2 research outputs found
Hit Recycling: Discovery of a Potent Carbonic Anhydrase Inhibitor by <i>in Silico</i> Target Fishing
<i>In silico</i> target
fishing is an emerging tool in
drug discovery, which is mostly used for primary target or off-target
prediction and drug repositioning. In this work, we developed an <i>in silico</i> target fishing protocol to identify the primary
target of GV2–20, a false-positive hit highlighted in a cell-based
screen for 14–3–3 modulators. Although GV2–20
does not bind to 14–3–3 proteins, it showed remarkable
antiproliferative effects in CML cells, thus raising interest toward
the identification of its primary target. Six potential targets of
GV2–20 were prioritized <i>in silico</i> and tested <i>in vitro</i>. Our results show that the molecule is a potent
inhibitor of carbonic anhydrase 2 (CA2), thus confirming the predictive
capability of our protocol. Most notably, GV2–20 experienced
a remarkable selectivity for CA2, CA7, CA9, and CA12, and its scaffold
was never explored before as a chemotype for CA inhibition, thus becoming
an interesting lead candidate for further development
Design, Synthesis, and Biological Evaluation of Pyrazolo[3,4‑<i>d</i>]pyrimidines Active in Vivo on the Bcr-Abl T315I Mutant
Starting from our in-house library
of pyrazoloÂ[3,4-<i>d</i>]Âpyrimidines, a cross-docking simulation
was conducted on Bcr-Abl
T315I mutant. Among the selected compounds (<b>2a</b>–<b>e</b>), the 4-bromo derivative <b>2b</b> showed the best
activity against the Bcr-Abl T315I mutant. Deeper computational studies
highlighted the importance of the bromine atom in the para position
of the N1 side chain phenyl ring for the interaction with the T315I
mutant. A series of 4-bromo derivatives was thus synthesized and biologically
evaluated. Compound <b>2j</b> showed a good balance of different
ADME properties, high activity in cell-free assays, and a submicromolar
potency against T315I Bcr-Abl expressing cells. In addition, it was
converted into a water-soluble formulation by liposome encapsulation,
preserving a good activity on leukemic T315I cells and avoiding the
use of DMSO as solubilizing agent. In vivo studies on mice inoculated
with 32D-T315I cells and treated with <b>2j</b> showed a more
than 50% reduction
in tumor volumes