Structure-based optimization of tyrosine kinase inhibitor CLM3. Design, synthesis, functional evaluation, and molecular modeling studies.
Recent advances in the knowledge of thyroid carcinomas development identified receptor tyrosine kinases, like VEGFR2 and RET, as viable and promising targets. Accordingly, their inhibition is emerging as the major therapeutic strategy to treat these pathologies. In this study we describe the synthesis and the functional evaluation of three different series of 4-substituted pyrazolo[3,4-d]pyrimidine derivatives, 8a-g, 9a-g, and 10a-g, designed exploiting a structure-based optimization of the previously developed inhibitor CLM3. Compared to the lead, the novel compounds markedly improved both their inhibitory profile against the target proteins, VEGFR2 and RET, and their antiproliferative efficacy against the medullary thyroid cancer cell line TT. Significantly, compounds 8b, 9c, and 10c proved to block the kinase activity of the mutant RET(V804L), which still lacks effective inhibitors.
Dipartimento di Farmacia, Università di Pisa , Via Bonanno 6, 56126 Pisa, Italy.
Stefania
S
Sartini
Vito
V
Coviello
Agostino
A
Bruno
Valeria
V
La Pietra
Luciana
L
Marinelli
Francesca
F
Simorini
Sabrina
S
Taliani
Silvia
S
Salerno
Anna Maria
AM
Marini
Anna
A
Fioravanti
Paola
P
Orlandi
Alessandro
A
Antonelli
Federico
F
Da Settimo
Ettore
E
Novellino
Guido
G
Bocci
Concettina
C
La Motta
D015195:Drug Design; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*
D047428:Protein Kinase Inhibitors