Design and synthesis of 2-amino-pyrazolopyridines as Polo-like kinase 1 inhibitors.
A series of 2-amino-pyrazolopyridines was designed and synthesized as Polo-like kinase (Plk) inhibitors based on a low micromolar hit. The SAR was developed to provide compounds exhibiting low nanomolar inhibitory activity of Plk1; the phenotype of treated cells is consistent with Plk1 inhibition. A co-crystal structure of one of these compounds with zPlk1 confirms an ATP-competitive binding mode.
Fucini
Raymond V
RV
Department of Biology, Sunesis Pharmaceuticals, Inc., 395 Oyster Point Boulevard Suite 400, South San Francisco, CA 94080, USA. rfucini@sunesis.com
Hanan
Emily J
EJ
Romanowski
Michael J
MJ
Elling
Robert A
RA
Lew
Willard
W
Barr
Kenneth J
KJ
Zhu
Jiang
J
Yoburn
Joshua C
JC
Liu
Yang
Y
Fahr
Bruce T
BT
Fan
Junfa
J
Lu
Yafan
Y
Pham
Phuongly
P
Choong
Ingrid C
IC
VanderPorten
Erica C
EC
Bui
Minna
M
Purkey
Hans E
HE
Evanchik
Marc J
MJ
Yang
Wenjin
W
D000255:Adenosine Triphosphate / Q000737:chemistry; D020816:Amino Acid Motifs; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D008968:Molecular Conformation; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D000097869:Polo-Like Kinase 1
D000255:Adenosine Triphosphate; D018797:Cell Cycle Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D011725:Pyridines; D000097869:Polo-Like Kinase 1; C118531:pyrazolopyridine