Patent Watch

July 23, 2012

These fatty acid synthase inhibitors may reduce cancer risks. Spirocyclic piperidines of formula 1 inhibit the function of fatty acid synthase (FAS), a multifunctional homodimeric enzyme protein. FAS is the primary enzyme required for the anabolic conversion of dietary carbohydrates to fatty acids. It synthesizes long-chain fatty acids by using acetyl coenzyme A (CoA) as a primer, malonyl CoA as a two-carbon donor, and NADPH as the reductant.

FAS activity levels in adult human cells are low because most normal tissues acquire fatty acids preferentially from dietary sources. Many cancer tumor cells, however, show high rates of fatty acid synthesis and FAS overexpression. These cancers include prostate, ovary, colon, endometrium, lung, bladder, stomach, and kidney.

The difference in FAS levels between tumors and normal cells suggests a link between increased FAS expression and increased risk of cancer. Controlling FAS levels may provide a means of cancer therapy that makes FAS inhibition a potential major target in cancer treatment. N. D. Adams and co-inventors describe 146 compounds of formula 1 as FAS inhibitors that could be used for treating cancer in humans. Ar is a substituted or unsubstituted phenyl or 5- or 6-membered heteroaryl group. Compounds 2 and 3 are two structural examples.

The authors measured the FAS inhibition activity of each compound by using one of two assays: detecting residual NADPH substrate after the FAS assay is quenched or detecting CoA products with a thio-reactive coumarin dye. The IC50 values ranged from ≈1 nM to ≈10 mM in the 146 test compounds. (IC50 is the half-maximal inhibitory concentration of the compound.) The most active compounds had <10 nM IC50; compounds 2 and 3 had 10 and 6 nm IC50 values, respectively. (GlaxoSmithKline [Philadelphia]. WIPO Publication WO2012064642, May 24, 2012; Ahmed F. Abdel-Magid)

This patent was originally reviewed in ACS Medicinal Chemistry Letters.

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