8ug1
Crystal structure of KHK-C and compound 13
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 PubMedThe 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[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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