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

  • Bioorg Med Chem Lett. 2019 Apr 15;29(8):1001-1006. doi: 10.1016/j.bmcl.2019.02.012.
Matthew W Martin  1 ,  David R Lancia Jr  2 ,  Hongbin Li  3 ,  Shawn E R Schiller  2 ,  Angela V Toms  2 ,  Zhongguo Wang  2 ,  Kenneth W Bair  2 ,  Jennifer Castro  2 ,  Shawn Fessler  2 ,  Deepali Gotur  2 ,  Stephen E Hubbs  3 ,  Goss S Kauffman  3 ,  Mark Kershaw  3 ,  George P Luke  3 ,  Crystal McKinnon  2 ,  Lili Yao  3 ,  Wei Lu  2 ,  David S Millan  2
Affiliations
  • 1. FORMA Therapeutics, 500 Arsenal Street, Suite 100, Watertown, MA 02472, USA. Electronic address: [email protected].
  • 2. FORMA Therapeutics, 500 Arsenal Street, Suite 100, Watertown, MA 02472, USA.
  • 3. FORMA Therapeutics, 35 Northeast Industrial Road, Branford, CT 06405, USA.
PMID: 30803804 DOI: 10.1016/j.bmcl.2019.02.012
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.

Keywords
FASN; Fatty acid synthase; Oncology; Piperazines; de novo lipogenesis.
Products