8UG3

Crystal structure of KHK-C and compound 23

8UG3 の概要

• エントリーDOI: 10.2210/pdb8ug3/pdb
• 関連するPDBエントリー: 8UG1
• 分子名称: Ketohexokinase, 2-[(4P)-4-{2-[(2S)-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-1H-pyrazol-1-yl]-1-(piperazin-1-yl)ethan-1-one, SULFATE ION, ... (5 entities in total)
• 機能のキーワード: inhibitor, sugar binding protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 70229.09

構造登録者

Durbin, J.D.,Guo, S.Y. (登録日: 2023-10-05, 公開日: 2023-12-06, 最終更新日: 2023-12-27)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.02 Å)