5C37

Structure of the beta-ketoacyl reductase domain of human fatty acid synthase bound to a spiro-imidazolone inhibitor

5C37 の概要

• エントリーDOI: 10.2210/pdb5c37/pdb
• 分子名称: Fatty acid synthase, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 6-{[(3R)-1-(cyclopropylcarbonyl)pyrrolidin-3-yl]methyl}-5-[4-(1-methyl-1H-indazol-5-yl)phenyl]-4,6-diazaspiro[2.4]hept-4-en-7-one, ... (6 entities in total)
• 機能のキーワード: fatty acid synthase, inhibitor, beta-ketoacyl reductase, cancer, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm : P49327
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 146722.89

構造登録者

Schubert, C.,Milligan, C.M.,Vo, K.,Grasberger, B. (登録日: 2015-06-17, 公開日: 2016-06-22, 最終更新日: 2024-06-19)

主引用文献

Lu, T.,Schubert, C.,Cummings, M.D.,Bignan, G.,Connolly, P.J.,Smans, K.,Ludovici, D.,Parker, M.H.,Meyer, C.,Rocaboy, C.,Alexander, R.,Grasberger, B.,De Breucker, S.,Esser, N.,Fraiponts, E.,Gilissen, R.,Janssens, B.,Peeters, D.,Van Nuffel, L.,Vermeulen, P.,Bischoff, J.,Meerpoel, L.
Design and synthesis of a series of bioavailable fatty acid synthase (FASN) KR domain inhibitors for cancer therapy.
Bioorg.Med.Chem.Lett., 28:2159-2164, 2018

PubMed 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 (IC = 28 nM) that effectively inhibits proliferation of A2780 ovarian cells (IC = 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 = 25 nM) and LnCaP-Vancouver prostate cells (IC = 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.

PubMed: 29779975
DOI: 10.1016/j.bmcl.2018.05.014

実験手法

X-RAY DIFFRACTION (2.3 Å)