Acss2 inhibitors and methods of use thereof
A CF3, C1-C5 technology, applied in the field of novel ACSS2 inhibitors, can solve problems such as targetable metabolic fragility
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Embodiment 1
[0444] The synthetic detail of compound of the present invention ( Figure 1-3 )
[0445] Experimental steps:
[0446] General Synthesis of Compound 3
[0447]
[0448] in N 2 A solution of Compound 1 (1.00 equiv), Compound 2 (1.0 equiv) in AcOH (0.5 to 10 mL) was stirred at 90°C for 3 to 10 hours. The mixture was concentrated in vacuo. The residue was purified by trituration (in ethyl acetate or EtOH) to afford compound 3.
[0449] General Preparation of Compound 5
[0450]
[0451] To a solution of compound 3 (1.00 equiv) in DCM (5 to 10 mL) was added Et 3 N (2.00 equiv). After stirring at 25 °C for 30 minutes, compound 4 (1.00 equiv) was added, and then 2 The mixture was stirred at 25°C for 2.5 hours. It was concentrated in vacuo to afford crude compound 5, which was used as such in the next step.
[0452] General Preparation of Final Compound 100-277
[0453] method 1
[0454]
[0455] To a solution of compound 5 (1.50 equiv) in MeCN (10 mL), HOBT (2.0...
Embodiment 2
[0998] Biological Activity of Compounds of the Invention
[0999] ACSS2 cell-free viability assay (cell-free IC 50 )
[1000] The assay is based on a coupled reaction with pyrophosphatase: ACSS2 is converting ATP+CoA+acetate => AMP+pyrophosphate+acetyl-CoA (Ac-CoA). Pyrophosphatase converts pyrophosphate, the product of the ACSS2 reaction, into phosphate, which can be detected by measuring absorbance at 620 nm after incubation with Biomol green reagent (Enzo life Science, BML-AK111).
[1001] cell-free IC 50 Determination:
[1002] 10 nM human ACSS2 protein (OriGene Technologies, Inc) was incubated at 37° C. for 90 minutes at various compound concentrations in reactions containing 50 mM Hepes pH 7.5, 10 mM DTT, 90mM KCl, 0.006% Tween-20, 0.1mg / ml BSA, 2mM MgCl 2 , 10 μM Coenzyme A, 5 mM NaAc, 300 μM ATP and 0.5 U / ml pyrophosphatase (Sigma). At the end of the reaction, Biomol Green was added for 30 minutes at room temperature, and the activity was measured by reading the ...
Embodiment 3
[1033] In Vivo Efficacy of Compound 265 in MDA-MB-468 Breast Cancer Cell Xenografts
[1034] In vivo efficacy studies were performed by Charles-River Laboratories, Freiburg, Germany site.
[1035] Tumor masses from the breast cancer cell line MDA-MB-468, passaged as subcutaneous xenografts, were implanted subcutaneously into female NMRI nude mice (Crl:NMRI-Foxn1nu). When the tumor volume reaches 50 to 250mm 3 , the animals were randomly grouped. Vehicle control or Compound 265 was dosed orally at 100 mg / kg once daily. Body weight and tumor volume [mm3] were measured by calipers twice a week.
[1036] The results showed that in the group treated with 100mg / kg compound 265, the growth of the tumor was significantly delayed ( Figure 4 ).
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