2. Academic Validation
  3. The Discovery of GS-1291269: A Neutral Ketohexokinase (KHK) Inhibitor with an Unusual Thietane Amine Functional Group

The Discovery of GS-1291269: A Neutral Ketohexokinase (KHK) Inhibitor with an Unusual Thietane Amine Functional Group

  • J Med Chem. 2026 Jan 8;69(1):501-516. doi: 10.1021/acs.jmedchem.5c02896.
Zachary A Kasun 1,  Xiaomin Liang 1,  Ryan D Ferrao 1,  Joshua A Kaplan 1,  Christopher T Clark 1,  Megan E Neubig 1,  Daniel H Byun 1,  Shawn S Badal 1,  Natalie Sroda 1,  Tina Mistry 1,  Nathaniel H Stanley 1,  Kirk L Stevens 1,  James L Bachman 1,  Jennifer R Lo 1,  Jennifer Loyer-Drew 1,  Maile Velasquez 1,  Jia Hao 1,  Judy Mwangi 1,  Brian Stafford 1,  Petr Jansa 1
Affiliations

Affiliation

  • 1 Gilead Sciences, Inc., Foster City, California 94404, United States.
PMID: 41433313 DOI: 10.1021/acs.jmedchem.5c02896
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.

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