2R0U

Crystal Structure of Chek1 in Complex with Inhibitor 54

Summary for 2R0U

• Entry DOI: 10.2210/pdb2r0u/pdb
• Descriptor: Serine/threonine-protein kinase Chk1, 6-(3-aminopropyl)-4-(3-hydroxyphenyl)-9-(1H-pyrazol-4-yl)benzo[h]isoquinolin-1(2H)-one (3 entities in total)
• Functional Keywords: chek1, kinase, cell cycle check point, atp-binding, cytoplasm, dna damage, dna repair, nucleotide-binding, nucleus, phosphorylation, polymorphism, serine/threonine-protein kinase, transferase, ubl conjugation
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: O14757
• Total number of polymer chains: 1
• Total formula weight: 37332.62

Authors

Yan, Y.,Ikuta, M. (deposition date: 2007-08-21, release date: 2007-10-30, Last modification date: 2023-08-30)

Primary citation

Garbaccio, R.M.,Huang, S.,Tasber, E.S.,Fraley, M.E.,Yan, Y.,Munshi, S.,Ikuta, M.,Kuo, L.,Kreatsoulas, C.,Stirdivant, S.,Drakas, B.,Rickert, K.,Walsh, E.S.,Hamilton, K.A.,Buser, C.A.,Hardwick, J.,Mao, X.,Beck, S.C.,Abrams, M.T.,Tao, W.,Lobell, R.,Sepp-Lorenzino, L.,Hartman, G.D.
Synthesis and evaluation of substituted benzoisoquinolinones as potent inhibitors of Chk1 kinase.
Bioorg.Med.Chem.Lett., 17:6280-6285, 2007

PubMed Abstract: From HTS lead 1, a novel benzoisoquinolinone class of ATP-competitive Chk1 inhibitors was devised and synthesized via a photochemical route. Using X-ray crystallography as a guide, potency was rapidly enhanced through the installation of a tethered basic amine designed to interact with an acidic residue (Glu91) in the enzyme pocket. Further SAR was explored at the solvent front and near to the H1 pocket and resulted in the discovery of low MW, sub-nanomolar inhibitors of Chk1.

PubMed: 17900896
DOI: 10.1016/j.bmcl.2007.09.007

Experimental method

X-RAY DIFFRACTION (1.9 Å)