and H4 was inhibited with IC50 values of 63 nM, 609 nM and 2430 nM, showing selectivity of the compound for BRD4. A strong reduction of c-Myc transcript and protein levels was observed in treated MOLM-13 (AML) and MOLP-8 (MM) cell lines. ChIP experiments performed in these models additionally revealed that BAY 1238097 prevented binding of BRD4 to c-Myc regulatory regions.
ln Vivo	In vivo, BAY 1238097 showed strong efficacy in the AML models THP-1, MOLM-13 and KG-1, with T/C between 13 and 20%. Overall, the compound was well tolerated at MTD, with body weight losses of 5-9% at nadir. BAY 1238097 was also active in MM models. Efficacy was observed against a human IGH-cyclin D1 translocated MOLP-8 model with a T/C of 3%, whereas the standard-of-care agents bortezomib and lenalidomide were inactive or poorly active. In this model, BAY 1238097 was well tolerated at 10 mg/kg applied over 14 days, with no body weight loss measured. BAY 1238097 was also active against the FGFR/MMSET translocated model NCIH929, with 19% T/C versus 49% T/C for the standard-of-care lenalidomide. The compound was well tolerated applied at 12 mg/kg for 9 days (maximum body weight loss 6%). Gene expression profiling performed in liver, blood and duodenum of rats treated daily with 2 mg/kg BAY 1238097 for 14 days demonstrated substantial effects on genes involved in cell proliferation and in the immune response in vivo.
References	[1]. (2015) Abstract 3524: BAY 1238097, a novel BET inhibitor with strong efficacy in hematological tumor models. Cancer Research, 75(15 Suppl), 884. [2]. Preclinical evaluation of the BET bromodomain inhibitor BAY 1238097 for the treatment of lymphoma. Br J Haematol. 2017 Sep;178(6):936-948.

Solubility Data

Solubility (In Vitro)

DMSO : ~150 mg/mL (~332.18 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.54 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 (5.54 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.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.2145 mL	11.0727 mL	22.1455 mL
	5 mM	0.4429 mL	2.2145 mL	4.4291 mL
	10 mM	0.2215 mL	1.1073 mL	2.2145 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.