5HX6

Crystal structure of RIP1 kinase with a benzo[b][1,4]oxazepin-4-one

5HX6 の概要

• エントリーDOI: 10.2210/pdb5hx6/pdb
• 分子名称: Receptor-interacting serine/threonine-protein kinase 1, 5-benzyl-N-[(3S)-5-methyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl]-1,2-oxazole-3-carboxamide (3 entities in total)
• 機能のキーワード: kinase, inhibitor complex, non-hinge binding, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm: Q13546
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 69948.57

構造登録者

Campobasso, N.,Ward, P. (登録日: 2016-01-29, 公開日: 2016-03-02, 最終更新日: 2024-03-06)

主引用文献

Harris, P.A.,King, B.W.,Bandyopadhyay, D.,Berger, S.B.,Campobasso, N.,Capriotti, C.A.,Cox, J.A.,Dare, L.,Dong, X.,Finger, J.N.,Grady, L.C.,Hoffman, S.J.,Jeong, J.U.,Kang, J.,Kasparcova, V.,Lakdawala, A.S.,Lehr, R.,McNulty, D.E.,Nagilla, R.,Ouellette, M.T.,Pao, C.S.,Rendina, A.R.,Schaeffer, M.C.,Summerfield, J.D.,Swift, B.A.,Totoritis, R.D.,Ward, P.,Zhang, A.,Zhang, D.,Marquis, R.W.,Bertin, J.,Gough, P.J.
DNA-Encoded Library Screening Identifies Benzo[b][1,4]oxazepin-4-ones as Highly Potent and Monoselective Receptor Interacting Protein 1 Kinase Inhibitors.
J.Med.Chem., 59:2163-2178, 2016

PubMed Abstract: The recent discovery of the role of receptor interacting protein 1 (RIP1) kinase in tumor necrosis factor (TNF)-mediated inflammation has led to its emergence as a highly promising target for the treatment of multiple inflammatory diseases. We screened RIP1 against GSK's DNA-encoded small-molecule libraries and identified a novel highly potent benzoxazepinone inhibitor series. We demonstrate that this template possesses complete monokinase selectivity for RIP1 plus unique species selectivity for primate versus nonprimate RIP1. We elucidate the conformation of RIP1 bound to this benzoxazepinone inhibitor driving its high kinase selectivity and design specific mutations in murine RIP1 to restore potency to levels similar to primate RIP1. This series differentiates itself from known RIP1 inhibitors in combining high potency and kinase selectivity with good pharmacokinetic profiles in rodents. The favorable developability profile of this benzoxazepinone template, as exemplified by compound 14 (GSK'481), makes it an excellent starting point for further optimization into a RIP1 clinical candidate.

PubMed: 26854747
DOI: 10.1021/acs.jmedchem.5b01898

実験手法

X-RAY DIFFRACTION (2.23 Å)