5L3A

Fragment-based discovery of 6-arylindazole JAK inhibitors

5L3A の概要

• エントリーDOI: 10.2210/pdb5l3a/pdb
• 分子名称: Tyrosine-protein kinase JAK2, ~{N}-(1~{H}-indazol-4-yl)methanesulfonamide (3 entities in total)
• 機能のキーワード: double f mutant, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34741.77

構造登録者

Soerensen, M.D.,Dack, K.N.,Greve, D.R.,Ritzen, A. (登録日: 2016-04-06, 公開日: 2016-04-27, 最終更新日: 2024-05-08)

主引用文献

Ritzen, A.,Srensen, M.D.,Dack, K.N.,Greve, D.R.,Jerre, A.,Carnerup, M.A.,Rytved, K.A.,Bagger-Bahnsen, J.
Fragment-Based Discovery of 6-Arylindazole JAK Inhibitors.
Acs Med.Chem.Lett., 7:641-646, 2016

PubMed Abstract: Janus kinase (JAK) inhibitors are emerging as novel and efficacious drugs for treating psoriasis and other inflammatory skin disorders, but their full potential is hampered by systemic side effects. To overcome this limitation, we set out to discover soft drug JAK inhibitors for topical use. A fragment screen yielded an indazole hit that was elaborated into a potent JAK inhibitor using structure-based design. Growing the fragment by installing a phenol moiety in the 6-position afforded a greatly improved potency. Fine-tuning the substituents on the phenol and sulfonamide moieties afforded a set of compounds with lead-like properties, but they were found to be phototoxic and unstable in the presence of light.

PubMed: 27326341
DOI: 10.1021/acsmedchemlett.6b00087

実験手法

X-RAY DIFFRACTION (1.98 Å)