Discovery and optimization of novel piperazines as potent inhibitors of fatty acid synthase (FASN)

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Abstract

The discovery, structure-activity relationships, and optimization of a novel class of fatty acid synthase (FASN) inhibitors is reported. High throughput screening identified a series of substituted piperazines with structural features that enable interactions with many of the potency-driving regions of the FASN KR domain binding site. Derived from this series was FT113, a compound with potent biochemical and cellular activity, which translated into excellent activity in in vivo models.

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Acknowledgments

We thank Hien Diep for in vitro ADME support, Scot Mente for statistical analysis and helpful discussions, and Mark Tebbe and James Loch for contributions to compound design and synthesis. We also thank Viva Biotech (Shanghai) Ltd. for the FASN co-crystal structure with compound 22.

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1

Current Address: KSQ Therapeutics, 610 Main Street, Cambridge, MA 02139, USA.

2

Current Address: Foghorn Therapeutics, 100 Binney Street, Suite 610, Cambridge, MA 02142, USA.

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