9Z2C

KHK Bound to GS-1291269

This is a non-PDB format compatible entry.

Summary for 9Z2C

• Entry DOI: 10.2210/pdb9z2c/pdb
• Descriptor: Ketohexokinase, 3-amino-3-(4-{7,7-difluoro-2-[(2R)-2-(trifluoromethyl)azetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl}phenyl)-1lambda~6~-thietane-1,1-dione, beta-D-fructofuranose, ... (4 entities in total)
• Functional Keywords: inhibitor, fructose, metabolism, phosphorylation, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 69282.22

Authors

Ferrao, R.D. (deposition date: 2025-11-04, release date: 2026-01-07, Last modification date: 2026-01-14)

Primary citation

Kasun, Z.A.,Liang, X.,Ferrao, R.D.,Kaplan, J.A.,Clark, C.T.,Neubig, M.E.,Byun, D.H.,Badal, S.S.,Sroda, N.,Mistry, T.,Stanley, N.H.,Stevens, K.L.,Bachman, J.L.,Lo, J.R.,Loyer-Drew, J.,Velasquez, M.,Hao, J.,Mwangi, J.,Stafford, B.,Jansa, P.
The Discovery of GS-1291269: A Neutral Ketohexokinase (KHK) Inhibitor with an Unusual Thietane Amine Functional Group.
J.Med.Chem., 69:501-516, 2026

PubMed Abstract: Ketohexokinase (KHK) is the primary enzyme involved in fructose metabolism, converting fructose to fructose-1-phosphate (F1P). KHK is implicated in diseases, including metabolic-dysfunction-associated steatotic liver disease (MASLD) and diabetic kidney disease (DKD), among others. Herein, we describe the discovery of GS-1291269, a potent, neutral KHK inhibitor. GS-1291269 has pharmacokinetic parameters in preclinical species that support once-daily dosing in humans. The high potency and favorable PK profile of GS-1291269 can be attributed to the uncommon dioxo-thietane amine functional group, which avoids potential PK liabilities associated with acidic or basic molecules yet provides a hydrogen bond donor that is critical for potency. Furthermore, GS-1291269 demonstrated liver and kidney fructose-1-phosphate (F1P) reduction in a fructose challenge model in rats.

PubMed: 41433313
DOI: 10.1021/acs.jmedchem.5c02896

Experimental method

X-RAY DIFFRACTION (2.02 Å)