Thieno[3,2-c]pyrazoles: a novel class of Aurora inhibitors with favorable antitumor activity.
A novel series of 3-amino-1H-thieno[3,2-c]pyrazole derivatives demonstrating high potency in inhibiting Aurora kinases was developed. Here we describe the synthesis and a preliminary structure-activity relationship, which led to the discovery of a representative compound (38), which showed low nanomolar inhibitory activity in the anti-proliferation assay and was able to block the cell cycle in HCT-116 cell line. This compound demonstrated favorable pharmacokinetic properties and good efficacy in the HL-60 xenograft tumor model.
Bindi
Simona
S
Nerviano Medical Sciences-Oncology, via Pasteur 10, 20014 Nerviano, Milan, Italy. simona.bindi@nervianoms.com
Fancelli
Daniele
D
Alli
Cristina
C
Berta
Daniela
D
Bertrand
Jay A
JA
Cameron
Alexander D
AD
Cappella
Paolo
P
Carpinelli
Patrizia
P
Cervi
Giovanni
G
Croci
Valter
V
D'Anello
Matteo
M
Forte
Barbara
B
Giorgini
M Laura
ML
Marsiglio
Aurelio
A
Moll
Juergen
J
Pesenti
Enrico
E
Pittalà
Valeria
V
Pulici
Maurizio
M
Riccardi-Sirtori
Federico
F
Roletto
Fulvia
F
Soncini
Chiara
C
Storici
Paola
P
Varasi
Mario
M
Volpi
Daniele
D
Zugnoni
Paola
P
Vianello
Paola
P
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D064127:Aurora Kinases; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019295:Computational Biology; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014183:Transplantation, Heterologous
C554997:3-(4-morpholin-4-yl-benzoylamino)-1H-thieno(3,2-c)pyrazole-5-carboxylic acid ((S)-1-phenyl-2-pyrrolidin-1-yl-ethyl)-amide; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D013876:Thiophenes; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases