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| 25mg |
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| Targets |
SNDX-5613 targets the menin-MLL (menin-KMT2A) interaction. Menin is a scaffold protein that binds to MLL (mixed-lineage leukemia) fusion proteins, which are oncogenic drivers in MLL-rearranged leukemias. By binding to menin with a Ki of 0.15-0.149 nM, SNDX-5613 disrupts this interaction, preventing the transcriptional activation of downstream target genes such as HOXA9 and MEIS1, which are essential for leukemia maintenance. This disruption leads to differentiation and apoptosis of leukemia cells. The compound is highly selective for the menin-MLL interaction, making it a promising therapeutic agent with reduced off-target effects.
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| ln Vitro |
SNDX-5613 (SNDX5613) is a novel, highly potent and selective inhibitor of Menin-MLL interaction with the potential to be used for MLL-rearranged (MLL-r) acute leukemias, including acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). It inhibits the interaction of Menin-MLL with a Ki of 0.149 nM and a cell based IC50 of 10-20 nM.
SNDX-5613 demonstrates potent in vitro anti-proliferative activity against multiple cell lines harboring MLL rearrangements (MLLr). It shows IC50 values ranging from 10-20 nM in cell lines such as MV4;11, RS4;11, MOLM-13, and KOPN-8. The compound inhibits cell proliferation by disrupting the menin-MLL interaction, leading to downregulation of HOXA9 and MEIS1 expression and induction of differentiation. SNDX-5613 is highly potent, with a Ki of 0.15 nM for menin binding. These in vitro activities confirm its potential as a targeted therapy for MLL-rearranged leukemias. |
| ln Vivo |
Revumenib (SNDX-5613) has an IC50 of 53 nM for plasma in vivo. Treatment with revumenib significantly improves survival and controls leukemia in aggressively disseminated MOLM-13 xenografts[1].
SNDX-5613 has demonstrated significant in vivo activity in preclinical models of MLL-rearranged leukemia. In MOLM-13 disseminated xenograft models, treatment with SNDX-5613 significantly improved survival benefit and leukemia control efficacy. The compound shows good plasma inhibitory activity in vivo, with an IC50 of 53 nM. These results indicate that SNDX-5613 is effective in vivo at inhibiting leukemia growth and improving survival. The compound is orally available, which facilitates its administration in preclinical and clinical studies. Further in vivo studies have supported its development as a clinical candidate for MLL-rearranged leukemias. |
| Enzyme Assay |
In vitro enzyme/receptor binding assays for SNDX-5613 involve measuring its binding affinity to menin. Surface plasmon resonance (SPR) or fluorescence polarization assays are typically used to determine the Ki value (0.15-0.149 nM). In these assays, recombinant menin protein is immobilized, and the compound is flowed over the surface. The binding kinetics are measured, and the dissociation constant is calculated. Competitive binding assays with fluorescently labeled menin-MLL interaction probes can also be used. These assays confirm the high-affinity binding of SNDX-5613 to menin and its ability to displace MLL from menin.
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| Cell Assay |
In vitro cellular assays for SNDX-5613 are conducted in MLL-rearranged leukemia cell lines such as MV4;11, RS4;11, MOLM-13, and KOPN-8. Cells are treated with SNDX-5613 at varying concentrations (typically 1-100 nM) for 72-120 hours. Cell proliferation is measured using CellTiter-Glo or MTT assays, and IC50 values (10-20 nM) are calculated. Differentiation is assessed by measuring cell surface marker expression (e.g., CD11b, CD14) using flow cytometry. Apoptosis is measured using Annexin V staining or caspase activity assays. Gene expression changes (e.g., HOXA9, MEIS1) are measured by qPCR. These assays confirm the compound’s mechanism and potency.
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| Animal Protocol |
In vivo animal experiments with SNDX-5613 are conducted in mouse xenograft models of MLL-rearranged leukemia. Immunodeficient mice are engrafted with MLL-rearranged cell lines such as MOLM-13. SNDX-5613 is administered orally at varying doses (e.g., 30-100 mg/kg) daily or twice daily. Tumor burden is measured by bioluminescence imaging (if luciferase-labeled cells are used) or by flow cytometry analysis of peripheral blood and bone marrow. Survival is monitored as a primary endpoint. Pharmacodynamic endpoints include inhibition of menin-MLL target gene expression (e.g., HOXA9, MEIS1) in leukemia cells. These studies demonstrate the compound’s in vivo efficacy and support its clinical development.
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| ADME/Pharmacokinetics |
SNDX-5613 is an orally available small molecule with favorable pharmacokinetic properties. In preclinical studies, it has demonstrated good oral bioavailability and plasma exposure. The compound shows good plasma inhibitory activity with an IC50 of 53 nM in vivo. Its pharmacokinetic profile supports once or twice daily oral dosing. The compound is metabolized in the liver and excreted via biliary and renal routes. Detailed PK parameters such as half-life, Cmax, and AUC have been characterized in preclinical species and support its clinical development. The compound’s favorable PK properties are important for its therapeutic application.
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| Toxicity/Toxicokinetics |
Toxicological data for SNDX-5613 have been evaluated in preclinical studies supporting its clinical development. The compound has been assessed in standard toxicology studies including repeat-dose toxicity in rodents and non-rodents. Common adverse effects observed at high doses may include gastrointestinal disturbances and hematological changes, consistent with its mechanism of action. The compound has shown a manageable safety profile at therapeutic doses. Genotoxicity and cardiovascular safety assessments have also been conducted. The overall toxicological profile supports the clinical investigation of SNDX-5613 in MLL-rearranged leukemias.
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| References | |
| Additional Infomation |
Revamenib is an orally bioavailable protein-protein interaction (PPI) inhibitor that inhibits the menin-mixed lineage leukemia (MLL; myeloid/lymphoid leukemia; KMT2A) protein, exhibiting potential antitumor activity. After oral administration, revamenib targets and binds to the nucleoprotein menin, thereby preventing the interaction between menin and MLL proteins and the formation of the menin-MLL complex. This reduces the expression of downstream target genes and inhibits the proliferation of MLL-rearranged leukemia cells. The menin-MLL complex plays a crucial role in the survival, growth, transformation, and proliferation of certain types of leukemia cells.
SNDX-5613 (Revumenib) is a potent and selective menin-KMT2A interaction inhibitor in clinical development for the treatment of MLL-rearranged acute leukemias. It has received FDA Breakthrough Therapy Designation and is being evaluated in clinical trials for both adult and pediatric patients with relapsed/refractory MLL-rearranged acute leukemia. The compound’s mechanism involves disrupting the menin-MLL interaction, leading to differentiation and apoptosis of leukemia cells. Clinical trial results have shown promising efficacy and a manageable safety profile. SNDX-5613 represents a major advance in targeted therapy for a high-risk leukemia subtype. |
| Molecular Formula |
C32H47FN6O4S
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|---|---|
| Molecular Weight |
630.8168
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| Exact Mass |
630.34
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| Elemental Analysis |
C, 60.93; H, 7.51; F, 3.01; N, 13.32; O, 10.14; S, 5.08
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| CAS # |
2169919-21-3
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| PubChem CID |
132212657
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| Appearance |
White to off-white solid powder
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| LogP |
4.3
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
11
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| Heavy Atom Count |
44
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| Complexity |
1040
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
FRVSRBKUQZKTOW-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C32H47FN6O4S/c1-5-39(23(3)4)31(40)27-17-25(33)9-12-28(27)43-29-18-34-22-35-30(29)38-20-32(21-38)13-15-37(16-14-32)19-24-7-10-26(11-8-24)36-44(41,42)6-2/h9,12,17-18,22-24,26,36H,5-8,10-11,13-16,19-21H2,1-4H3
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| Chemical Name |
N-ethyl-2-[4-[7-[[4-(ethylsulfonylamino)cyclohexyl]methyl]-2,7-diazaspiro[3.5]nonan-2-yl]pyrimidin-5-yl]oxy-5-fluoro-N-propan-2-ylbenzamide
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| Synonyms |
SNDX-5613; SNDX 5613; SNDX5613; Revumenib;
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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 : ≥ 25 mg/mL (~39.63 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 4.17 mg/mL (6.61 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 41.7 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: ≥ 4.17 mg/mL (6.61 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 41.7 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: ≥ 4.17 mg/mL (6.61 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: ≥ 2.5 mg/mL (3.96 mM) (saturation unknown) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 5: ≥ 2.5 mg/mL (3.96 mM) (saturation unknown) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. 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. Solubility in Formulation 6: ≥ 0.5 mg/mL (0.79 mM) (saturation unknown) in 1% DMSO 99% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.5852 mL | 7.9262 mL | 15.8524 mL | |
| 5 mM | 0.3170 mL | 1.5852 mL | 3.1705 mL | |
| 10 mM | 0.1585 mL | 0.7926 mL | 1.5852 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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