0000000000409820
AUTHOR
Jessica Caciolla
Single-digit nanomolar inhibitors lock the aromatase active site via a dualsteric targeting strategy
The most frequently diagnosed breast cancer (BC) type in women expresses estrogen receptor (ER) , depends on estrogens for its growth, being classified as ER positive (ER+). The gold standard therapy for the treatment of this tumor relies on the inhibition of the aromatase enzyme, which catalyzes estrogen biosynthesis. Despite the clinical success of current aromatase inhibitors (AIs), after prolonged therapeutic regimens, BC ER + patients experience acquired resistance and disease relapse. This points up the urgent need for a newer generation of AIs able to overcome resistance issues, while mitigating toxicity and side effects of current therapies. Here we performed the synthesis, biologic…
Switching from Aromatase Inhibitors to Dual Targeting Flavonoid-Based Compounds for Breast Cancer Treatment
Despite the significant outcomes attained by scientific research, breast cancer (BC) still represents the second leading cause of death in women. Estrogen receptor-positive (ER+) BC accounts for the majority of diagnosed BCs, highlighting the disruption of estrogenic signalling as target for first-line treatment. This goal is presently pursued by inhibiting aromatase (AR) enzyme or by modulating Estrogen Receptor (ER) α. An appealing strategy for fighting BC and reducing side effects and resistance issues may lie in the design of multifunctional compounds able to simultaneously target AR and ER. In this paper, previously reported flavonoid-related potent AR inhibitors were suitably modified…
Targeting Orthosteric and Allosteric Pockets of Aromatase via Dual-Mode Novel Azole Inhibitors
[Image: see text] Breast cancer (BC) is the most diffused cancer type in women and the second leading cause of death among the female population. Effective strategies to fight estrogen responsive (ER+) BC, which represents 70% of all BC cases, rely on estrogen deprivation, via the inhibition of the aromatase enzyme, or the modulation of its cognate estrogen receptor. Current clinical therapies significantly increased patient survival time. Nevertheless, the onset of resistance in metastatic BC patients undergoing prolonged treatments is becoming a current clinical challenge, urgently demanding to devise innovative strategies. In this context, here we designed, synthesized, and performed in …
Balanced dual acting compounds targeting aromatase and estrogen receptor α as an emerging therapeutic opportunity to counteract estrogen responsive breast cancer
Abstract Breast Cancer (BC) is a leading cause of death in women, currently affecting 13% of female population worldwide. First-line clinical treatments against Estrogen Receptor positive (ER+) BC rely on suppressing estrogen production, by inhibiting the aromatase (AR) enzyme, or on blocking estrogen-dependent pro-oncogenic signaling, by targeting Estrogen Receptor (ER) α with selective Modulators/Degraders (SERMs/SERDs). The development of dual acting molecules targeting AR and ERα represents a tantalizing alternative strategy to fight ER + BC, reducing the incidence of adverse effects and resistance onset that limit the effectiveness of these gold-standard therapies. Here, in silico desi…