Discovery of novel covalent selective estrogen receptor degraders against endocrine-resistant breast cancer

Endocrine-resistance remains a major challenge in estrogen receptorαpositive(ERα^(+))breast cancer(BC)treatment and constitutively active somatic mutations in ERαare a common mechanism.There is an urgent need to develop novel drugs with new mode of mechanism to fight endocrineresistance.Given aberrant ERαactivity,we herein report the identification of novel covalent selective estrogen receptor degraders(cSERDs)possessing the advantages of both covalent and degradation strategies.A highly potent cSERD 29c was identified with superior anti-proliferative activity than fulvestrant against a panel of ERa+breast cancer cell lines including mutant ERα.Crystal structure of ERα-29c complex alongside intact mass spectrometry revealed that 29c disrupted ERa protein homeostasis through covalent targeting C530 and strong hydrophobic interaction collied on H11,thus enforcing a unique antagonist conformation and driving the ERαdegradation.These significant effects of the cSERD on ERαhomeostasis,unlike typical ERαdegraders that occur directly via long side chains perturbing the morphology of H12,demonstrating a distinct mechanism of action(MoA).In vivo,29c showed potent antitumor activity in MCF-7 tumor xenograft models and low toxicity.This proof-of-principle study verifies that novel cSERDs offering new opportunities for the development of innovative therapies for endocrine-resistant BC.

Overcoming resistance to endocrine therapy in hormone receptorpositive human epidermal growth factor receptor 2-negative(HR^(+)/HER2^(-))advanced breast cancer:a meta-analysis and systemic review of randomized clinical trials

New targeted therapies have been developed to overcome resistance to endocrine therapy(ET)and improve the outcome of HR^(+)/HER2^(-)advanced breast cancer(ABC).We conducted a meta-analysis and systemic review on randomized controlled trials evaluating various targeted therapies in combination with ET in HR^(+)/HER2^(-)ABC.PUBMED and EMBASE databases were searched for eligible trials.Hazard ratios(HRs)for progression-free survival(PFS),odds ratios(ORs)for objective response rate(ORR),clinical benefit rate(CBR),and toxicity were meta-analyzed.Twenty-six studies with data on 10347 patients were included and pooled.The addition of cyclin-dependent kinase 4/6 inhibitors to ET significantly improved median PFS(pooled HR=0.547,P<0.001),overall survival(pooled HR=0.755,P<0.001),and tumor response rates(ORR,pooled OR=1.478,P<0.001;CBR,pooled OR=1.201,P<0.001)with manageable toxicities(pooled OR=3.280,P<0.001).The mammalian targets of rapamycin inhibitors and exemestane were not clinically beneficial for this pooled population including ET-naïve and ET-resistant patients.Moderate improvement in PFS(pooled HR=0.686,P<0.001)yet pronounced toxicities(pooled OR=2.154,P<0.001)were noted in the combination of phosphatidylinositol-4,5-bisphosphate 3-kinase inhibitors with fulvestrant.Future studies are warranted to optimize the population and the dosing sequence of these available options.