Synonym
MI-503; MI 503; MI503.
IUPAC/Chemical 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
InChi Key
DETOMBLLEOZTMZ-UHFFFAOYSA-N
InChi Code
InChI=1S/C28H27F3N8S/c1-17-19(2-3-25-23(17)8-21(11-32)39(25)14-18-12-35-36-13-18)15-38-6-4-20(5-7-38)37-26-24-9-22(10-28(29,30)31)40-27(24)34-16-33-26/h2-3,8-9,12-13,16,20H,4-7,10,14-15H2,1H3,(H,35,36)(H,33,34,37)
SMILES Code
N#CC(N1CC2=CNN=C2)=CC3=C1C=CC(CN4CCC(NC5=C(C=C(CC(F)(F)F)S6)C6=NC=N5)CC4)=C3C
Purity
>98% (or refer to the Certificate of Analysis)
Shipping Condition
Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility
Soluble in DMSO
Shelf Life
>2 years if stored properly
Drug Formulation
This drug may be formulated in DMSO
Stock Solution Storage
0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code
2934.99.9001
More Info
MI-503 reduces sphere formation and cell migration in in vitro HCC models. When applied in vivo, MI-503 gives a strong antitumor effect both as a single agent and in combination with sorafenib in mice xenograft models of HCC. Mechanistically, treatment with MI-503 downregulates expression of several genes known to play a critical role in proliferation and migration of HCC cells, including PEG10, and displaces the menin-MLL1 complex from the PEG10 promoter, resulting in reduced H3K4 methylation and transcriptional repression. Overall,
Biological target:
MI-503 is a highly potent and orally bioavailable small molecule inhibitor of the menin-mLL interaction.
In vitro activity:
Treatment with MI-503 and transfection with either MLL siRNA or menin siRNA inhibited TGF-β1-induced upregulation of α-SMA, fibronectin and Snail, phosphorylation of Smad3 and AKT, and downregulation of E-cadherin in cultured renal epithelial cells. Finally, MI-503 was effective in abrogating serum or TGFβ1-induced transformation of renal interstitial fibroblasts to myofibroblasts in vitro.
Reference: FASEB J. 2023 Jan;37(1):e22712. https://pubmed.ncbi.nlm.nih.gov/36527439/
In vivo activity:
After cholesteatoma was induced in ICR mice (n = 7) by keratinocyte growth factor expression vector transfection, MI503 (50 μM) or phosphate-buffered saline was topically injected for 14 days. MI503 reduced keratinocyte growth factor-induced cholesteatoma in vivo (4 of 4 [100%]). MI503 does not demonstrate any deleterious effects on murine hair cells when assessed by immunostaining.
Reference: Otol Neurotol. 2023 Mar 1;44(3):273-280. https://pubmed.ncbi.nlm.nih.gov/36593557/
|
Solvent |
mg/mL |
mM |
comments |
| Solubility |
| DMSO |
25.0 |
44.28 |
|
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.
Preparing Stock Solutions
The following data is based on the
product
molecular weight
564.64
Batch specific molecular weights may vary
from batch to batch
due to the degree of hydration, which will
affect the solvent
volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass |
1 mg |
5 mg |
10 mg |
| 1 mM |
1.15 mL |
5.76 mL |
11.51 mL |
| 5 mM |
0.23 mL |
1.15 mL |
2.3 mL |
| 10 mM |
0.12 mL |
0.58 mL |
1.15 mL |
| 50 mM |
0.02 mL |
0.12 mL |
0.23 mL |
Formulation protocol:
1. Zou J, Yu C, Zhang C, Guan Y, Zhang Y, Tolbert E, Zhang W, Zhao T, Bayliss G, Li X, Ye Z, Zhuang S. Inhibition of MLL1-menin interaction attenuates renal fibrosis in obstructive nephropathy. FASEB J. 2023 Jan;37(1):e22712. doi: 10.1096/fj.202100634RRR. PMID: 36527439.
2. Svoboda LK, Teh SSK, Sud S, Kerk S, Zebolsky A, Treichel S, Thomas D, Halbrook CJ, Lee HJ, Kremer D, Zhang L, Klossowski S, Bankhead AR, Magnuson B, Ljungman M, Cierpicki T, Grembecka J, Lyssiotis CA, Lawlor ER. Menin regulates the serine biosynthetic pathway in Ewing sarcoma. J Pathol. 2018 Jul;245(3):324-336. doi: 10.1002/path.5085. Epub 2018 May 28. PMID: 29672864; PMCID: PMC6388767.
3. Yamamoto-Fukuda T, Akiyama N, Hirabayashi M, Shimmura H, Kojima H. Epigenetic Regulation as a New Therapeutic Target for Middle Ear Cholesteatoma. Otol Neurotol. 2023 Mar 1;44(3):273-280. doi: 10.1097/MAO.0000000000003795. Epub 2022 Dec 31. PMID: 36593557.
4. 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;17(1):26-38. doi: 10.1158/1535-7163.MCT-17-0580. Epub 2017 Nov 15. PMID: 29142068; PMCID: PMC5752584.
In vitro protocol:
1. Zou J, Yu C, Zhang C, Guan Y, Zhang Y, Tolbert E, Zhang W, Zhao T, Bayliss G, Li X, Ye Z, Zhuang S. Inhibition of MLL1-menin interaction attenuates renal fibrosis in obstructive nephropathy. FASEB J. 2023 Jan;37(1):e22712. doi: 10.1096/fj.202100634RRR. PMID: 36527439.
2. Svoboda LK, Teh SSK, Sud S, Kerk S, Zebolsky A, Treichel S, Thomas D, Halbrook CJ, Lee HJ, Kremer D, Zhang L, Klossowski S, Bankhead AR, Magnuson B, Ljungman M, Cierpicki T, Grembecka J, Lyssiotis CA, Lawlor ER. Menin regulates the serine biosynthetic pathway in Ewing sarcoma. J Pathol. 2018 Jul;245(3):324-336. doi: 10.1002/path.5085. Epub 2018 May 28. PMID: 29672864; PMCID: PMC6388767.
In vivo protocol:
1. Yamamoto-Fukuda T, Akiyama N, Hirabayashi M, Shimmura H, Kojima H. Epigenetic Regulation as a New Therapeutic Target for Middle Ear Cholesteatoma. Otol Neurotol. 2023 Mar 1;44(3):273-280. doi: 10.1097/MAO.0000000000003795. Epub 2022 Dec 31. PMID: 36593557.
2. 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;17(1):26-38. doi: 10.1158/1535-7163.MCT-17-0580. Epub 2017 Nov 15. PMID: 29142068; PMCID: PMC5752584.
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;17(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.
