Structure-based optimization of pyrazolo[3,4-d]pyrimidines as Abl inhibitors and antiproliferative agents toward human leukemia cell lines.
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.
Manetti
Fabrizio
F
Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via Alcide de Gasperi 2, I-53100, Siena, Italy.
Brullo
Chiara
C
Magnani
Matteo
M
Mosci
Francesca
F
Chelli
Beatrice
B
Crespan
Emmanuele
E
Schenone
Silvia
S
Naldini
Antonella
A
Bruno
Olga
O
Trincavelli
Maria Letizia
ML
Maga
Giovanni
G
Carraro
Fabio
F
Martini
Claudia
C
Bondavalli
Francesco
F
Botta
Maurizio
M
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
D000970:Antineoplastic Agents; D011720:Pyrazoles; D011743:Pyrimidines; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl