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.
