8UG1

Crystal structure of KHK-C and compound 13

Summary for 8UG1

• Entry DOI: 10.2210/pdb8ug1/pdb
• Descriptor: Ketohexokinase, {(2R)-1-[(4M)-4-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-6-(trifluoromethyl)pyrimidin-2-yl]azetidin-2-yl}methanol, SULFATE ION, ... (5 entities in total)
• Functional Keywords: inhibitor, sugar binding protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 70363.19

Authors

Durbin, J.D.,Guo, S.Y. (deposition date: 2023-10-05, release date: 2023-12-06, Last modification date: 2023-12-27)

Primary citation

Durham, T.B.,Hao, J.,Spinazze, P.,Stack, D.R.,Toth, J.L.,Massey, S.,Mbofana, C.T.,Johnston, R.D.,Lineswala, J.P.,Wrobleski, A.,Minguez, J.M.,Perez, C.,Smith, D.L.,Lamar, J.,Leon, R.,Corkins, C.,Durbin, J.,Tung, F.,Guo, S.,Linder, R.J.,Yumibe, N.,Wang, W.,MacKrell, J.,Antonellis, M.,Mascaro, B.
Identification of LY3522348: A Highly Selective and Orally Efficacious Ketohexokinase Inhibitor.
J.Med.Chem., 66:15960-15976, 2023

PubMed Abstract: The identification of clinical candidate LY3522348 (compound ) 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 ()-2-(2-methylazetidin-1-yl)-6-(1-pyrazol-4-yl)-4-(trifluoromethyl)nicotinonitrile (). 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.

PubMed: 37992274
DOI: 10.1021/acs.jmedchem.3c01410

Experimental method

X-RAY DIFFRACTION (1.99 Å)