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

Endocrine-resistance remains a major challenge in estrogen receptor a positive (ERa +/-) breast cancer (BC) treatment and constitutively active somatic mutations in ERa are a common mechanism. There is an urgent need to develop novel drugs with new mode of mechanism to fight endocrineresistance. Given aberrant ERa 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 29c was identified with superior anti-proliferative activity than fulvestrant against a panel of ERa +/- breast cancer cell lines including mutant ERa. Crystal structure of ERa-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 un-ique antagonist conformation and driving the ERa degradation. These significant effects of the cSERD on ERa homeostasis, unlike typical ERa degraders 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 ver-ifies that novel cSERDs offering new opportunities for the development of innovative therapies for endocrine-resistant BC. 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).