title: Structure-based optimization of pyrazolo[3,4-d]pyrimidines as Abl inhibitors and antiproliferative agents toward human leukemia cell lines.
abstract: Results from molecular docking calculations and Grid mapping laid the foundations for a structure-based optimization approach to improve the biological properties of pyrazolo-pyrimidine derivatives in terms of inhibition of Abl enzymatic activity and antiproliferative properties toward human leukemia cells. Insertion of halogen substituents with various substitution patterns, suggested by simulations, led to a significant improvement of leukemia cell growth inhibition and to an increase up to 1 order of magnitude of the affinity toward Abl.
authors.affiliation: Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via Alcide de Gasperi 2, I-53100, Siena, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Manetti
authors.forename: Chiara
authors.initials: C
authors.lastname: Brullo
authors.forename: Matteo
authors.initials: M
authors.lastname: Magnani
authors.forename: Francesca
authors.initials: F
authors.lastname: Mosci
authors.forename: Beatrice
authors.initials: B
authors.lastname: Chelli
authors.forename: Emmanuele
authors.initials: E
authors.lastname: Crespan
authors.forename: Silvia
authors.initials: S
authors.lastname: Schenone
authors.forename: Antonella
authors.initials: A
authors.lastname: Naldini
authors.forename: Olga
authors.initials: O
authors.lastname: Bruno
authors.forename: Maria Letizia
authors.initials: ML
authors.lastname: Trincavelli
authors.forename: Giovanni
authors.initials: G
authors.lastname: Maga
authors.forename: Fabio
authors.initials: F
authors.lastname: Carraro
authors.forename: Claudia
authors.initials: C
authors.lastname: Martini
authors.forename: Francesco
authors.initials: F
authors.lastname: Bondavalli
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D016044:Fusion Proteins, bcr-abl; D006801:Humans; D007938:Leukemia; D008958:Models, Molecular; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D011720:Pyrazoles; D011743:Pyrimidines; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl