3KB7

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

Summary for 3KB7

• Entry DOI: 10.2210/pdb3kb7/pdb
• Descriptor: Serine/threonine-protein kinase PLK1, 8-{[2-methoxy-5-(4-methylpiperazin-1-yl)phenyl]amino}-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, ZINC ION, ... (5 entities in total)
• Functional Keywords: protein kinase, atp-binding, cell cycle, cell division, kinase, mitosis, nucleotide-binding, nucleus, phosphoprotein, polymorphism, serine/threonine-protein kinase, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: P53350
• Total number of polymer chains: 1
• Total formula weight: 36323.56

Authors

Bossi, R.T.,Bertrand, J.A. (deposition date: 2009-10-20, release date: 2010-05-19, Last modification date: 2024-04-03)

Primary citation

Beria, I.,Ballinari, D.,Bertrand, J.A.,Borghi, D.,Bossi, R.T.,Brasca, M.G.,Cappella, P.,Caruso, M.,Ceccarelli, W.,Ciavolella, A.,Cristiani, C.,Croci, V.,De Ponti, A.,Fachin, G.,Ferguson, R.D.,Lansen, J.,Moll, J.K.,Pesenti, E.,Posteri, H.,Perego, R.,Rocchetti, M.,Storici, P.,Volpi, D.,Valsasina, B.
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, 2010

PubMed 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.

PubMed: 20397705
DOI: 10.1021/jm901713n

Experimental method

X-RAY DIFFRACTION (2.5 Å)