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De novo GTP synthesis is a metabolic vulnerability for the interception of brain metastases
Agata M. Kieliszek ; Daniel Mobilio ; Blessing I. Bassey-Archibong , et al. Cell,2024,101755. DOI: 10.1016/j.xcrm.2024.101755 PubMed ID: 39366383
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Abstract: Patients with brain metastases (BM) face a 90% mortality rate within one year of diagnosis and the current standard of care is palliative. Targeting BM-initiating cells (BMICs) is a feasible strategy to treat BM, but druggable targets are limited. Here, we apply Connectivity Map analysis to lung-, breast-, and melanoma-pre-metastatic BMIC gene expression signatures and identify inosine monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme in the de novo GTP synthesis pathway, as a target for BM. We show that pharmacological and genetic perturbation of IMPDH attenuates BMIC proliferation in vitro and the formation of BM in vivo. Metabolomic analyses and CRISPR knockout studies confirm that de novo GTP synthesis is a potent metabolic vulnerability in BM. Overall, our work employs a phenotype-guided therapeutic strategy to uncover IMPDH as a relevant target for attenuating BM outgrowth, which may provide an alternative treatment strategy for patients who are otherwise limited to palliation.
Purchased from AmBeed: 24280-93-1
CAS No. : | 24280-93-1 | MDL No. : | MFCD00036814 |
Formula : | C17H20O6 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | HPNSFSBZBAHARI-RUDMXATFSA-N |
M.W : | 320.34 | Pubchem ID : | 446541 |
Synonyms : |
Mycophenolate;MPA;Mycophenolic acid, Mycophenolate mofetil, Cellcept, Myfortic, RS-61443;NSC 129185;RS-61443
|
Chemical Name : | (E)-6-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoic acid |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In acetonitrile; at 20℃; for 18h; | Example 7; Preparation of (4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-((2-((E)-6-(4-hydroxy-6-methoxy-7- methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4- enamido)ethyl)(methyl)amino)ethyl)docosa-4,7,10,13,16,19-hexaenamide (I-3); N1-(2-Aminoethyl)-N1-methylethane-1,2-diamine (5.0 g, 42.7 mmol) was dissolved in 100 mL of CH2Cl2 and cooled to 0 C. A solution of di-tert-butylcarbonate (0.93 g, 4.27 mmol) in CH2Cl2 (10 mL) was then added dropwise at 0 C. over a period of 15 min The resulting reaction mixture was stirred at 0 C. for 30 min and then warmed to room temperature. After stirring at room temperature for 2 h, the reaction mixture was diluted with CH2Cl2 (100 mL). The organic layer was washed with brine (3×25 mL), dried (Na2SO4) and concentrated under reduced pressure to afford 1.1 g of <strong>[263162-13-6]tert-butyl 2-((2-aminoethyl)(methyl)amino)ethylcarbamate</strong>.<strong>[263162-13-6]tert-butyl 2-((2-aminoethyl)(methyl)amino)ethylcarbamate</strong> (200 mg, 0.922 mmol) was taken up in 5 mL of CH3CN along with mycophenolic acid (295 mg, 0.922 mmol) and EDC (194 mg, 1.01 mmol). The resulting reaction mixture was stirred at room temperature for 18 h and diluted with EtOAc. The organic layer was washed with brine, dried (Na2SO4) and concentrated under reduced pressure. Purification by chromatography (95% CH2Cl2, 5% MeOH) afforded 400 mg of (E)-tert-butyl 2-((2-(6-(4-hydroxy-6-methoxy- 7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4- enamido)ethyl)(methyl)amino)ethylcarbamate (84% yield). This material was taken up in 10 mL of 4 M HCl in dioxane and allowed to stir at room temperature for 2 h. The mixture was diluted with EtOAc (30 mL) and concentrated under reduced pressure to afford the HC1 salt of (E)-N-(2-((2-aminoethyl)(methyl)amino)ethyl)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo- 1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enamide. This material was then taken up in 10 mL of CH3CN along with (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid (DHA, 252 mg, 0.77 mmol), HATU (322 mg, 0.85 mmol) and DIEA (540 3.1 mmol). The resulting reaction mixture was stirred at room temperature for 2 h and diluted with EtOAc (50 mL). The organic layer was washed with brine, dried (Na2SO4) and concentrated under reduced pressure. Purification by chromatography (95% CH2Cl2, 5% MeOH) afforded 300 mg of (4Z,7Z,10Z,13Z,16Z,19Z)-N-(2-((2-((E)-6-(4-hydroxy-6- methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4- enamido)ethyl)(methyl)amino)ethyl)docosa-4,7,10,13,16,19-hexaenamide (53% yield). MS (EI) calcd for C44H63N3O6: 729.47; found 730 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | General procedure: To a solution of mycophenolic acid (2 mmol) in absolute DMF (1.5 mL) carbonyldiimidazole(2.2 mmol) was added and stirred for 2 h at room temperature. Then appropriate amine (2.2 mmol) wasadded and the reaction mixture is stirred at 70 C for 10 h. The mixture was cooled to room temperatureand distilled water (10 mL) was added. The precipitate formed was filtered and crystallized fromaqueous methanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | General procedure: To a solution of mycophenolic acid (2 mmol) in absolute DMF (1.5 mL) carbonyldiimidazole(2.2 mmol) was added and stirred for 2 h at room temperature. Then appropriate amine (2.2 mmol) wasadded and the reaction mixture is stirred at 70 C for 10 h. The mixture was cooled to room temperatureand distilled water (10 mL) was added. The precipitate formed was filtered and crystallized fromaqueous methanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | General procedure: To a solution of mycophenolic acid (2 mmol) in absolute DMF (1.5 mL) carbonyldiimidazole(2.2 mmol) was added and stirred for 2 h at room temperature. Then appropriate amine (2.2 mmol) wasadded and the reaction mixture is stirred at 70 C for 10 h. The mixture was cooled to room temperatureand distilled water (10 mL) was added. The precipitate formed was filtered and crystallized fromaqueous methanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | General procedure: To a solution of mycophenolic acid (2 mmol) in absolute DMF (1.5 mL) carbonyldiimidazole(2.2 mmol) was added and stirred for 2 h at room temperature. Then appropriate amine (2.2 mmol) wasadded and the reaction mixture is stirred at 70 C for 10 h. The mixture was cooled to room temperatureand distilled water (10 mL) was added. The precipitate formed was filtered and crystallized fromaqueous methanol. |
A1378826[ 37415-62-6 ]
Sodium (E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enoate
Reason: Free-salt