II399
II399 is a nicotinamide N-methyltransferase (NNMT) inhibitor (human NNMT IC50 = 0.049-8.800 μM; Ki = 5.9-77 nM; Kd = 336 nM). II399 competitively blocks the transfer of methyl from SAM to nicotinamide by occupying the Nicotinamide (HY-B0150) and SAM binding pockets, and inhibits NNMT-mediated shunting of nicotinamide from the NAD+ salvage pathway. II399 reduces cellular MNA, inhibits renal cancer cell viability, and in combination with SHMT2/MEPCE inhibits lipotoxicity and Cholesterol (from animal) (HY-N0322)-induced hepatocyte injury. II399 can be used for research on clear cell renal cell carcinoma and cholesterol-induced hepatotoxicity.
For research use only. We do not sell to patients.
- CAS No.: 2928480-72-0
- Formula: C24H24ClN5O4
- Molecular Weight:481.93
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Storage:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Biological Activity
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Chemical Information
- Protocols
- Purity & Documentation
- References
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Help & FAQs
Biological Activity
Description
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NNMT 0.077/0.07 μM (Ki, FP assay) |
NNMT 0.049 μM (IC50, SAHH-coupled assay) |
NNMT 5.9 nM (Ki, SAHH-coupled assay) |
NNMT 8.8 μM (IC50, 769-P cells (24 h)) |
NNMT 2.0 μM (IC50, 769-P cells (48 h)) |
NNMT 336 nM (Kd) |
Cellular Effect
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Cell Line
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Type | Value | Description | References |
|---|---|---|---|---|
| 769-P | IC50 |
8.8 μM
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Inhibition of cellular NNMT activity in human renal cancer 769-P cells assessed by MNA levels after 24 hrs incubation by LC-MS/MS.
Inhibition of cellular NNMT activity in human renal cancer 769-P cells assessed by MNA levels after 24 hrs incubation by LC-MS/MS.
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37523719 |
| 769-P | IC50 |
2.0 μM
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Inhibition of cellular NNMT activity in human renal cancer 769-P cells assessed by MNA levels after 48 hrs incubation by LC-MS/MS.
Inhibition of cellular NNMT activity in human renal cancer 769-P cells assessed by MNA levels after 48 hrs incubation by LC-MS/MS.
|
37523719 |
| 769-P | IC50 |
1.9 μM
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Inhibition of cellular NNMT activity in human renal cancer 769-P cells assessed by MNA levels by LC-MS/MS.
Inhibition of cellular NNMT activity in human renal cancer 769-P cells assessed by MNA levels by LC-MS/MS.
|
37523719 |
In Vitro
II399 (300 μM; 8 days) completely inhibits the viability of 786-O and Caki-1 renal cancer cells at 300 μM after 8 days[1].
II399 (10 μM; 2 hours) protects AML12 hepatocytes and primary mouse hepatocytes from cholesterol-induced cytotoxicity[4].
II399 (10 μM; 2 hours) completely rescues cholesterol-induced AMPK inhibition in cholesterol-loaded AML12 hepatocytes[4].
II399 (Ki 5.9 nM; IC50 49 nM; 30 minutes) is a potent inhibitor of recombinant human NNMT[2].
II399 (> 333 μM; 10 minutes) exhibits weak ssSAHH inhibition, supporting its improved selectivity relative to SAM-dependent enzymes[2].
II399 (0.03-62.5 μM; 5 minutes) directly binds to recombinant human SHMT2 with a Kd of 2.11 μM, and binds to RNMT with a Kd > 300 μM[2].
II399 (50 μM; 2 hours) binds to SHMT2 and MEPCE and shows a more selective target profile than LL320 in HeLa whole-cell lysates, with 18 candidate targets[2].
II399 (50 μM; 1 hour on ice) binds to NNMT and MEPCE by CETSA and does not thermally stabilize RNMT or DPH5 in HeLa cell lysates[2].
II399 is a competitive NNMT inhibitor in the SAHH-coupled fluorescence assay with a Ki of 5.9 nM and >1000-fold selectivity relative to the tested methyltransferases and SAHH[5].
II399 binds both the SAM and substrate pockets in the NNMT co-crystal structure, with a chloride ion-Asp142 distance of approximately 3 Å and a Tyr204-phenyl stacking distance of approximately 3.6 Å[5].
II399 binds to hNNMT with Kd = 336 nM[1].
The PAMPA permeability of II399 (200 μM; 5 hours) is 0.3 × 10-6 cm/s[1].
II399 inhibits NNMT in FP competition assays with a Ki of 77 nM[5].
II399 binds to NNMT as determined by ITC, with a Kd of 336 nM[5].
II399 (1 μM; 5 hours) is cell-permeable, and an intracellular concentration of 1 μM is detected in cells after 5 hours[5].
II399 (24-48 hours) reduces cellular MNA, with an IC50 of 7.9 μM at 24 hours and 1.9 μM at 48 hours in cells, representing a cell-active NNMT bisubstrate inhibitor[5].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:786-O and Caki-1
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Concentration:300 μM
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Incubation Time:8 days
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Result:Exhibited potent growth inhibition, with complete suppression on 786-O and Caki-1 at 300 μM after 8 days.
Chemical Information
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CAS No. 2928480-72-0
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Molecular Weight 481.93
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Formula C24H24ClN5O4
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SMILES
O[C@H]1[C@@H](C[C@@H]([C@H]1O)CN(C(C)=O)CC#CC2=CC(C(N)=O)=CC=C2)N3C4=NC=NC(Cl)=C4C=C3
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Shipping
Room temperature in continental US; may vary elsewhere.
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Storage
Please store the product under the recommended conditions in the Certificate of Analysis.
Purity & Documentation
References
[1]. Iyamu ID, et al. Structure-Activity Relationship Studies on Cell-Potent Nicotinamide -Methyltransferase Bisubstrate Inhibitors. Journal of medicinal chemistry. 2023 Aug 10;66(15):10510-10527. [Content Brief]
[2]. Meng Y, et al. Comparative Analysis of Two NNMT Bisubstrate Inhibitors through Chemoproteomic Studies: Uncovering the Role of Unconventional SAM Analogue Moiety for Improved Selectivity. ACS chemical biology. 2024 Jan 19;19(1):89-100. [Content Brief]
[3]. Song Q, et al. Nicotinamide N-methyltransferase upregulation contributes to palmitate-elicited peroxisome proliferator-activated receptor transactivation in hepatocytes. American journal of physiology. Cell physiology. 2023 Jul 01;325(1):C29-C41. [Content Brief]
[5]. Iyamu ID, et al. Exploring Unconventional SAM Analogues To Build Cell-Potent Bisubstrate Inhibitors for Nicotinamide N-Methyltransferase. Angewandte Chemie (International ed. in English). 2022 Apr 11;61(16):e202114813. [Content Brief]
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
II399 Related Classifications
HY-163174 Related Classifications
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