title: Synthesis, modeling, and RET protein kinase inhibitory activity of 3- and 4-substituted beta-carbolin-1-ones.
abstract: 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.
authors.affiliation: Dipartimento di Scienze Molecolari Agroalimentari, Universita di Milano, Via Celoria 2, 20133 Milano, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Cincinelli
authors.forename: Giuliana
authors.initials: G
authors.lastname: Cassinelli
authors.forename: Sabrina
authors.initials: S
authors.lastname: Dallavalle
authors.forename: Cinzia
authors.initials: C
authors.lastname: Lanzi
authors.forename: Lucio
authors.initials: L
authors.lastname: Merlini
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
authors.forename: Tiziano
authors.initials: T
authors.lastname: Tuccinardi
authors.forename: Adriano
authors.initials: A
authors.lastname: Martinelli
authors.forename: Sergio
authors.initials: S
authors.lastname: Penco
authors.forename: Franco
authors.initials: F
authors.lastname: Zunino
mesh_terms: 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
chemical_list: D002243:Carbolines; D004791:Enzyme Inhibitors; D051096:Proto-Oncogene Proteins c-ret