Reversible, Orally Bioavailable Small-Molecule Inhibitors Occupy the Substrate Tunnel of the Thioesterase Domain of Fatty Acid Synthase
Fromm, J.; Aleshin, A.; Lambert, L. J.; De Backer, L.; Reddy Ganji, S.; Mattmann, M. E.; Limpert, A. S.; Gosalia, P.; Wimer, C. D.; Layng, F. I. A. L.; Celeridad, M.; Ardecky, R.; Teriete, P.; Scott, D. A.; Hedrick, M. P.; Smith, J. W.; Sheffler, D. J.; Cosford, N. D. P.
Show abstract
Fatty acid synthase (FASN) is the sole enzyme capable of lipogenesis in cells and is upregulated in many cancers. Herein we report the discovery and development of SBP-5917 (78S), a novel, reversible, small-molecule probe which targets the thioesterase (TE) domain of FASN. SBP-5917 and other compounds in the series possess IC50 < 1 M and < 5 M for inhibiting recombinantly purified FASN-TE and cellular FASN respectively. Co-crystal structures of our inhibitors bound to the FASN-TE domain show that they are positioned in the substrate tunnel of the enzyme. Biochemical and biophysical analyses quantify the strength of compound binding and demonstrate their selectivity for FASN-TE. Preliminary pharmacokinetic studies indicate promising in vivo potency for many of the compounds in the series. SBP-5917 is the first structurally validated, reversible inhibitor of FASN-TE with demonstrated cellular target engagement and can serve as a chemical probe to investigate FASN as a therapeutic target.
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