Discovery and optimization of novel piperazines as potent inhibitors of fatty acid synthase (FASN). Issue 8 (15th April 2019)

• Record Type: Journal Article
• Authors: Martin, Matthew W.; Lancia, David R.; Li, Hongbin; Schiller, Shawn E.R.; Toms, Angela V.; Wang, Zhongguo; Bair, Kenneth W.; Castro, Jennifer; Fessler, Shawn; Gotur, Deepali; Hubbs, Stephen E.; Kauffman, Goss S.; Kershaw, Mark; Luke, George P.; McKinnon, Crystal; Yao, Lili; Lu, Wei; Millan, David S.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 29:Issue 8(2019)
• Page Start: 1001
• Page End: 1006
• Publication Date: 2019-04-15
• Subjects: Fatty acid synthase -- FASN -- de novo lipogenesis -- Oncology -- Piperazines; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2019.02.012
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: 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. 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.