8ug3

Crystal structure of KHK-C and compound 23

spinqualitylabelsall models 8ug3, resolution 2.02Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8ug3 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.02Å Ligands: GOL, SO4, WRE Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease KHK_HUMAN Defects in KHK are the cause of fructosuria (FRUCT) [MIM:229800. Benign defect of intermediary metabolism. Function KHK_HUMAN Publication Abstract from PubMed The identification of clinical candidate LY3522348 (compound 23) is described. LY3522348 is a highly selective, oral dual inhibitor of human ketohexokinase isoforms C and A (hKHK-C, hKHK-A). Optimization began with highly efficient (S)-2-(2-methylazetidin-1-yl)-6-(1H-pyrazol-4-yl)-4-(trifluoromethyl)nicotinonitrile (3). Efforts focused on developing absorption, distribution, metabolism, potency, and in vitro safety profiles to support oral QD dosing in patients. Structure-based design leveraged vectors for substitution of the pyrazole ring, which provided an opportunity to interact with several different proximal amino acid residues in the protein. LY3522348 displayed a robust pharmacodynamic response in a mouse model of fructose metabolism and was advanced into clinical trials. Identification of LY3522348: A Highly Selective and Orally Efficacious Ketohexokinase Inhibitor.,Durham TB, Hao J, Spinazze P, Stack DR, Toth JL, Massey S, Mbofana CT, Johnston RD, Lineswala JP, Wrobleski A, Minguez JM, Perez C, Smith DL, Lamar J, Leon R, Corkins C, Durbin J, Tung F, Guo S, Linder RJ, Yumibe N, Wang W, MacKrell J, Antonellis M, Mascaro B J Med Chem. 2023 Nov 22. doi: 10.1021/acs.jmedchem.3c01410. PMID:37992274 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Proteopedia Page Contributors and Editors (what is this?)

OCA