6UCG

Retinoic acid receptor-related orphan receptor (ROR) gamma in complex with allosteric compound 28

6UCG の概要

• エントリーDOI: 10.2210/pdb6ucg/pdb
• 関連するPDBエントリー: 5C4T
• 分子名称: Nuclear receptor ROR-gamma, (3S,4R)-1-[1-(2-chloro-6-cyclopropylbenzene-1-carbonyl)-4-fluoro-1H-indazol-3-yl]-3-hydroxypiperidine-4-carboxylic acid (3 entities in total)
• 機能のキーワード: ror gamma t, allosteric, nuclear receptor, transcription
• 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: 28642.55

構造登録者

Palte, R.L.,Parthasarathy, G. (登録日: 2019-09-16, 公開日: 2020-03-04, 最終更新日: 2024-03-13)

主引用文献

Zhang, H.,Lapointe, B.T.,Anthony, N.,Azevedo, R.,Cals, J.,Correll, C.C.,Daniels, M.,Deshmukh, S.,van Eenenaam, H.,Ferguson, H.,Hegde, L.G.,Karstens, W.J.,Maclean, J.,Miller, J.R.,Moy, L.Y.,Simov, V.,Nagpal, S.,Oubrie, A.,Palte, R.L.,Parthasarathy, G.,Sciammetta, N.,van der Stelt, M.,Woodhouse, J.D.,Trotter, B.W.,Barr, K.
Discovery ofN-(Indazol-3-yl)piperidine-4-carboxylic Acids as ROR gamma t Allosteric Inhibitors for Autoimmune Diseases.
Acs Med.Chem.Lett., 11:114-119, 2020

PubMed Abstract: The clinical success of anti-IL-17 monoclonal antibodies (i.e., Cosentyx and Taltz) has validated Th17 pathway modulation for the treatment of autoimmune diseases. The nuclear hormone receptor RORγt is a master regulator of Th17 cells and affects the production of a host of cytokines, including IL-17A, IL-17F, IL-22, IL-26, and GM-CSF. Substantial interest has been spurred across both academia and industry to seek small molecules suitable for RORγt inhibition. A variety of RORγt inhibitors have been reported in the past few years, the majority of which are orthosteric binders. Here we disclose the discovery and optimization of a class of inhibitors, which bind differently to an allosteric binding pocket. Starting from a weakly active hit , a tool compound was quickly identified that demonstrated superior potency, selectivity, and off-target profile. Further optimization focused on improving metabolic stability. Replacing the benzoic acid moiety with piperidinyl carboxylate, modifying the 4-aza-indazole core in to 4-F-indazole, and incorporating a key hydroxyl group led to the discovery of , which possesses exquisite potency and selectivity, as well as an improved pharmacokinetic profile suitable for oral dosing.

PubMed: 32071676
DOI: 10.1021/acsmedchemlett.9b00431

実験手法

X-RAY DIFFRACTION (2.87 Å)