8TVM

IRAK4 in complex with compound 24

8TVM の概要

• エントリーDOI: 10.2210/pdb8tvm/pdb
• 関連するPDBエントリー: 8TVN
• 分子名称: Interleukin-1 receptor-associated kinase 4, N-{1-[(1R,2R)-2-fluorocyclopropyl]-2-oxo-1,2-dihydropyridin-3-yl}-2-[(1R,4r)-1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl]-6-[(propan-2-yl)oxy]-2H-pyrazolo[3,4-b]pyridine-5-carboxamide (3 entities in total)
• 機能のキーワード: kinase, transferase, transferase-inhibitor complex, transferase/inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 140501.72

構造登録者

Metrick, C.M.,Chodaparambil, J.V. (登録日: 2023-08-18, 公開日: 2024-06-26, 最終更新日: 2024-11-06)

主引用文献

Bolduc, P.N.,Pfaffenbach, M.,Evans, R.,Xin, Z.,Henry, K.L.,Gao, F.,Fang, T.,Silbereis, J.,Vera Rebollar, J.,Li, P.,Chodaparambil, J.V.,Metrick, C.,Peterson, E.A.
A Tiny Pocket Packs a Punch: Leveraging Pyridones for the Discovery of CNS-Penetrant Aza-indazole IRAK4 Inhibitors.
Acs Med.Chem.Lett., 15:714-721, 2024

PubMed Abstract: We herein report the discovery, synthesis, and evolution of a series of indazoles and azaindazoles as CNS-penetrant IRAK4 inhibitors. Described is the use of structure-based and property-based drug design strategically leveraged to guide the property profile of a key series into a favorable property space while maintaining potency and selectivity. Our rationale that led toward functionalities with potency improvements, CNS-penetration, solubility, and favorable drug-like properties is portrayed. In vivo evaluation of an advanced analogue showed significant, dose-dependent modulation of inflammatory cytokines in a mouse model. In pursuit of incorporating a highly engineered bridged ether that was crucial to metabolic stability in this series, significant synthetic challenges were overcome to enable the preparation of the analogues.

PubMed: 38746903
DOI: 10.1021/acsmedchemlett.4c00102

実験手法

X-RAY DIFFRACTION (2.1 Å)