1628317-18-9

1628317-18-9 - Names and Identifiers

Name	4-methyl-5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indole-2-carbonitrile
Synonyms	MI463 MI 463 MI-463 1628317-18-9 4-Methyl-5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)meth 4-methyl-5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indole-2-carbonitrile 1H-Indole-2-carbonitrile, 4-methyl-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]-1-piperidinyl]methyl]-
CAS	1628317-18-9

1628317-18-9 - Physico-chemical Properties

Molecular Formula	C24H23F3N6S
Molar Mass	484.54
Density	1.43±0.1 g/cm3(Predicted)
Boling Point	663.2±55.0 °C(Predicted)
Solubility	DMSO : 100 mg/mL mother liquor preservation: sub-package and freeze storage to avoid repeated freezing and thawing;-20 ℃,1 month;-80 ℃,6 months (after dilution, the solution temperature is low and storage may precipitate, try to use it now) Cell experiment: dissolve with DMSO first: dilute with culture medium then, and the dilution process is recommended to be carried out in stages to avoid too fast concentration change leading to compound precipitation. If the compound is precipitated during the dilution process, it can be redissolved by ultrasound. During dilution, ensure that the final concentration of DMSO in the working fluid should be below 0.1% as far as possible, and the maximum should not exceed 0.5%, and set up a DMSO control group with corresponding concentration. Animal experiment: Dissolve with DMSO first: dilute with water or normal saline, etc. The dilution process is recommended to be carried out in sections to avoid excessive concentration changes leading to compound
pKa	14.56±0.30(Predicted)
Storage Condition	-20℃
Use	MI-463 is a potent menin-MLL inhibitor with IC50=15.3 nM and Kd=9.9 nM. MI-463 shows its profound effects in MLL leukemia cells and substantial survival benefit in mouse models of MLL leukemia. Pharmacologic inhibition of the menin-MLL interaction represents an effective treatment for MLL leukemias in vivo and provide advanced molecular scaffold for clinical lead identification. Chromosomal translocations affecting mixed lineage leukemia gene (MLL) result in acute leukemias resistant to therapy. The leukemogenic activity of MLL fusion proteins is dependent on their interaction with menin, providing basis for therapeutic intervention.
In vitro study	MI-463 has accurate and effective activity in MLL leukemia cells. MI-463 results resulted in substantial growth inhibition of MLL leukemia cells with a GI50 of 0.23 μm. MI-463 can induce the differentiation of MLL leucema cells. In MLL leukemia, treatment with submicromolar (0.1-1 μm) MI-463 also resulted in a significant decrease in the expression of Hoxa9 and meis1, the downstream target of the MLL fusion protein is significantly up-regulated.
In vivo study	MI-463 in the mouse model of MLL leucemia, there was a significant benefit to its survival. It has good drug-like properties with stable metabolism and good pharmacokinetics in mice. MI-463 after a single intravenous injection or oral dose, in the peripheral blood can reach a relatively high concentration, oral bioavailability is higher (~ 45%). In a mouse xenograft model (implantation of MV4;11 human MLL leukemia cells into BALB/c nude mice for tumor formation), a daily intraperitoneal injection of MI-463 induces potent tumor growth inhibition. In vivo, MI-463 does not impair normal hematopoiesis.

1628317-18-9 - Reference

Reference

1: Borkin D, He S, Miao H, Kempinska K, Pollock J, Chase J, Purohit T, Malik B, Zhao T, Wang J, Wen B, Zong H, Jones M, Danet-Desnoyers G, Guzman ML, Talpaz M, Bixby DL, Sun D, Hess JL, Muntean AG, Maillard I, Cierpicki T, Grembecka J. Pharmacologic inhibition of the Menin-MLL interaction blocks progression of MLL leukemia in vivo. Cancer Cell. 2015 Apr 13;27(4):589-602. doi: 10.1016/j.ccell.2015.02.016. Epub 2015 Mar 26. PMID: 25817203; PMCID: PMC4415852.
2: Kato I, Kasukabe T, Kumakura S. Menin‑MLL inhibitors induce ferroptosis and enhance the anti‑proliferative activity of auranofin in several types of cancer cells. Int J Oncol. 2020 Oct;57(4):1057-1071. doi: 10.3892/ijo.2020.5116. Epub 2020 Aug 28. PMID: 32945449.

1628317-18-9 - Preparation solution concentration reference

	1mg	5mg	10mg
1 mM	2.064 ml	10.319 ml	20.638 ml
5 mM	0.413 ml	2.064 ml	4.128 ml
10 mM	0.206 ml	1.032 ml	2.064 ml
5 mM	0.041 ml	0.206 ml	0.413 ml

Last Update：2024-01-02 23:10:35

1628317-18-9 - Cell Experiment

Leukemia cells are treated with MI-463 or 0.25% DMSO and cultured at 37 °C for 7 days. Media is changed on day 4, viable cell numbers are restored to the original concentration and MI-463 is re-supplied. MTT cell proliferation assay kit is then employed, and plates are read for absorbance at 570 nm using a microplate reader.

Last Update：2023-08-16 21:32:38

1628317-18-9 - Animal Experiment

For efficacy studies in MV4;11 subcutaneous xenograft mice model, 5×10^6 cells are injected into the 4-6 week old female BALB/c nude mice. Treatment is started when the tumor size reached ~100 mm^3. Vehicle (25% DMSO, 25% PEG400, 50% PBS) or MI-463 are administrated once daily at designated doses using i.p. injections.

Last Update：2023-08-16 21:32:38

1628317-18-9 - Reference Information

biological activity	MI-463 is an effective inhibitor of Menin-MLL interaction, IC50 is 15.3 nM.
target	TargetValue Menin-MLL interaction 15.3 nM
Target	Value
Menin-MLL interaction (Cell-free assay)	15.3 nM
in vitro study	MI-463 has accurate and effective activity in MLL leukemia cells. MI-463 results can lead to substantial growth inhibition of MLL leukemia cells with GI50 of 0.23 μM. MI-463 can induce MLL leukemia cells differentiation. In MLL leukemia, treatment with submicromolar (0.1-1 μM)MI-463 will also lead to significant reduction of Hoxa9 and Meis1 expression and significant upregulation of downstream targets of MLL fusion protein.
in vivo research	MI-463 has a significant survival effect in MLL-leukemia mouse models. It has good drug-like properties, stable metabolism and good pharmacokinetics in mice. After a single intravenous injection or oral dose of MI-463, it can reach a relatively high concentration in peripheral blood and has a high oral bioavailability (~ 45%). In a mouse xenograft tumor model (MV4;11 human MLL leukemia cells implanted into BALB/c nude mice for tumorigenesis), daily intraperitoneal injection of MI-463 can induce potent tumor growth inhibition. In the body, MI-463 does not impair normal hematopoietic function.

Last Update：2024-04-09 20:48:19