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8ug1

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Crystal structure of KHK-C and compound 13

Structural highlights

8ug1 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 1.99Å
Ligands:	, ,
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.^[1] ^[2]

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^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Trinh CH, Asipu A, Bonthron DT, Phillips SE. Structures of alternatively spliced isoforms of human ketohexokinase. Acta Crystallogr D Biol Crystallogr. 2009 Mar;65(Pt 3):201-11. Epub 2009, Feb 20. PMID:19237742 doi:S0907444908041115
↑ Bonthron DT, Brady N, Donaldson IA, Steinmann B. Molecular basis of essential fructosuria: molecular cloning and mutational analysis of human ketohexokinase (fructokinase). Hum Mol Genet. 1994 Sep;3(9):1627-31. PMID:7833921
↑ Durham TB, Hao J, Spinazze P, Stack DR, Toth JL, Massey S, Mbofana CT, Johnston RD, Lineswala JP, Wrobleski A, Mínguez 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. Identification of LY3522348: A Highly Selective and Orally Efficacious Ketohexokinase Inhibitor. J Med Chem. 2023 Nov 22. PMID:37992274 doi:10.1021/acs.jmedchem.3c01410