2. Academic Validation
  3. Design and synthesis of a series of bioavailable fatty acid synthase (FASN) KR domain inhibitors for cancer therapy

Design and synthesis of a series of bioavailable fatty acid synthase (FASN) KR domain inhibitors for cancer therapy

  • Bioorg Med Chem Lett. 2018 Jul 1;28(12):2159-2164. doi: 10.1016/j.bmcl.2018.05.014.
Tianbao Lu 1,  Carsten Schubert 2,  Maxwell D Cummings 2,  Gilles Bignan 2,  Peter J Connolly 2,  Karine Smans 3,  Donald Ludovici 2,  Michael H Parker 2,  Christophe Meyer 4,  Christian Rocaboy 5,  Richard Alexander 2,  Bruce Grasberger 2,  Sabine De Breucker 3,  Norbert Esser 3,  Erwin Fraiponts 3,  Ron Gilissen 3,  Boudewijn Janssens 3,  Danielle Peeters 3,  Luc Van Nuffel 3,  Peter Vermeulen 3,  James Bischoff 2,  Lieven Meerpoel 3
Affiliations

Affiliations

  • 1 Janssen Research & Development, LLC, 1400 McKean Road, Spring House, PA 19477, USA. Electronic address: tlu3@its.jnj.com.
  • 2 Janssen Research & Development, LLC, 1400 McKean Road, Spring House, PA 19477, USA.
  • 3 Janssen Research & Development, Turnhoutseweg 30, B-2340 Beerse, Belgium.
  • 4 Janssen Research & Development, CS10615, Campus de Maigremont 27106 Val de Reuil, France.
  • 5 Villapharma Research, Parque Tecnologico de Fuente Alamo, Carretera El Estrecho-Lobosillo, 30320 Murcia, Spain.
PMID: 29779975 DOI: 10.1016/j.bmcl.2018.05.014
Abstract

We designed and synthesized a new series of fatty acid synthase (FASN) inhibitors with potential utility for the treatment of Cancer. Extensive SAR studies led to highly active FASN inhibitors with good cellular activity and oral bioavailability, exemplified by compound 34. Compound 34 is a potent inhibitor of human FASN (IC50 = 28 nM) that effectively inhibits proliferation of A2780 ovarian cells (IC50 = 13 nM) in lipid-reduced serum (LRS). This cellular activity can be rescued by addition of palmitate, consistent with an on-target effect. Compound 34 is also active in many Other cell types, including PC3M (IC50 = 25 nM) and LnCaP-Vancouver prostate cells (IC50 = 66 nM), and is highly bioavailable (F 61%) with good exposure after oral administration. In a pharmacodynamics study in H460 lung xenograft-bearing mice, oral treatment with compound 34 results in elevated tumor levels of malonyl-CoA and decreased tumor levels of palmitate, fully consistent with the desired target engagement.

Keywords

Cancer; Cell proliferation; Enzyme inhibitor; Fatty acid synthase; SAR; X-ray crystal structure.

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