MI-503

Catalog No.S7817 Batch:S781701

Technical Data

Formula	C₂₈H₂₇F₃N₈S
Molecular Weight	564.63	CAS No.	1857417-13-0
Solubility (25°C)*	In vitro	DMSO	100 mg/mL (177.1 mM)
		Ethanol	15 mg/mL (26.56 mM)
		Water	Insoluble
* <1 mg/ml means slightly soluble or insoluble. * Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations. * Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

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Biological Activity

Description

MI-503 is a potent and selective Menin-MLL inhibitor with IC50 of 14.7 nM. It shows pronounced growth suppressive activity in a panel of human MLL leukemia cell lines(GI50 at 250 nM-570 nM range), but only a minimal effect in human leukemia cell lines without MLL translocations.

Targets

Menin-MLL interaction ^[1]
(Cell-free assay)

14.7 nM

In vitro

Treatment of murine bone marrow cells (BMC) transformed with the MLL-AF9 oncogene with MI-503 results in substantial growth inhibition, with half-maximal growth inhibitory concentration (GI50) values of 0.22 μM, measured after 7 days of treatment. The cell growth inhibitory effect of MI-503 is time-dependent, with a pronounced effect achieved after 7-10 days of treatment. MI-503 is also very effective in inducing differentiation of MLL leukemia cells and substantially increases expression of CD11b, a myeloid differentiation marker. These effects are accompanied by reduced c-kit (CD117) expression, a marker associated with leukemia stem cells (LSCs). Treatment with sub-micromolar concentrations of MI-503 also leads to markedly reduced expression of Hoxa9 and Meis1, downstream targets of MLL fusion proteins substantially upregulated in MLL leukemias^[1].

In vivo

MI-503 has very favorable drug-like properties, including metabolic stability and pharmacokinetic profile in mice. It blocks hematologic tumors in vivo and reduces MLL leukemia tumor burden. MI-503 achieves high level in peripheral blood following a single intravenous or oral dose, while also showing high oral bioavailability (~75%). Prolonged treatment (38 days) with MI-503 induces no toxicity in mice as reflected by no alterations in the body weight and no morphological changes in liver and kidney tissues. MI-503 could substantially improve survival of MLL leukemic mice and does not impair normal hematopoiesis in vivo^[1].

Protocol (from reference)

Cell Assay:^{^[1]}	Cell lines MV4;11 human leukemia cells expressing MLL-AF4 Concentrations -- Incubation Time 7days Method For viability assays, leukemia cells are plated at relevant concentrations and treated with compounds or 0.25% DMSO and cultured at 37 °C for 7 days. Media is changed at day 4, viable cell numbers are restored to the original concentration and compounds are re-supplied. MTT cell proliferation assay kit is then employed, and plates are read for absorbance at 570 nm using a PHERAstar BMG microplate reader. Effect of menin-MLL inhibitors on expression level is assessed by Real-time quantitative PCR (qRT-PCR) after 6 days of incubation of compounds with cells, with media changed and compound re-supply at day 3. For cell differentiation studies, leukemia cells are treated with menin-MLL inhibitors for 7 days, then harvested, washed and incubated with Pacific Blue rat anti-mouse CD11b antibody before being analyzed by flow cytometry.
Animal Study:^{^[1]}	Animal Models Mouse models of MLL leukemia (BALB/c nude mice) Dosages 15 mg/kg Administration i.v.

Cell Assay:^{^[1]}

Cell lines
MV4;11 human leukemia cells expressing MLL-AF4
Concentrations
--
Incubation Time
7days
Method
For viability assays, leukemia cells are plated at relevant concentrations and treated with compounds or 0.25% DMSO and cultured at 37 °C for 7 days. Media is changed at day 4, viable cell numbers are restored to the original concentration and compounds are re-supplied. MTT cell proliferation assay kit is then employed, and plates are read for absorbance at 570 nm using a PHERAstar BMG microplate reader. Effect of menin-MLL inhibitors on expression level is assessed by Real-time quantitative PCR (qRT-PCR) after 6 days of incubation of compounds with cells, with media changed and compound re-supply at day 3. For cell differentiation studies, leukemia cells are treated with menin-MLL inhibitors for 7 days, then harvested, washed and incubated with Pacific Blue rat anti-mouse CD11b antibody before being analyzed by flow cytometry.

Animal Study:^{^[1]}

Animal Models
Mouse models of MLL leukemia (BALB/c nude mice)
Dosages
15 mg/kg
Administration
i.v.

References

[1] Borkin D, et al. Cancer Cell. 2015, 27(4):589-602.

Selleck's MI-503 has been cited by 9 publications

MLL1 regulates cytokine-driven cell migration and metastasis [ Sci Adv, 2024, 10(11):eadk0785]	PubMed: 38478601
Targeting Menin disrupts the KMT2A/B and polycomb balance to paradoxically activate bivalent genes [ Nat Cell Biol, 2023, 25(2):258-272]	PubMed: 36635503
Therapeutic targeting of metabolic vulnerabilities in cancers with MLL3/4-COMPASS epigenetic regulator mutations [ J Clin Invest, 2023, 133(13)e169993]	PubMed: 37252797
Combinatorial targeting of a chromatin complex comprising Dot1L, menin and the tyrosine kinase BAZ1B reveals a new therapeutic vulnerability of endocrine therapy-resistant breast cancer [ Breast Cancer Res, 2022, 24(1):52]	PubMed: 35850772
Combinatorial targeting of menin and the histone methyltransferase DOT1L as a novel therapeutic strategy for treatment of chemotherapy-resistant ovarian cancer [ Cancer Cell Int, 2022, 22(1):336]	PubMed: 36333801
Super-enhancer Acquisition Drives FOXC2 Expression in Middle Ear Cholesteatoma [ J Assoc Res Otolaryngol, 2021, 10.1007/s10162-021-00801-7]	PubMed: 33861394
Combined targeting of the Menin-MLL chromatin regulatory complex and the FLT3 tyrosine kinase as a novel therapeutic approach against NPM1mut and MLL-r [ Johannes Gutenberg-Universität Mainz, 2021, 10.25358/openscience-5949]	PubMed: None
Menin and Menin-Associated Proteins Coregulate Cancer Energy Metabolism [ Cancers (Basel), 2020, 12(9)E2715]	PubMed: 32971831
Menin-MLL inhibitor blocks progression of middle ear cholesteatoma in vivo [ Int J Pediatr Otorhinolaryngol, 2020, 140:110545]	PubMed: 33302022

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