9z2b
KHK Bound to Compound 18
Structural highlights
DiseaseKHK_HUMAN Defects in KHK are the cause of fructosuria (FRUCT) [MIM:229800. Benign defect of intermediary metabolism.[1] [2] FunctionPublication Abstract from PubMedKetohexokinase (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. The Discovery of GS-1291269: A Neutral Ketohexokinase (KHK) Inhibitor with an Unusual Thietane Amine Functional Group.,Kasun ZA, Liang X, Ferrao RD, Kaplan JA, Clark CT, Neubig ME, Byun DH, Badal SS, Sroda N, Mistry T, Stanley NH, Stevens KL, Bachman JL, Lo JR, Loyer-Drew J, Velasquez M, Hao J, Mwangi J, Stafford B, Jansa P J Med Chem. 2025 Dec 23. doi: 10.1021/acs.jmedchem.5c02896. PMID:41433313[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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