4AOF

Selective small molecule inhibitor discovered by chemoproteomic assay platform reveals regulation of Th17 cell differentiation by PI3Kgamma

4AOF の概要

• エントリーDOI: 10.2210/pdb4aof/pdb
• 関連するPDBエントリー: 1E8Y 1E8Z 1HE8 2A4Z 2A5U 2CHW 2CHX 2CHZ 2V4L 3ZVV 3ZW3 4ANU 4ANV 4ANW 4ANX
• 分子名称: PHOSPHATIDYLINOSITOL-4,5-BISPHOSPHATE 3-KINASE CATALYTIC SUBUNIT GAMMA ISOFORM, N-[6-(5-methylsulfonylpyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]ethanamide (3 entities in total)
• 機能のキーワード: transferase
• 由来する生物種: HOMO SAPIENS (HUMAN)
• 細胞内の位置: Cytoplasm: P48736
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 110229.55

構造登録者

Bergamini, G.,Bell, K.,Shimamura, S.,Werner, T.,Cansfield, A.,Muller, K.,Perrin, J.,Rau, C.,Ellard, K.,Hopf, C.,Doce, C.,Leggate, D.,Mangano, R.,Mathieson, T.,OMahony, A.,Plavec, I.,Rharbaoui, F.,Reinhard, F.,Savitski, M.M.,Ramsden, N.,Hirsch, E.,Drewes, G.,Rausch, O.,Bantscheff, M.,Neubauer, G. (登録日: 2012-03-26, 公開日: 2012-05-09, 最終更新日: 2023-12-20)

主引用文献

Bergamini, G.,Bell, K.,Shimamura, S.,Werner, T.,Cansfield, A.,Muller, K.,Perrin, J.,Rau, C.,Ellard, K.,Hopf, C.,Doce, C.,Leggate, D.,Mangano, R.,Mathieson, T.,O'Mahony, A.,Plavec, I.,Rharbaoui, F.,Reinhard, F.,Savitski, M.M.,Ramsden, N.,Hirsch, E.,Drewes, G.,Rausch, O.,Bantscheff, M.,Neubauer, G.
A Selective Inhibitor Reveals Pi3Kgamma Dependence of T(H)17 Cell Differentiation.
Nat.Chem.Biol., 8:576-, 2012

PubMed Abstract: We devised a high-throughput chemoproteomics method that enabled multiplexed screening of 16,000 compounds against native protein and lipid kinases in cell extracts. Optimization of one chemical series resulted in CZC24832, which is to our knowledge the first selective inhibitor of phosphoinositide 3-kinase γ (PI3Kγ) with efficacy in in vitro and in vivo models of inflammation. Extensive target- and cell-based profiling of CZC24832 revealed regulation of interleukin-17-producing T helper cell (T(H)17) differentiation by PI3Kγ, thus reinforcing selective inhibition of PI3Kγ as a potential treatment for inflammatory and autoimmune diseases.

PubMed: 22544264
DOI: 10.1038/NCHEMBIO.957

実験手法

X-RAY DIFFRACTION (3.3 Å)