5M4K

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

Summary for 5M4K

• Entry DOI: 10.2210/pdb5m4k/pdb
• Descriptor: [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial, N-(2-AMINOETHYL)-2-{3-CHLORO-4-[(4-ISOPROPYLBENZYL)OXY]PHENYL} ACETAMIDE, ~{N}-[2-(ethylamino)-2-oxidanylidene-ethyl]-~{N}-(4-methoxyphenyl)-2,4-bis(oxidanyl)benzamide, ... (5 entities in total)
• Functional Keywords: off-rate screening, pdhk, hsp90, spr, kinase inhibitors, fragment screening, cancer, pdk1, pdk2, pdk3, pdk4, transferase
• Biological source: Homo sapiens (Human)
• Cellular location: Mitochondrion matrix: Q15119
• Total number of polymer chains: 1
• Total formula weight: 47020.27

Authors

Baker, L.M.,Brough, P.,Surgenor, A. (deposition date: 2016-10-18, release date: 2017-02-22, Last modification date: 2024-01-17)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.6 Å)