| Breast cancer(BC)is the most common cancer among women,with approximately 70%of patients having estrogen receptor(ER)positive.Endocrine therapy is the main clinical treatment including aromatase inhibitors,selective estrogen receptor modulators and degraders.However,drug resistance developed in the majority of patients having endocrine therapy.Deep sequencing analysis revealed that mutations in ERα was the main cause,with Y537 S and D538 G located in the ligand binding domain LBD being hotspot mutations.Overcoming acquired drug resistance is a major challenge in ER-positive breast cancer.Given the complexity of multifactorial diseases and the worrisome efficacy of singletargeted drugs,finding effective dual-or multi-targets drug can be a solution to overcome drug resistance.Thus,a series of OBHS compounds were designed and synthesized to effectively inhibit the signal transduction of both aromatase(ARO)and ER.The crystal structure of ERαin complex with compound 30 a and 30 o was obtained.Crystallization studies revealed that combining the efficacy of the ARO inhibitor with phenol from OBHS is a suitable fusion approach.According to the complex structural data,the deflection of H524 by the sulfonate side chain disrupts the hydrogen bonding network and the spatial hindrance of the triazole with L540 promotes the movement of H12,both of which lead to the creation of the antagonistic conformation by indirect and direct action.Therefore,the antagonistic activity of 30 o was superior to 30 a.In MCF-7 anti-proliferation assays,30 i and 30 o also showed better ER inhibition than 30 a,while ARO inhibitory efficacy was comparable to LTZ.Drug design strategies based on ligand-receptor interactions are emerging with the understanding of the three-dimensional structure of drug target proteins.Analysis of drug fusion patterns and structural analysis of lead compounds in this study provides guidance for further optimization of subsequent dual target drugs. |
PDF Full Text Request