biostudies-literatureWang YFundamental Research Funds for the Central UniversitiesChina Postdoctoral Science FoundationNational Natural Science Foundation of ChinaNational Key Research and Development Program of China4963-4982https://www.ebi.ac.uk/biostudies/studies/S-EPMC10692362biostudies-literatureUnknown13(12)Endocrine-resistance remains a major challenge in estrogen receptor <i>α</i> positive (ER<i>α</i>⁺) breast cancer (BC) treatment and constitutively active somatic mutations in ER<i>α</i> are a common mechanism. There is an urgent need to develop novel drugs with new mode of mechanism to fight endocrine-resistance. Given aberrant ER<i>α</i> activity, 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 <b>29c</b> was identified with superior anti-proliferative activity than fulvestrant against a panel of ER<i>α</i>⁺ breast cancer cell lines including mutant ER<i>α</i>. Crystal structure of ER<i>α</i>‒<b>29c</b> complex alongside intact mass spectrometry revealed that <b>29c</b> disrupted ER<i>α</i> protein homeostasis through covalent targeting C530 and strong hydrophobic interaction collied on H11, thus enforcing a unique antagonist conformation and driving the ER<i>α</i> degradation. These significant effects of the cSERD on ER<i>α</i> homeostasis, unlike typical ER<i>α</i> degraders that occur directly <i>via</i> long side chains perturbing the morphology of H12, demonstrating a distinct mechanism of action (MoA). <i>In vivo</i>, <b>29c</b> 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.Acta pharmaceutica Sinica. BDiscovery of novel covalent selective estrogen receptor degraders against endocrine-resistant breast cancer.PMC106923622020YFA0908800817735572021YFC21003002042022kf0056821736768210399482273774820736902020M672435Guo XChen CCGuo RTCheng YMin JYang YHu HFeng TWang YZhou HBDeng XDong CXie BfalseDiscovery of novel covalent selective estrogen receptor degraders against endocrine-resistant breast cancer.Endocrine-resistance remains a major challenge in estrogen receptor <i>α</i> positive (ER<i>α</i>⁺) breast cancer (BC) treatment and constitutively active somatic mutations in ER<i>α</i> are a common mechanism. There is an urgent need to develop novel drugs with new mode of mechanism to fight endocrine-resistance. Given aberrant ER<i>α</i> activity, 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 <b>29c</b> was identified with superior anti-proliferative activity than fulvestrant against a panel of ER<i>α</i>⁺ breast cancer cell lines including mutant ER<i>α</i>. Crystal structure of ER<i>α</i>‒<b>29c</b> complex alongside intact mass spectrometry revealed that <b>29c</b> disrupted ER<i>α</i> protein homeostasis through covalent targeting C530 and strong hydrophobic interaction collied on H11, thus enforcing a unique antagonist conformation and driving the ER<i>α</i> degradation. These significant effects of the cSERD on ER<i>α</i> homeostasis, unlike typical ER<i>α</i> degraders that occur directly <i>via</i> long side chains perturbing the morphology of H12, demonstrating a distinct mechanism of action (MoA). <i>In vivo</i>, <b>29c</b> 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.2023-01-01T00:00:00Z2023 Dec2026-05-28T21:35:16.879Z2025-04-19T20:20:43.895ZS-EPMC106923623804506310.1016/j.apsb.2023.05.005