DB2313

Alias: DB-2313; DB 2313; DB2313

Cat No.:V19210 Purity: ≥98%

COA Product Data Instructions for use SDS

DB2313 is a potent inhibitor of the transcription factor PU.

DB2313 Chemical Structure CAS No.: 2170606-74-1
Product category: New1

This product is for research use only, not for human use. We do not sell to patients.

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Nature 2021, 597(7874):119-125.

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Cell Stem Cell 2024, 31:106-126.e13.

Nature 597, 119–125 (2021)

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Cell 2020,183:1202-1218.e25.

Science Adv 2022:8,eabm9427.

Nature 2021,597(7874):119-125.

Cell 2020,183:1202-1218.e25.

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Product Description
Bioactivity & Protocols
Physicochemical Properties
Solubility Data
Calculators
Biological Data

Product Description

DB2313 is a potent inhibitor of the transcription factor PU.1 with an apoptosis of 14 nM. DB2313 disrupts the interaction of PU.1 with target gene promoters. DB2313 can cause apoptosis in acute myeloid leukemia (AML) cells and has anti-cancer effects.

Biological Activity I Assay Protocols (From Reference)

ln Vitro	Treatment with DB2313 significantly inhibited the proliferation of PU.1 URE–/– acute myeloid leukemia (AML) cells (IC50 of 7.1 μM), but at identical concentrations, had no effect on normal hematopoietic cells. In mouse PU.1 URE–/– AML cells, DB2313 therapy led to a 3.5-fold increase in apoptotic cells. Additionally, in the second and third rounds of plating, DB2313 significantly reduces clonogenicity; in the fourth and succeeding rounds, clonogenicity is completely disrupted [1]. PU.1 occupancy on the E2f1, Junb, and Csf1r promoters is decreased in AML cells by DB2313 [1].
ln Vivo	Mice treated with DB2313 (17 mg/kg; intraperitoneal injection; three times per week; for three weeks) had enhanced survival and delayed the course of leukemia [1].
Animal Protocol	Animal/Disease Models: NSG mice receiving sublethal radiation (2.0 Gy) and injected with PU.1 URE–/– AML cells [1] Doses: 17 mg/kg Route of Administration: intraperitoneal (ip) injection; three times per week; for 3 weeks Experimental Results: Tumor burden diminished and resulted in increased survival.
References	[1]. Iléana Antony-Debré, et al. Pharmacological inhibition of the transcription factor PU.1 in leukemia. J Clin Invest. 2017 Dec 1;127(12):4297-4313. [2]. Zhang S, Zhao S, Qi Y, et al. SPI1-induced downregulation of FTO promotes GBM progression by regulating pri-miR-10a processing in an m6A-dependent manner. Mol Ther Nucleic Acids. 2022;27:699-717.

These protocols are for reference only. InvivoChem does not independently validate these methods.

Physicochemical Properties

Molecular Formula	C42H41FN8O2
Molecular Weight	708.825752019882
Exact Mass	708.333
CAS #	2170606-74-1
PubChem CID	138556040
Appearance	Typically exists as solid at room temperature
LogP	6.9
Hydrogen Bond Donor Count	4
Hydrogen Bond Acceptor Count	7
Rotatable Bond Count	12
Heavy Atom Count	53
Complexity	1130
Defined Atom Stereocenter Count	0
InChi Key	NUVPJXUYFGWDGB-UHFFFAOYSA-N
InChi Code	InChI=1S/C42H41FN8O2/c1-24(2)46-39(44)28-12-18-34-36(20-28)50-41(48-34)26-8-14-32(15-9-26)52-22-30-6-5-7-31(38(30)43)23-53-33-16-10-27(11-17-33)42-49-35-19-13-29(21-37(35)51-42)40(45)47-25(3)4/h5-21,24-25H,22-23H2,1-4H3,(H2,44,46)(H2,45,47)(H,48,50)(H,49,51)
Chemical Name	2-[4-[[2-fluoro-3-[[4-[6-(N'-propan-2-ylcarbamimidoyl)-1H-benzimidazol-2-yl]phenoxy]methyl]phenyl]methoxy]phenyl]-N'-propan-2-yl-3H-benzimidazole-5-carboximidamide
Synonyms	DB-2313; DB 2313; DB2313
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 Data

Solubility (In Vitro)	DMSO : ~3.7 mg/mL (~5.22 mM ()
Solubility (In Vivo)	Solubility in Formulation 1: 5 mg/mL (7.05 mM) in 50% PEG300 +50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	1.4108 mL	7.0539 mL	14.1078 mL
	5 mM	0.2822 mL	1.4108 mL	2.8216 mL
	10 mM	0.1411 mL	0.7054 mL	1.4108 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.

Calculator

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An example of molarity calculation using the molarity calculator is shown below:
What is the mass of compound required to make a 10 mM stock solution in 5 ml of DMSO given that the molecular weight of the compound is 350.26 g/mol?

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The answer of 17.513 mg appears in the Mass box. In a similar way, you may calculate the volume and concentration.

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Dilution Calculator allows you to calculate how to dilute a stock solution of known concentrations. For example, you may Enter C1, C2 & V2 to calculate V1, as detailed below:

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Using the equation C1V1 = C2V2, where C1=10 mM, C2=25 μM, V2=25 ml and V1 is the unknown:

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The answer of 62.5 μL (0.1 ml) appears in the Volume (Start) box

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Molecular Weight Calculator allows you to calculate the molar mass and elemental composition of a compound, as detailed below:

Note: Chemical formula is case sensitive: C12H18N3O4 c12h18n3o4
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In vivo Formulation Calculator (Clear solution)

Step 1: Enter information below (Recommended: An additional animal to make allowance for loss during the experiment)

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Step 2: Enter in vivo formulation (This is only a calculator, not the exact formulation for a specific product. Please contact us first if there is no in vivo formulation in the solubility section.)

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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.

Note： (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.

Biological Data

Expanded heterocyclic diamidines target the DNA minor groove and inhibit PU.1 binding by an allosteric mechanism. (A) Chemical structures of the heterocyclic diamidines. (B) Model of DB2313 docked to the track (5′-AAATAAAA-3′) upstream of the 5′-GGAA-3′ ETS core consensus in the λB motif. (C) Representative SPR sensorgrams for the interaction of DB2313 with the 5′ AT-rich binding site of the λB promoter DNA sequence. Note the lack of binding by DB2313 to an alternative site specific to the ETS homolog ETS1 (5′-GCCGGAAGTG-3′), even at high concentrations (100 nM, asterisk). (D) Comparison of the binding affinities for the λB promoter DNA sequence with different compounds. RU values from the SPR sensorgrams, as in B, were converted to r (r = RU/RUmax, moles of compound bound/mole of promoter DNA) and are plotted against the unbound compound concentration. (E) Specificity of the λB motif for PU.1. Under identical solution conditions, ETS1 bound negligibly at concentrations that saturated the target in the case of PU.1. (F) Normalized PU.1 inhibition resulted from biosensor SPR experiments. The plots represent the amount of PU.1-DNA complex inhibition as a function of the added compound concentration. (G) Perturbations of DNA minor groove width and depth by bound DB2313 or PU.1. The base steps marked “Xi” denote the bases 5′ to the ETS consensus (G0G1AA). Dashed lines indicate the expected values of B-form DNA. Aligned structures of the DB2313-bound (gray) and PU.1-bound (orange) DNA, rendered as van der Waals surfaces, show the mutually incompatible minor groove conformations induced by the diamidine and protein. (H) DNase I footprints of compound binding to the λB motif. The subsite at which the compounds bind is marked by a bracket. Arrows indicate distinct perturbations to the drug-induced DNA structure among the compounds as detected by DNase I. As a reference, the PU.1-bound footprint is also shown (red); note the DNase I–hypersensitive band (asterisk) in the reverse strand that is diagnostic of site-specific ETS-DNA complexes. J Clin Invest . 2017 Dec 1;127(12):4297-4313.

Small-molecule PU.1 inhibitors decrease cell growth and increase apoptosis of AML cells. (A) Cell viability of PU.1 URE–/– AML cells and WT BM cells after treatment with increasing concentrations of vehicle or small molecules (n = 3). (B) Cell viability of human CD34+, THP1, and MOLM13 cells after treatment with increasing concentrations of vehicle or small molecules (n = 3). (C) Apoptosis induction (annexin-V+PI–) in PU.1 URE–/– AML cells after 48 hours of treatment with DB1976 (n = 6), DB2115 (n = 6), or DB2313 (n = 3). Fold change compared with vehicle is shown. (D) Clonogenic capacities of PU.1 URE–/– AML cells after treatment with DB1976 (n = 5), DB2115 (n = 3) and DB2313 (n = 4). (E) Serial replating capacity of PU.1 URE–/– AML cells after treatment with DB2313 (n = 3). (F–H) Primary human AML cells were plated in semisolid media containing DB1976, DB2115, or DB2313; colony numbers, viable cell numbers, and apoptotic cells were assessed after 14 days of culture. Error bars represent the mean ± SD, and each AML sample is represented by an individual dot. The percentage (F and G) or fold change (H) compared with vehicle (dotted line) is shown. (F) Number of viable cells (n = 10) and (G) clonogenic capacity (n = 11) after treatment. (H) Apoptotic cell (annexin-V+PI–) fraction after treatment (n = 10). *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 1-way ANOVA (C, D, and F–H) or 2-tailed Student’s t test (E). J Clin Invest . 2017 Dec 1;127(12):4297-4313.

Inhibitors show on-target PU.1 inhibitory activity in AML cells. (A) qRT-PCR analysis of PU.1 target genes after PU.1 URE–/– AML cell treatment (n = 3–7), normalized to Gapdh. Fold change compared with vehicle is shown. (B) Mean fluorescence intensity (MFI) of BM MNCs isolated from PU.1/GFP-knockin mice (38) after treatment (n = 5). Fold change compared with vehicle is shown. (C) Quantitative ChIP assays of PU.1 occupancy after treatment of PU.1 URE+/–Msh2–/– AML cells (n = 5). Myogenin was used as a negative control. (D–I) Transcriptome analysis of PU.1 URE–/– AML cells after a 24-hour treatment with DB2313 (n = 3) versus vehicle (n = 3). (D) Differentially expressed genes upon treatment were tested for enrichment of genes directly regulated by PU.1, or regulated by the other ETS transcription factors using Ingenuity Knowledge Base (generated with the use of IPA). Dotted line represents the significance threshold (–log P value >1.3). (E and F) Comparative analysis of deregulated genes in PU.1 URE–/– AML cells after treatment and in PUER cells after PU.1 induction (GEO GSE13125). (E) Venn diagram shows significant overlap between the 2 data sets. (F) Deregulated canonical pathways between the data sets. Colored squares indicate the activation Z score. (G) GSEA enrichment plot of PU.1 positively regulated genes (regulon) in AML cells (from the MILE AML network, as determined by the ARACNe algorithm) against the global list of differentially expressed genes upon treatment, ranked by the drug response (as measured by t score of DB2313 vs. vehicle). (H) Heatmap of leading-edge genes showing row-normalized relative expression. (I) Enrichment of PU.1 binding at promoters of deregulated genes in PU.1 URE–/– AML cells upon treatment. Publicly available PU.1 ChIP-seq data from PUER cells (GSE63317) were used for this analysis. Up, upregulated; Down, downregulated. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 1-way ANOVA (A–C), hypergeometric test (E), Fisher’s exact test (I), or according to ref. 57 (G). J Clin Invest . 2017 Dec 1;127(12):4297-4313.