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
  • 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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