TY - JOUR
T1 - NMS-P937, a 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivative as potent and selective Polo-like kinase 1 inhibitor
AU - Beria, Italo
AU - Bossi, Roberto T.
AU - Brasca, Maria Gabriella
AU - Caruso, Michele
AU - Ceccarelli, Walter
AU - Fachin, Gabriele
AU - Fasolini, Marina
AU - Forte, Barbara
AU - Fiorentini, Francesco
AU - Pesenti, Enrico
AU - Pezzetta, Daniele
AU - Posteri, Helena
AU - Scolaro, Alessandra
AU - Depaolini, Stefania Re
AU - Valsasina, Barbara
N1 - Copyright:
© 2011 Elsevier Ltd. All rights reserved.
PY - 2011/5/15
Y1 - 2011/5/15
N2 - As part of our drug discovery effort, we identified and developed 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives as PLK1 inhibitors. We now report the optimization of this class that led to the identification of NMS-P937, a potent, selective and orally available PLK1 inhibitor. Also, in order to understand the source of PLK1 selectivity, we determined the crystal structure of PLK1 with NMS-P937. The compound was active in vivo in HCT116 xenograft model after oral administration and is presently in Phase I clinical trials evaluation.
AB - As part of our drug discovery effort, we identified and developed 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives as PLK1 inhibitors. We now report the optimization of this class that led to the identification of NMS-P937, a potent, selective and orally available PLK1 inhibitor. Also, in order to understand the source of PLK1 selectivity, we determined the crystal structure of PLK1 with NMS-P937. The compound was active in vivo in HCT116 xenograft model after oral administration and is presently in Phase I clinical trials evaluation.
KW - In vivo activity
KW - Kinase inhibitor
KW - Phase I clinical trials
KW - PLK1
KW - Polo-like kinase
UR - http://www.scopus.com/inward/record.url?scp=79955560817&partnerID=8YFLogxK
U2 - 10.1016/j.bmcl.2011.03.054
DO - 10.1016/j.bmcl.2011.03.054
M3 - Article
C2 - 21470862
AN - SCOPUS:79955560817
SN - 0960-894X
VL - 21
SP - 2969
EP - 2974
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
IS - 10
ER -