PDBsum entry 3kb7

Transferase

PDB id: 3kb7

Contents

Protein chain

290 a.a. *

Ligands

071

TLA

Metals

_ZN

Waters ×75

* Residue conservation analysis

PDB id:

3kb7

Name:

Transferase

Title:

Crystal structure of polo-like kinase 1 in complex with a pyrazoloquinazoline inhibitor

Structure:

Serine/threonine-protein kinase plk1. Chain: a. Fragment: kinase domain. Synonym: polo-like kinase 1, plk-1, serine/threonine-protein kinase 13, stpk13. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: plk1. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: h5.

Resolution:

2.50Å R-factor: 0.212 R-free: 0.303

Authors:

R.T.Bossi,J.A.Bertrand

Key ref:

I.Beria et al. (2010). Identification of 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives as a new class of orally and selective Polo-like kinase 1 inhibitors. J Med Chem, 53, 3532-3551. PubMed id: 20397705

Date:

20-Oct-09 Release date: 19-May-10

Protein chain

P53350  (PLK1_HUMAN) -  Serine/threonine-protein kinase PLK1 from Homo sapiens

Seq: 603 a.a.

Struc: 290 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.2.7.11.21 - polo kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

J Med Chem 53:3532-3551 (2010)

PubMed id: 20397705

Identification of 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives as a new class of orally and selective Polo-like kinase 1 inhibitors.

I.Beria, D.Ballinari, J.A.Bertrand, D.Borghi, R.T.Bossi, M.G.Brasca, P.Cappella, M.Caruso, W.Ceccarelli, A.Ciavolella, C.Cristiani, V.Croci, A.De Ponti, G.Fachin, R.D.Ferguson, J.Lansen, J.K.Moll, E.Pesenti, H.Posteri, R.Perego, M.Rocchetti, P.Storici, D.Volpi, B.Valsasina.

ABSTRACT

Polo-like kinase 1 (Plk1) is a fundamental regulator of mitotic progression whose overexpression is often associated with oncogenesis and therefore is recognized as an attractive therapeutic target in the treatment of proliferative diseases. Here we discuss the structure-activity relationship of the 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline class of compounds that emerged from a high throughput screening (HTS) campaign as potent inhibitors of Plk1 kinase. Furthermore, we describe the discovery of 49, 8-{[2-methoxy-5-(4-methylpiperazin-1-yl)phenyl]amino}-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, as a highly potent and specific ATP mimetic inhibitor of Plk1 (IC(50) = 0.007 microM) as well as its crystal structure in complex with the methylated Plk1(36-345) construct. Compound 49 was active in cell proliferation against different tumor cell lines with IC(50) values in the submicromolar range and active in vivo in the HCT116 xenograft model where it showed 82% tumor growth inhibition after repeated oral administration.