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

Autor: Lu T; Janssen Research & Development, LLC, 1400 McKean Road, Spring House, PA 19477, USA. Electronic address: tlu3@its.jnj.com., Schubert C; Janssen Research & Development, LLC, 1400 McKean Road, Spring House, PA 19477, USA., Cummings MD; Janssen Research & Development, LLC, 1400 McKean Road, Spring House, PA 19477, USA., Bignan G; Janssen Research & Development, LLC, 1400 McKean Road, Spring House, PA 19477, USA., Connolly PJ; Janssen Research & Development, LLC, 1400 McKean Road, Spring House, PA 19477, USA., Smans K; Janssen Research & Development, Turnhoutseweg 30, B-2340 Beerse, Belgium., Ludovici D; Janssen Research & Development, LLC, 1400 McKean Road, Spring House, PA 19477, USA., Parker MH; Janssen Research & Development, LLC, 1400 McKean Road, Spring House, PA 19477, USA., Meyer C; Janssen Research & Development, CS10615, Campus de Maigremont 27106 Val de Reuil, France., Rocaboy C; Villapharma Research, Parque Tecnologico de Fuente Alamo, Carretera El Estrecho-Lobosillo, 30320 Murcia, Spain., Alexander R; Janssen Research & Development, LLC, 1400 McKean Road, Spring House, PA 19477, USA., Grasberger B; Janssen Research & Development, LLC, 1400 McKean Road, Spring House, PA 19477, USA., De Breucker S; Janssen Research & Development, Turnhoutseweg 30, B-2340 Beerse, Belgium., Esser N; Janssen Research & Development, Turnhoutseweg 30, B-2340 Beerse, Belgium., Fraiponts E; Janssen Research & Development, Turnhoutseweg 30, B-2340 Beerse, Belgium., Gilissen R; Janssen Research & Development, Turnhoutseweg 30, B-2340 Beerse, Belgium., Janssens B; Janssen Research & Development, Turnhoutseweg 30, B-2340 Beerse, Belgium., Peeters D; Janssen Research & Development, Turnhoutseweg 30, B-2340 Beerse, Belgium., Van Nuffel L; Janssen Research & Development, Turnhoutseweg 30, B-2340 Beerse, Belgium., Vermeulen P; Janssen Research & Development, Turnhoutseweg 30, B-2340 Beerse, Belgium., Bischoff J; Janssen Research & Development, LLC, 1400 McKean Road, Spring House, PA 19477, USA., Meerpoel L; Janssen Research & Development, Turnhoutseweg 30, B-2340 Beerse, Belgium.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2018 Jul 01; Vol. 28 (12), pp. 2159-2164. Date of Electronic Publication: 2018 May 08.
DOI: 10.1016/j.bmcl.2018.05.014
Abstrakt: 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 (IC 50  = 28 nM) that effectively inhibits proliferation of A2780 ovarian cells (IC 50  = 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 (IC 50  = 25 nM) and LnCaP-Vancouver prostate cells (IC 50  = 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.
(Copyright © 2018 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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