5M4E

Application of Off-Rate Screening in the Identification of Novel Pan-Isoform Inhibitors of Pyruvate Dehydrogenase Kinase

5M4E の概要

• エントリーDOI: 10.2210/pdb5m4e/pdb
• 分子名称: Heat shock protein HSP 90-alpha, ~{N}-[2-(ethylamino)-2-oxidanylidene-ethyl]-~{N}-(4-methoxyphenyl)-2,4-bis(oxidanyl)benzamide, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: off-rate screening, pdhk, hsp90, spr, kinase inhibitors, fragment screening, cancer, pdk1, pdk2, pdk3, pdk4, transferase
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm : P07900
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 28964.29

構造登録者

Baker, L.M. (登録日: 2016-10-18, 公開日: 2017-02-22, 最終更新日: 2024-01-17)

主引用文献

Brough, P.A.,Baker, L.,Bedford, S.,Brown, K.,Chavda, S.,Chell, V.,D'Alessandro, J.,Davies, N.G.,Davis, B.,Le Strat, L.,Macias, A.T.,Maddox, D.,Mahon, P.C.,Massey, A.J.,Matassova, N.,McKenna, S.,Meissner, J.W.,Moore, J.D.,Murray, J.B.,Northfield, C.J.,Parry, C.,Parsons, R.,Roughley, S.D.,Shaw, T.,Simmonite, H.,Stokes, S.,Surgenor, A.,Stefaniak, E.,Robertson, A.,Wang, Y.,Webb, P.,Whitehead, N.,Wood, M.
Application of Off-Rate Screening in the Identification of Novel Pan-Isoform Inhibitors of Pyruvate Dehydrogenase Kinase.
J. Med. Chem., 60:2271-2286, 2017

PubMed Abstract: Libraries of nonpurified resorcinol amide derivatives were screened by surface plasmon resonance (SPR) to determine the binding dissociation constant (off-rate, k) for compounds binding to the pyruvate dehydrogenase kinase (PDHK) enzyme. Parallel off-rate measurements against HSP90 and application of structure-based drug design enabled rapid hit to lead progression in a program to identify pan-isoform ATP-competitive inhibitors of PDHK. Lead optimization identified selective sub-100-nM inhibitors of the enzyme which significantly reduced phosphorylation of the E1α subunit in the PC3 cancer cell line in vitro.

PubMed: 28199108
DOI: 10.1021/acs.jmedchem.6b01478

実験手法

X-RAY DIFFRACTION (1.9 Å)