Lysine-specific demethylase 1 (LSD1)

Bomedemstat increases p53 expression and methylation while concurrently inhibiting proliferation and inducing apoptosis in Jak2V617F cells[1]. Cell cycle arrest and enhanced survival are caused by bomedemstat (50 nM-1 μM; 96 h), which also promotes apoptosis via BCL-XL and PUMA in a TP53-dependent manner[1].

Treatment with bomedemstat (oral gavage; 45 mg/kg; once daily; 56 d) improves or returns blood cell counts to normal, decreases spleen sizes, reestablishes normal splenic architecture, and lessens fibrosis in the bone marrow[1].

Apoptosis Analysis[1]
Cell Types: SET-2 cells
Tested Concentrations: 50 nM, 100 nM, and 1 μM
Incubation Duration: 96 hrs (hours)
Experimental Results: diminished levels of the antiapoptotic protein BCL-XL and increased levels of the pro-apoptotic protein PUMA.

Animal/Disease Models: Mx-Jak2V617F mice[1]
Doses: 45 mg/kg
Route of Administration: po (oral gavage); 45 mg/kg; one time/day; 56 days
Experimental Results: decreased splenomegaly Dramatically with a few treated mice normalizing their spleen weight, the 56-day course led to partial restoration of lymph follicles and spleen architecture by histological examination.

[1]. LSD1 Inhibition Prolongs Survival in Mouse Models of MPN by Selectively Targeting the Disease Clone. Hemasphere.2018 Jun 8;2(3):e54.

[2]. LSD1/KDM1A inhibitors in clinical trials: advances and prospects. J Hematol Oncol. 2019 Dec 4;12(1):129.

IMG-7289 is currently undergoing clinical trial NCT03136185 (IMG-7289 for the treatment of patients with myelofibrosis).
Bromidesistat is an oral, irreversible lysine-specific demethylase 1 (LSD1) inhibitor with potential antitumor activity. After administration, bromedistat binds to LSD1 and inhibits its activity. LSD1 is a demethylase that inhibits the expression of target genes by converting the dimethylated and monomethylated forms of histone H3 lysine 4 (H3K4) to monomethylated and unmethylated H3K4. LSD1 inhibition enhances H3K4 methylation and increases the expression of tumor suppressor genes. Furthermore, LSD1 can demethylate monomethylated or dimethylated H3K9, thereby increasing the expression of pro-tumorigenic genes; therefore, inhibiting LSD1 can also promote H3K9 methylation and reduce the transcription of these genes. In summary, this may lead to the inhibition of growth in LSD1-overexpressing tumor cells. LSD1 is an enzyme belonging to the flavin adenine dinucleotide (FAD)-dependent amine oxidase family, overexpressed in certain tumor cells, and plays a crucial role in the regulation of gene expression, tumor cell growth, and survival. Despite recent advances, myeloproliferative neoplasms (MPNs) still have a considerably high morbidity and mortality rate. Janus kinase (JAK) inhibitors, such as ruxotinib, can control symptoms but do not significantly alter the natural course of the disease. In this report, we demonstrate the effect of IMG-7289 (an irreversibly epigenetically active lysine-specific demethylase 1 (LSD1) inhibitor) in a mouse model of MPN. Once-daily treatment with IMG-7289 normalized or improved blood cell counts, reduced spleen volume, restored normal spleen structure, and alleviated myelofibrosis. More importantly, the LSD1 inhibitor reduced the mutant allele load and improved survival. IMG-7289 selectively inhibits the proliferation of JAK2 V617F cells and induces their apoptosis by simultaneously increasing the expression and methylation of p53, as well as independently increasing the expression and methylation of the pro-apoptotic factor PUMA, and decreasing the level of its anti-apoptotic antagonist BCLXL. These data provide a molecular understanding of the disease-modifying activity of the LSD1 inhibitor IMG-7289, which is currently being clinically evaluated in high-risk myelofibrosis patients. In addition, low-dose IMG-7289 and ruxolitinib have a synergistic effect in mice, normalizing the MPN phenotype, which provides a theoretical basis for studying combination therapy. [1]

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Histone demethylase LSD1 plays a key role in tumorigenesis, and targeting LSD1 is becoming an emerging option for cancer treatment. To date, a number of LSD1 inhibitors have been reported, some of which, such as TCP, ORY-1001, GSK-2879552, IMG-7289, INCB059872, CC-90011 and ORY-2001, are currently undergoing clinical evaluation for cancer treatment, particularly for small cell lung cancer (SCLC) and acute myeloid leukemia (AML). This review aims to provide a comprehensive overview of clinical trials of LSD1 inhibitors, including studies on molecular mechanisms, clinical efficacy, adverse reactions and pharmacodynamic/pharmacokinetic studies, and to provide an outlook on the future development of this field. [2]

C42H50FN7O8S2

864.016911029816

863.314

C, 58.39; H, 5.83; F, 2.20; N, 11.35; O, 14.81; S, 7.42

1990504-72-7

Bomedemstat hydrochloride;Bomedemstat dihydrochloride;Bomedemstat;1990504-34-1; 1990504-72-7

131801105

White to off-white solid powder

4

13

12

60

986

3

CC1=CC=C(C=C1)S(=O)(=O)O.CC1=CC=C(C=C1)S(=O)(=O)O.CN1CCN(CC1)C(=O)[C@H](CCCN[C@@H]2C[C@H]2C3=CC=C(C=C3)F)NC(=O)C4=CC=C(C=C4)N5C=CN=N5

WLRWBXFBIJMKHG-DVNXTAPYSA-N

InChI=1S/C28H34FN7O2.2C7H8O3S/c1-34-15-17-35(18-16-34)28(38)25(3-2-12-30-26-19-24(26)20-4-8-22(29)9-5-20)32-27(37)21-6-10-23(11-7-21)36-14-13-31-33-36;2*1-6-2-4-7(5-3-6)11(8,9)10/h4-11,13-14,24-26,30H,2-3,12,15-19H2,1H3,(H,32,37);2*2-5H,1H3,(H,8,9,10)/t24-,25-,26+;;/m0../s1

N-[(2S)-5-[[(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino]-1-(4-methylpiperazin-1-yl)-1-oxopentan-2-yl]-4-(triazol-1-yl)benzamide;4-methylbenzenesulfonic acid

IMG7289 ditosylate; IMG-7289; IMG 7289; BOMEDEMSTAT DITOSYLATE; IMG-7289 ditosylate; 1990504-72-7; Bomedemstat tosylate; Bomedemstat (ditosylate); Bomedemstat ditosylate (IMG 7289); 2PYF2U9JNF; Bomedemstat tosylate [USAN]; Bomedemstat ditosylate

2934.99.9001

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, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~115.74 mM)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)