5T8F

p110delta/p85alpha with taselisib (GDC-0032)

5T8F の概要

• エントリーDOI: 10.2210/pdb5t8f/pdb
• 分子名称: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform, Phosphatidylinositol 3-kinase regulatory subunit alpha, 2-methyl-2-(4-{2-[3-methyl-1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl}-1H-pyrazol-1-yl)propanamide, ... (4 entities in total)
• 機能のキーワード: pi3kdelta kinase, proteros biostructures gmbh, inhibitor, lipid kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human); 詳細
• 細胞内の位置: Cytoplasm : O00329
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 137527.25

構造登録者

Moertl, M.,Steinbacher, S.,Eigenbrot, C. (登録日: 2016-09-07, 公開日: 2017-01-11, 最終更新日: 2023-10-04)

主引用文献

Castanedo, G.M.,Blaquiere, N.,Beresini, M.,Bravo, B.,Brightbill, H.,Chen, J.,Cui, H.F.,Eigenbrot, C.,Everett, C.,Feng, J.,Godemann, R.,Gogol, E.,Hymowitz, S.,Johnson, A.,Kayagaki, N.,Kohli, P.B.,Knuppel, K.,Kraemer, J.,Kruger, S.,Loke, P.,McEwan, P.,Montalbetti, C.,Roberts, D.A.,Smith, M.,Steinbacher, S.,Sujatha-Bhaskar, S.,Takahashi, R.,Wang, X.,Wu, L.C.,Zhang, Y.,Staben, S.T.
Structure-Based Design of Tricyclic NF-kappa B Inducing Kinase (NIK) Inhibitors That Have High Selectivity over Phosphoinositide-3-kinase (PI3K).
J. Med. Chem., 60:627-640, 2017

PubMed Abstract: We report here structure-guided optimization of a novel series of NF-κB inducing kinase (NIK) inhibitors. Starting from a modestly potent, low molecular weight lead, activity was improved by designing a type 11/2 binding mode that accessed a back pocket past the methionine-471 gatekeeper. Divergent binding modes in NIK and PI3K were exploited to dampen PI3K inhibition while maintaining NIK inhibition within these series. Potent compounds were discovered that selectively inhibit the nuclear translocation of NF-κB2 (p52/REL-B) but not canonical NF-κB1 (REL-A/p50).

PubMed: 28005357
DOI: 10.1021/acs.jmedchem.6b01363

実験手法

X-RAY DIFFRACTION (2.91 Å)