Hot-Spot Residue-Based Virtual Screening of Novel Selective Estrogen-Receptor Degraders for Breast Cancer Treatment

The estrogen-receptor alfa (ERα) is considered
pivotal for
breast cancer treatment. Although selective estrogen-receptor degraders
(SERDs) have been developed to induce ERα degradation and antagonism,
their agonistic effect on the uterine tissue and poor pharmacokinetic
properties limit further application of ERα; thus, discovering
novel SERDs is necessary. The ligand preferentially interacts with
several key residues of the protein (defined as hot-spot residues).
Improving the interaction with hot-spot residues of ERα offers
a promising avenue for obtaining novel SERDs. In this study, pharmacophore
modeling, molecular mechanics/generalized Born surface area (MM/GBSA),
and amino-acid mutation were combined to determine several hot-spot
residues. Focusing on the interaction with these hot-spot residues,
hit fragments A1-A3 and A9 were virtually
screened from two fragment libraries. Finally, these hit fragments
were linked to generate compounds B1–B3, and their
biological activities were evaluated. Remarkably, compound B1 exhibited potent antitumor activity against MCF-7 cells (IC50 = 4.21 nM), favorable ERα binding affinity (Ki = 14.6 nM), and excellent
ERα degradative ability (DC50 = 9.7 nM), which indicated
its potential to evolve as a promising SERD for breast cancer treatment.