6B8Y

TGF-BETA RECEPTOR TYPE 1 KINASE DOMAIN (T204D) IN COMPLEX WITH N-(3-fluoropyridin-4-yl)-2-[6-(trifluoromethyl)pyridin-2-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

6B8Y の概要

• エントリーDOI: 10.2210/pdb6b8y/pdb
• 分子名称: TGF-beta receptor type-1, N-(3-fluoropyridin-4-yl)-2-[6-(trifluoromethyl)pyridin-2-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (3 entities in total)
• 機能のキーワード: alk5, kinase domain, transferase-transferase inhibitor complex, transferase, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cell membrane ; Single-pass type I membrane protein : P36897
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 35539.77

構造登録者

Sheriff, S. (登録日: 2017-10-09, 公開日: 2018-02-07, 最終更新日: 2023-10-04)

主引用文献

Harikrishnan, L.S.,Warrier, J.,Tebben, A.J.,Tonukunuru, G.,Madduri, S.R.,Baligar, V.,Mannoori, R.,Seshadri, B.,Rahaman, H.,Arunachalam, P.N.,Dikundwar, A.G.,Fink, B.E.,Fargnoli, J.,Fereshteh, M.,Fan, Y.,Lippy, J.,Ho, C.P.,Wautlet, B.,Sheriff, S.,Ruzanov, M.,Borzilleri, R.M.
Heterobicyclic inhibitors of transforming growth factor beta receptor I (TGF beta RI).
Bioorg. Med. Chem., 26:1026-1034, 2018

PubMed Abstract: The TGFβ-TGFβR signaling pathway has been reported to play a protective role in the later stages of tumorigenesis via increasing immunosuppressive Treg cells and facilitating the epithelial to mesenchymal transition (EMT). Therefore, inhibition of TGFβR has the potential to enhance antitumor immunity. Herein we disclose the identification and optimization of novel heterobicyclic inhibitors of TGFβRI that demonstrate potent inhibition of SMAD phosphorylation. Application of structure-based drug design to the novel pyrrolotriazine chemotype resulted in improved binding affinity (Ki apparent = 0.14 nM), long residence time (T > 120 min) and significantly improved potency in the PSMAD cellular assay (IC = 24 nM). Several analogs inhibited phosphorylation of SMAD both in vitro and in vivo. Additionally, inhibition of TGFβ-stimulated phospho-SMAD was observed in primary human T cells.

PubMed: 29422332
DOI: 10.1016/j.bmc.2018.01.014

実験手法

X-RAY DIFFRACTION (1.65 Å)