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

[Display omitted] •Identified novel and potent inhibitors of FASN KR domain.•Synthesis and structure activity relationships of compounds are reported.•FT113 displays excellent cellular activity and pharmacokinetic properties.•FT113 is a valuable tool to develop POC models of DNL driven disease. 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.