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allied
academies
February 25-26, 2019 | Paris, France
13
th
World Cancer Congress
Journal of Medical Oncology and Therapeutics | Volume 4
Combined in silico/in vitro strategies for the identification of new highly selective ADP/ATP carrier
inhibitors for triggering mitochondrial apoptosis in Cancer Cells.
Ciro Leonardo Pierri
University of Bari, Italy
T
he mitochondrial ADP/ATP carriers (AACs) translocate
the ATP synthesized within mitochondria to the cytosol
in exchange for the cytosolic ADP, playing a key role in
energy production, in promoting cell viability and regulating
mitochondrial apoptosis through the opening of permeability
transition pore. In Homo sapiens four genes code for AACs
with different tissue distribution and expression patterns.
Since AACs are dysregulated in several cancer types, the
employment of known and new AAC inhibitors might be
crucial for inducing mitochondrial-mediated apoptosis
in cancer cells. Albeit carboxyatractyloside (CATR) and
bongkrekic acid (BKA) are known to be powerful and highly
selective AAC inhibitors, able to induce mitochondrial
dysfunction at molecular level and poisoning at physiological
level, we estimated for the first time their affinity for the
human recombinant AAC2 through in vitro transport assays
as reported in. We found that the inhibition constants (Ki)
of CATR and BKA for the human AAC2 are 4 nM and 2.0
μM, respectively. For identifying new AAC inhibitors we
also performed a docking-based virtual screening of an in-
house developed chemical library and we identified about
100 ligands showing high affinity for the AAC2 binding
region according to our validated protocols. By testing 13
commercially available molecules, out of the 100 predicted
candidates, we found that 2 of them, namely suramin and
chebulinic acid, are competitive AAC2 inhibitors with Ki equal
to 0.3 μM and 2.1 μM, respectively. We also demonstrated
that chebulinic acid and suramin are “highly selective”
AAC2 inhibitors, since they poorly inhibit other human
mitochondrial carriers (namely ORC1, APC1 and AGC1).
e:
ciro.pierri@uniba.it