Reversible, Orally Bioavailable Small-Molecule Inhibitors Occupy the Substrate Tunnel of the Thioesterase Domain of Fatty Acid Synthase
- 1Center for Therapeutics Discovery, Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Instit
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 SBP-5917 (78S), a novel, reversible, small-molecule probe which targets the thioesterase (TE) domain of FASN. SBP-5917 and other compounds in the series possess IC50 < 1 M and < 5 M 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. SBP-5917 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.
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BibTeX
@misc{fromm2026reversible,
title = {{Reversible, Orally Bioavailable Small-Molecule Inhibitors Occupy the Substrate Tunnel of the Thioesterase Domain of Fatty Acid Synthase}},
author = {J. Fromm and A. Aleshin and L. J. Lambert and L. De Backer and S. Reddy Ganji and M. E. Mattmann and A. S. Limpert and P. Gosalia and C. D. Wimer and F. I. A. L. Layng and M. Celeridad and R. Ardecky and P. Teriete and D. A. Scott and M. P. Hedrick and J. W. Smith and D. J. Sheffler and N. D. P. Cosford},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.01.756096},
url = {https://www.biorxiv.org/content/10.64898/2026.10.01.756096v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Reversible, Orally Bioavailable Small-Molecule Inhibitors Occupy the Substrate Tunnel of the Thioesterase Domain of Fatty Acid Synthase
AU - J. Fromm
AU - A. Aleshin
AU - L. J. Lambert
AU - L. De Backer
AU - S. Reddy Ganji
AU - M. E. Mattmann
AU - A. S. Limpert
AU - P. Gosalia
AU - C. D. Wimer
AU - F. I. A. L. Layng
AU - M. Celeridad
AU - R. Ardecky
AU - P. Teriete
AU - D. A. Scott
AU - M. P. Hedrick
AU - J. W. Smith
AU - D. J. Sheffler
AU - N. D. P. Cosford
PY - 2026
DA - 2026/10/01
PB - bioRxiv
DO - 10.64898/2026.10.01.756096
UR - https://www.biorxiv.org/content/10.64898/2026.10.01.756096v1
AB - 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 SBP-5917 (78S), a novel, reversible, small-molecule probe which targets the thioesterase (TE) domain of FASN. SBP-5917 and other compounds in the series possess IC50 < 1 M and < 5 M 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. SBP-5917 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.
ER -