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Exploring the Chemical Space around the Privileged Pyrazolo[3,4‑d]pyrimidine Scaffold: Toward Novel Allosteric Inhibitors of T315I-Mutated Abl
journal contribution
posted on 2014-04-14, 00:00 authored by Giulia Vignaroli, Martina Mencarelli, Deborah Sementa, Emmanuele Crespan, Miroslava Kissova, Giovanni Maga, Silvia Schenone, Marco Radi, Maurizio BottaA 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).