6W0Y

Structure of KHK in complex with compound 6 (2-[(1~{R},5~{S})-3-[5-cyano-6-[(2~{S},3~{R})-2-methyl-3-oxidanyl-azetidin-1-yl]-4-(trifluoromethyl)pyridin-2-yl]-3-azabicyclo[3.1.0]hexan-6-yl]ethanoic acid)

Summary for 6W0Y

• Entry DOI: 10.2210/pdb6w0y/pdb
• Descriptor: Ketohexokinase, 2-[(1~{R},5~{S})-3-[5-cyano-6-[(2~{S},3~{R})-2-methyl-3-oxidanyl-azetidin-1-yl]-4-(trifluoromethyl)pyridin-2-yl]-3-azabicyclo[3.1.0]hexan-6-yl]ethanoic acid, SULFATE ION, ... (4 entities in total)
• Functional Keywords: ketohexokinase, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 69234.09

Authors

Jasti, J. (deposition date: 2020-03-03, release date: 2020-09-23, Last modification date: 2023-10-11)

Primary citation

Futatsugi, K.,Smith, A.C.,Tu, M.,Raymer, B.,Ahn, K.,Coffey, S.B.,Dowling, M.S.,Fernando, D.P.,Gutierrez, J.A.,Huard, K.,Jasti, J.,Kalgutkar, A.S.,Knafels, J.D.,Pandit, J.,Parris, K.D.,Perez, S.,Pfefferkorn, J.A.,Price, D.A.,Ryder, T.,Shavnya, A.,Stock, I.A.,Tsai, A.S.,Tesz, G.J.,Thuma, B.A.,Weng, Y.,Wisniewska, H.M.,Xing, G.,Zhou, J.,Magee, T.V.
Discovery of PF-06835919: A Potent Inhibitor of Ketohexokinase (KHK) for the Treatment of Metabolic Disorders Driven by the Overconsumption of Fructose.
J.Med.Chem., 63:13546-13560, 2020

PubMed Abstract: Increased fructose consumption and its subsequent metabolism have been implicated in metabolic disorders such as nonalcoholic fatty liver disease and steatohepatitis (NAFLD/NASH) and insulin resistance. Ketohexokinase (KHK) converts fructose to fructose-1-phosphate (F1P) in the first step of the metabolic cascade. Herein we report the discovery of a first-in-class KHK inhibitor, PF-06835919 (), currently in phase 2 clinical trials. The discovery of was built upon our originally reported, fragment-derived lead and the recognition of an alternative, rotated binding mode upon changing the ribose-pocket binding moiety from a pyrrolidinyl to an azetidinyl ring system. This new binding mode enabled efficient exploration of the vector directed at the Arg-108 residue, leading to the identification of highly potent 3-azabicyclo[3.1.0]hexane acetic acid-based KHK inhibitors by combined use of parallel medicinal chemistry and structure-based drug design.

PubMed: 32910646
DOI: 10.1021/acs.jmedchem.0c00944

Experimental method

X-RAY DIFFRACTION (2.54 Å)