9ZLX

Thioesterase Domain of Human Fatty Acid Synthase (FASN-TE) in apo form

Summary for 9ZLX

• Entry DOI: 10.2210/pdb9zlx/pdb
• Descriptor: Fatty acid synthase (2 entities in total)
• Functional Keywords: thioesterase domain, fatty acid synthase, fasn-te, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 32524.67

Authors

Aleshin, A.E.,Lambert, L.J.,Fromm, J.,Cosford, N.D.P. (deposition date: 2025-12-09, release date: 2026-11-04)

Primary citation

Fromm, J.,Aleshin, A.,Lambert, L.J.,De Backer, L.J.S.,Ganji, S.R.,Mattmann, M.E.,Limpert, A.S.,Gosalia, P.,Wimer, C.D.,Layng, F.I.,Celeridad, M.,Ardecky, R.,Teriete, P.,Scott, D.A.,Hedrick, M.P.,Smith, J.W.,Sheffler, D.J.,Cosford, N.D.P.
Reversible, Orally Bioavailable Small-Molecule Inhibitors Occupy the Substrate Tunnel of the Thioesterase Domain of Fatty Acid Synthase.
Biorxiv, 2026

PubMed Abstract: Fatty acid synthase (FASN) is the sole enzyme capable of lipogenesis in cells and is upregulated in many cancers. Herein we report the discovery and development of ( ), a novel, reversible, small-molecule probe which targets the thioesterase (TE) domain of FASN. and other compounds in the series possess IC < 1 µM and < 5 µM for inhibiting recombinantly purified FASN-TE and cellular FASN respectively. Co-crystal structures of our inhibitors bound to the FASN-TE domain show that they are positioned in the substrate tunnel of the enzyme. Biochemical and biophysical analyses quantify the strength of compound binding and demonstrate their selectivity for FASN-TE. Preliminary pharmacokinetic studies indicate promising in vivo potency for many of the compounds in the series. is the first structurally validated, reversible inhibitor of FASN-TE with demonstrated cellular target engagement and can serve as a chemical probe to investigate FASN as a therapeutic target.

PubMed: 42926451
DOI: 10.64898/2026.10.01.756096

Experimental method

X-RAY DIFFRACTION (2.6 Å)