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

Summary for 6B8Y

• Entry DOI: 10.2210/pdb6b8y/pdb
• Descriptor: 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)
• Functional Keywords: alk5, kinase domain, transferase-transferase inhibitor complex, transferase, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cell membrane ; Single-pass type I membrane protein : P36897
• Total number of polymer chains: 1
• Total formula weight: 35539.77

Authors

Sheriff, S. (deposition date: 2017-10-09, release date: 2018-02-07, Last modification date: 2023-10-04)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.65 Å)