Targeting Orthosteric and Allosteric Pockets of Aromatase via Dual-Mode Novel Azole Inhibitors

Abstract

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 vitro inhibitory tests on the aromatase enzyme and distinct ER+/ER– BC cell line types of novel azole bridged xanthones. These compounds are active in the low μM range and behave as dual-mode inhibitors, targeting both the orthosteric and the allosteric sites of the enzyme placed along one access channel. Classical and quantum-classical molecular dynamics simulations of the new compounds, as compared with selected steroidal and nonsteroidal inhibitors, provide a rationale to the observed inhibitory potency and supply the guidelines to boost the activity of inhibitors able to exploit coordination to iron and occupation of the access channel to modulate estrogen production.

Rational Design of CYP3A4 Inhibitors: A One-Atom Linker Elongation in Ritonavir-Like Compounds Leads to a Marked Improvement in the Binding Strength

“…This, in turn, could explain why the backbone flexibility and proper spacing between the functional groups are important and greatly improve the binding and inhibitory strength. Considering recent findings on P450 aromatase inhibitors [ 43 ], it is plausible to suggest that strong heme ligation, favourable stereochemistry (when applicable), H-bonding to the active site residue(s), and the deformation of the active site (induced fit) might be common features leading to the potent inhibition of CYP enzymes.…”

Reconsidering Aromatase for Breast Cancer Treatment: New Roles for an Old Target

“…Based on the abovementioned results and with the aim of developing dual-acting AIs, non-steroidal compounds purposely designed to interact with both the active and the postulated allosteric sites, our research group has recently performed some modifications on a series of imidazolylmethylxanthones (compounds 10 – 12 , Figure 10 ) [ 62 ] that had previously been shown to be potent and selective AIs. In particular, the introduction on the scaffold of a pentynyloxy chain, which had proven to be the most suitable group for interacting with the residues lining the access channel in steroidal compounds [ 56 ], was suggested (compounds 10a – 12a , Figure 10 ) [ 63 ]. Docking studies of xanthones 10 – 12 , imposing a constraint on Fe-N bond, were first performed and indicated that, for the design of the new derivatives, the best position to insert the pentynyloxy chain in order to fit into the access channel was meta with respect to the imidazole ring.…”

How Computational Chemistry and Drug Delivery Techniques Can Support the Development of New Anticancer Drugs

“…The information obtained from these studies, in particular those concerning the localization of the channels, have been later used to identify new allosteric or dual-mode (allosteric and orthosteric) HA inhibitors [54,55]. Specifically, they used docking based virtual screening, molecular dynamics and free energy calculations to identify some hits that represent the starting point for subsequent optimization studies.…”

“…Specifically, they used docking based virtual screening, molecular dynamics and free energy calculations to identify some hits that represent the starting point for subsequent optimization studies. To note, the ability of the identified compounds to inhibit HA was proved by biochemical and cellular experiments [54,55].…”