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| Targets |
MLLT1 (ENL) and MLLT3 (AF9) YEATS domains. These are histone acetylation reader domains that recognize acetylated lysine residues on histones and play critical roles in transcriptional regulation. SGC-iMLLT specifically binds to the YEATS domains of MLLT1 and MLLT3, blocking their interaction with acetylated histones.
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| ln Vitro |
SGC-iMLLT inhibits MLLT1/3-histone interactions with an IC50 of 0.26 microM. It shows high binding affinity to MLLT1 YEATS domain (Kd = 0.129 microM) and MLLT3 YEATS domain (Kd = 0.077 microM). The compound demonstrates excellent selectivity for MLLT1/3 over other epigenetic reader domains.
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| ln Vivo |
SGC-iMLLT showed most of the consumption resistance, with t1/2 of 53 minutes and 48% remaining after 60 minutes. The main consumption mechanism is N methylation [1].
SGC-iMLLT shows moderate metabolic resistance with a half-life of 53 minutes and 48% remaining after 60 minutes in metabolic stability assays. Cellular target engagement has been demonstrated, confirming that the compound reaches its intracellular targets at sufficient concentrations to inhibit MLLT1/3-histone interactions. |
| Enzyme Assay |
The biochemical assay for YEATS domain binding typically employs fluorescence polarization (FP) or AlphaScreen technology. A fluorescently labeled acetylated histone peptide is incubated with recombinant MLLT1 or MLLT3 YEATS domain protein. Test compound is added at various concentrations, and the displacement of the labeled peptide is measured to determine IC50 and Kd values.
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| Cell Assay |
Cells (e.g., HEK293T or cancer cell lines) are treated with SGC-iMLLT at various concentrations for a defined period (typically 4-24 hours). Cellular target engagement is assessed by a nanoBRET assay or by Western blotting for downstream effects. Cell viability and proliferation assays can be performed to evaluate phenotypic consequences of MLLT1/3 inhibition.
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| Animal Protocol |
SGC-iMLLT is typically administered to mice via intraperitoneal (IP) or oral gavage in appropriate formulations. Pharmacodynamic studies involve harvesting tissues (e.g., spleen, thymus, or tumor xenografts) at various time points post-administration to measure compound concentration and target engagement. Efficacy studies in disease models (e.g., leukemia) would assess tumor growth inhibition and survival.
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| ADME/Pharmacokinetics |
SGC-iMLLT has a molecular weight of 388.47 g/mol and formula C22H24N₆O. It shows moderate metabolic stability with t1/2 of 53 minutes in liver microsomes. Standard PK parameters (AUC, Cmax, clearance, volume of distribution, oral bioavailability) would be determined in rodent PK studies following IV and PO administration. The compound is typically formulated in DMSO or suitable vehicles.
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| Toxicity/Toxicokinetics |
Toxicology data for SGC-iMLLT are not publicly available. As a chemical probe, standard toxicity screening would include assessment of cytotoxicity in a panel of cancer and normal cell lines, hERG inhibition testing, and preliminary rodent toxicology studies to determine tolerability and identify potential off-target effects.
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| References | |
| Additional Infomation |
SGC-iMLLT is a chemical probe developed by the Structural Genomics Consortium (SGC) for epigenetic research. It is not approved for clinical use. The compound is useful for studying the role of MLLT1/3 YEATS domains in transcriptional regulation, cancer, and development. It serves as a tool compound for validating MLLT1/3 as therapeutic targets.
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| Molecular Formula |
C22H24N6O
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|---|---|
| Molecular Weight |
388.465563774109
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| Exact Mass |
388.201
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| CAS # |
2255338-25-9
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| PubChem CID |
134820948
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
2.8
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
29
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| Complexity |
602
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| Defined Atom Stereocenter Count |
1
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| SMILES |
O=C(C1C=CC2=C(C=NN2C)C=1)NC1C=CC2=C(C=1)NC(CN1CCC[C@@H]1C)=N2
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| InChi Key |
QGNDVASWIHEXCL-AWEZNQCLSA-N
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| InChi Code |
InChI=1S/C22H24N6O/c1-14-4-3-9-28(14)13-21-25-18-7-6-17(11-19(18)26-21)24-22(29)15-5-8-20-16(10-15)12-23-27(20)2/h5-8,10-12,14H,3-4,9,13H2,1-2H3,(H,24,29)(H,25,26)/t14-/m0/s1
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| Chemical Name |
1-methyl-N-[2-[[(2S)-2-methylpyrrolidin-1-yl]methyl]-3H-benzimidazol-5-yl]indazole-5-carboxamide
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~83.33 mg/mL (~214.51 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (5.35 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 2.08 mg/mL (5.35 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. 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. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (5.35 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5742 mL | 12.8710 mL | 25.7420 mL | |
| 5 mM | 0.5148 mL | 2.5742 mL | 5.1484 mL | |
| 10 mM | 0.2574 mL | 1.2871 mL | 2.5742 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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