1H-Indole-2-carbonitrile, 4-methyl-1-(1H-pyrazol-4-ylmethyl)-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]-1-piperidinyl]methyl]-

1H-Indole-2-carbonitrile, 4-methyl-1-(1H-pyrazol-4-ylmethyl)-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]-1-piperidinyl]methyl]- - Names and Identifiers

Name	4-Methyl-1-(1H-pyrazol-4-ylmethyl)-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]-1-piperidinyl]methyl]-1H-indole-2-carbonitrile
Synonyms	mi503 MI503 mi-503 MI 503 MI-503 CS-1946 1-((1H-Pyrazol-4-yl)methyl)-4-methyl-5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4- 4-Methyl-1-(1H-pyrazol-4-ylmethyl)-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]-1-piperidinyl]methyl]-1H-indole-2-carbonitrile 1H-Indole-2-carbonitrile, 4-methyl-1-(1H-pyrazol-4-ylmethyl)-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]-1-piperidinyl]methyl]-
CAS	1857417-13-0

1H-Indole-2-carbonitrile, 4-methyl-1-(1H-pyrazol-4-ylmethyl)-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]-1-piperidinyl]methyl]- - Physico-chemical Properties

Molecular Formula	C28H27F3N8S
Molar Mass	564.63
Density	1.48±0.1 g/cm3(Predicted)
Boling Point	782.9±60.0 °C(Predicted)
Solubility	Soluble in DMSO
pKa	14.10±0.50(Predicted)
Storage Condition	-20℃
Use	MI-503 is a potent and selective Menin-MLL inhibitor with IC50 = 14.7 nM. MI-503 shows antitumor activity in in vitro and in vivo models of HCC and reveals the potential mechanism of menin contribution to HCC. Treatment with MI-503 selectively kills various HCC cell lines and this effect is significantly enhanced by a combination of MI-503 with sorafenib, the standard-of-care therapy for HCC.
In vitro study	Treatment of mouse bone marrow cells (BMC) transformed with MI-503 of the oncogene with MLL-AF9 resulted in significant growth inhibition, with GI50 = 0.22 μm after 7 days of treatment. The MI-503 inhibition of cell growth was time-dependent and significant after 7-10 days of treatment. MI-503 is very effective in inducing MLL white blood cell differentiation, and can greatly enhance the expression of CD11b (CD11b is a marker of bone marrow differentiation), accompanied by c-kit (leukemia stem cell related marker). In MLL leukemia cells, treatment at <1 μm of MI-503 also resulted in a significant decrease in Hoxa9 and Meis1 expression levels, with a large upregulation of the downstream target genes of the MLL fusion protein.
In vivo study	MI-503 has good drug class properties in mice, including metabolic stability, pharmacokinetics. It is able to prevent hematologic malignancies and reduce MLL leukemia tumor burden in vivo. After intravenous or oral administration of words, high levels can be achieved in peripheral blood MI-503, and oral bioavailability is also high (-75%). Prolongation of the treatment time by MI-503 (38 days) caused no toxic effects in mice, no change in body weight and no change in liver and kidney tissue morphology. MI-503 can greatly improve the survival of MLL leukemia mice, without affecting the normal hematopoietic function.

1H-Indole-2-carbonitrile, 4-methyl-1-(1H-pyrazol-4-ylmethyl)-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]-1-piperidinyl]methyl]- - Reference

Reference

1: Kempinska K, Malik B, Borkin D, Klossowski S, Shukla S, Miao H, Wang J, Cierpicki T, Grembecka J. Pharmacologic Inhibition of the Menin-MLL Interaction Leads to Transcriptional Repression of PEG10 and Blocks Hepatocellular Carcinoma. Mol Cancer Ther. 2018 Jan;1 (1):26-38. doi: 10.1158/1535-7163.MCT-17-0580. Epub 2017 Nov 15. PubMed PMID: 29142068; PubMed Central PMCID: PMC5752584.
2: Svoboda LK, Bailey N, Van Noord RA, Krook MA, Harris A, Cramer C, Jasman B, Patel RM, Thomas D, Borkin D, Cierpicki T, Grembecka J, Lawlor ER. Tumorigenicity of Ewing sarcoma is critically dependent on the trithorax proteins MLL1 and menin. Oncotarget. 2017 Jan 3;8(1):458-471. doi: 10.18632/oncotarget.13444. PubMed PMID: 27888797; PubMed Central PMCID: PMC5352134.
3: 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. PubMed PMID: 25817203; PubMed Central PMCID: PMC4415852.

1H-Indole-2-carbonitrile, 4-methyl-1-(1H-pyrazol-4-ylmethyl)-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]-1-piperidinyl]methyl]- - Preparation solution concentration reference

	1mg	5mg	10mg
1 mM	1.771 ml	8.855 ml	17.711 ml
5 mM	0.354 ml	1.771 ml	3.542 ml
10 mM	0.177 ml	0.886 ml	1.771 ml
5 mM	0.035 ml	0.177 ml	0.354 ml

Last Update：2024-01-02 23:10:35

1H-Indole-2-carbonitrile, 4-methyl-1-(1H-pyrazol-4-ylmethyl)-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]-1-piperidinyl]methyl]- - Cell Experiment

Leukemia cells are treated with MI-503 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-503 are 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

1H-Indole-2-carbonitrile, 4-methyl-1-(1H-pyrazol-4-ylmethyl)-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]-1-piperidinyl]methyl]- - 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 compounds (MI-463 or MI-503) are administrated once daily at designated doses using i.p. injections.

Last Update：2023-08-16 21:32:38

1H-Indole-2-carbonitrile, 4-methyl-1-(1H-pyrazol-4-ylmethyl)-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]-1-piperidinyl]methyl]- - Reference Information

biological activity	MI-503 is an effective and selective Menin-MLL inhibitor with IC50 of 14.7 nM. In human MLL leukemia cell lines, there is a significant growth inhibition effect (GI = 250 nM-570 nM), but in human leukemia cells without MLL translocation, the effect is very small. MI-503 is used to inhibit menin-MLL interactions that prevent the progression of MLL leukemia in vivo.
target	TargetValue Menin-MLL interaction 14.7 nM
Target	Value
Menin-MLL interaction (Cell-free assay)	14.7 nM
in vitro study	mouse bone marrow cells (BMC) transformed with MLL-AF9 oncogenes were treated with MI-503, and significant growth inhibition would occur. after 7 days of treatment, GI50 = 0.22 μM. The inhibitory effect of MI-503 on cell growth is time-dependent, and the effect is significant after 7-10 days of treatment. MI-503 is very effective in inducing MLL white blood cell differentiation. It can greatly enhance the expression of CD11b (CD11b is a marker of bone marrow differentiation), and is accompanied by a decrease in the expression of c-kit (leukemia stem cell-related marker). In MLL leukemia cells, treatment with a MI-503 of <1 μM can also lead to a significant decrease in the expression levels of Hoxa9 and Meis1, and the downstream target genes of MLL fusion protein are greatly up-regulated.
in vivo studies	MI-503 have good drug properties in mice, including metabolic stability, pharmacokinetics. It is able to block hematological malignancies in the body and reduce the MLL leukemia tumor burden. After intravenous injection or oral administration of words, the MI-503 can reach a high level in the peripheral blood and its oral bioavailability is also very high (~ 75%). The prolonged MI-503 treatment time (38 days) did not cause toxic effects in mice, no change in body weight, and no change in liver and kidney tissue morphology. MI-503 can greatly improve the survival of MLL leukemia mice without affecting normal hematopoietic function.

Last Update：2024-04-10 22:29:15

1H-Indole-2-carbonitrile, 4-methyl-1-(1H-pyrazol-4-ylmethyl)-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]-1-piperidinyl]methyl]-

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Product Name: 4-Methyl-1-(1H-pyrazol-4-ylmethyl)-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]-1-piperidinyl]methyl]-1H-indole-2-carbonitrile Visit Supplier Webpage Request for quotation
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1H-Indole-2-carbonitrile, 4-methyl-1-(1H-pyrazol-4-ylmethyl)-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]-1-piperidinyl]methyl]-

1H-Indole-2-carbonitrile, 4-methyl-1-(1H-pyrazol-4-ylmethyl)-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]-1-piperidinyl]methyl]-

4-Methyl-1-(1H-pyrazol-4-ylmethyl)-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]-1-piperidinyl]methyl]-1H-indole-2-carbonitrile

CAS: 1857417-13-0

Molecular Formula: C28H27F3N8S

1H-Indole-2-carbonitrile, 4-methyl-1-(1H-pyrazol-4-ylmethyl)-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]-1-piperidinyl]methyl]- - Names and Identifiers

1H-Indole-2-carbonitrile, 4-methyl-1-(1H-pyrazol-4-ylmethyl)-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]-1-piperidinyl]methyl]- - Physico-chemical Properties

1H-Indole-2-carbonitrile, 4-methyl-1-(1H-pyrazol-4-ylmethyl)-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]-1-piperidinyl]methyl]- - Reference

1H-Indole-2-carbonitrile, 4-methyl-1-(1H-pyrazol-4-ylmethyl)-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]-1-piperidinyl]methyl]- - Preparation solution concentration reference

1H-Indole-2-carbonitrile, 4-methyl-1-(1H-pyrazol-4-ylmethyl)-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]-1-piperidinyl]methyl]- - Cell Experiment

1H-Indole-2-carbonitrile, 4-methyl-1-(1H-pyrazol-4-ylmethyl)-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]-1-piperidinyl]methyl]- - Animal Experiment

1H-Indole-2-carbonitrile, 4-methyl-1-(1H-pyrazol-4-ylmethyl)-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]-1-piperidinyl]methyl]- - Reference Information

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1H-Indole-2-carbonitrile, 4-methyl-1-(1H-pyrazol-4-ylmethyl)-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]-1-piperidinyl]methyl]- Request for Quotation

4-Methyl-1-(1H-pyrazol-4-ylmethyl)-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]-1-piperidinyl]methyl]-1H-indole-2-carbonitrile

CAS: 1857417-13-0

Molecular Formula: C28H27F3N8S

1H-Indole-2-carbonitrile, 4-methyl-1-(1H-pyrazol-4-ylmethyl)-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]-1-piperidinyl]methyl]- - Names and Identifiers

1H-Indole-2-carbonitrile, 4-methyl-1-(1H-pyrazol-4-ylmethyl)-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]-1-piperidinyl]methyl]- - Physico-chemical Properties

1H-Indole-2-carbonitrile, 4-methyl-1-(1H-pyrazol-4-ylmethyl)-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]-1-piperidinyl]methyl]- - Reference

1H-Indole-2-carbonitrile, 4-methyl-1-(1H-pyrazol-4-ylmethyl)-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]-1-piperidinyl]methyl]- - Preparation solution concentration reference

1H-Indole-2-carbonitrile, 4-methyl-1-(1H-pyrazol-4-ylmethyl)-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]-1-piperidinyl]methyl]- - Cell Experiment

1H-Indole-2-carbonitrile, 4-methyl-1-(1H-pyrazol-4-ylmethyl)-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]-1-piperidinyl]methyl]- - Animal Experiment

1H-Indole-2-carbonitrile, 4-methyl-1-(1H-pyrazol-4-ylmethyl)-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]-1-piperidinyl]methyl]- - Reference Information

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1H-Indole-2-carbonitrile, 4-methyl-1-(1H-pyrazol-4-ylmethyl)-5-[[4-[[6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl]amino]-1-piperidinyl]methyl]-