5C37

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

Summary for 5C37

• Entry DOI: 10.2210/pdb5c37/pdb
• Descriptor: 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)
• Functional Keywords: fatty acid synthase, inhibitor, beta-ketoacyl reductase, cancer, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm : P49327
• Total number of polymer chains: 2
• Total formula weight: 146722.89

Authors

Schubert, C.,Milligan, C.M.,Vo, K.,Grasberger, B. (deposition date: 2015-06-17, release date: 2016-06-22, Last modification date: 2024-06-19)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.3 Å)