TY - JOUR
T1 - Rational design of allosteric modulators of the aromatase enzyme
T2 - An unprecedented therapeutic strategy to fight breast cancer
AU - Spinello, Angelo
AU - Martini, Silvia
AU - Berti, Federico
AU - Pennati, Marzia
AU - Pavlin, Matic
AU - Sgrignani, Jacopo
AU - Grazioso, Giovanni
AU - Colombo, Giorgio
AU - Zaffaroni, Nadia
AU - Magistrato, Alessandra
PY - 2019/4/15
Y1 - 2019/4/15
N2 - Estrogens play a key role in cellular proliferation of estrogen-receptor-positive (ER+) breast cancers (BCs). Suppression of estrogen production by competitive inhibitors of the enzyme aromatase (AIs) is currently one of the most effective therapies against ER + BC. Yet, the development of acquired resistance, after prolonged treatments with AIs, represents a clinical major concern. Serendipitous findings indicate that aromatase may be non-competitively inhibited by clinically employed drugs and/or industrial chemicals. Here, by performing in silico screening on two putative allosteric sites, molecular dynamics and free energy simulations, supported by enzymatic and cell-based assays, we identified five leads inhibiting the enzyme via a non-active site-directed mechanism. This study provides new compelling evidences for the existence of an allosteric regulation of aromatase and for the possibility of exploiting it to modulate estrogens biosynthesis. Such modulation can aptly reduce side effects caused by the complete estrogen deprivation therapy, and, possibly, delay/avoid the onset of resistance.
AB - Estrogens play a key role in cellular proliferation of estrogen-receptor-positive (ER+) breast cancers (BCs). Suppression of estrogen production by competitive inhibitors of the enzyme aromatase (AIs) is currently one of the most effective therapies against ER + BC. Yet, the development of acquired resistance, after prolonged treatments with AIs, represents a clinical major concern. Serendipitous findings indicate that aromatase may be non-competitively inhibited by clinically employed drugs and/or industrial chemicals. Here, by performing in silico screening on two putative allosteric sites, molecular dynamics and free energy simulations, supported by enzymatic and cell-based assays, we identified five leads inhibiting the enzyme via a non-active site-directed mechanism. This study provides new compelling evidences for the existence of an allosteric regulation of aromatase and for the possibility of exploiting it to modulate estrogens biosynthesis. Such modulation can aptly reduce side effects caused by the complete estrogen deprivation therapy, and, possibly, delay/avoid the onset of resistance.
KW - Aromatase
KW - Aromatase inhibitors
KW - Breast cancer
KW - Cytochromes P450
KW - Docking
KW - Mixed inhibition mechanism
KW - Molecular dynamics
KW - Resistance onset
UR - http://www.scopus.com/inward/record.url?scp=85062045600&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85062045600&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2019.02.045
DO - 10.1016/j.ejmech.2019.02.045
M3 - Article
C2 - 30822713
AN - SCOPUS:85062045600
VL - 168
SP - 253
EP - 262
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
SN - 0223-5234
ER -