title: Exploring the chemical space around the privileged pyrazolo[3,4-d]pyrimidine scaffold: toward novel allosteric inhibitors of T315I-mutated Abl.
abstract: A library of pyrazolo[3,4-d]pyrimidines, endowed with a high level of molecular diversity, has been developed applying a synthetic sequence that allowed C3, N1, C4, and C6 substitution. The enzymatic screening of this "privileged scaffold"-based compound collection, validated the use of a diversity-oriented approach in a field characteristically explored by target-oriented synthesis. In fact, several compounds showed high activity against the selected kinases (i.e., Src, Abl wt, and T315I mutated-form), furthermore and interestingly a new compound has emerged as an allosteric inhibitor of the T315I mutated-form of Abl, opening up new opportunities for the development of a novel class of noncompetitive inhibitors of Abl (T315I).
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena , Via Aldo Moro 2, 53100 Siena, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Vignaroli
authors.forename: Martina
authors.initials: M
authors.lastname: Mencarelli
authors.forename: Deborah
authors.initials: D
authors.lastname: Sementa
authors.forename: Emmanuele
authors.initials: E
authors.lastname: Crespan
authors.forename: Miroslava
authors.initials: M
authors.lastname: Kissova
authors.forename: Giovanni
authors.initials: G
authors.lastname: Maga
authors.forename: Silvia
authors.initials: S
authors.lastname: Schenone
authors.forename: Marco
authors.initials: M
authors.lastname: Radi
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C014175:pyrazolo(3,4-d)pyrimidine; D016044:Fusion Proteins, bcr-abl