Synthesis, modeling, and RET protein kinase inhibitory activity of 3- and 4-substituted beta-carbolin-1-ones.
A series of beta-carbolin-2-ones and 3,10-dihydro-2H-azepino[3,4-b]indol-1-ones have been designed, synthesized, and evaluated as RET protein kinase inhibitors on the basis of their structural similarity with the prototype indolin-2-one RPI-1. Some beta-carbolin-2-ones (structure 2) showed an ability to inhibit RET enzymatic activity in vitro and proliferation of RETC634R oncogene-transformed NIH3T3 cells comparable to that of the reference compound. The docking analysis of the interaction of these compounds with the crystallographic structure of RET tyrosine kinase domain suggested a new binding interaction scheme different from the one proposed during their design. The rigid structure of the compounds of this series represents a new scaffold with potential advantages in the design of RET protein kinase inhibitors.
Cincinelli
Raffaella
R
Dipartimento di Scienze Molecolari Agroalimentari, Universita di Milano, Via Celoria 2, 20133 Milano, Italy.
Cassinelli
Giuliana
G
Dallavalle
Sabrina
S
Lanzi
Cinzia
C
Merlini
Lucio
L
Botta
Maurizio
M
Tuccinardi
Tiziano
T
Martinelli
Adriano
A
Penco
Sergio
S
Zunino
Franco
F
D000818:Animals; D002243:Carbolines / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D051379:Mice; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D041681:NIH 3T3 Cells; D051096:Proto-Oncogene Proteins c-ret / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013816:Thermodynamics
D002243:Carbolines; D004791:Enzyme Inhibitors; D051096:Proto-Oncogene Proteins c-ret