Thursday, November 21, 2024
11/21/2024
Project Summary Constitutively active somatic mutations in the estrogen receptor (ER) ligand binding domain (LBD) have emerged as a frequent mechanism of endocrine therapy resistance in patients with metastatic ER+ breast cancers. Unfortunately, there are no therapeutic agents to address this patient population. The long-term goal is to develop therapeutically useful irreversible ER inhibitors for the treatment of ER+ metastatic breast cancer, which will create therapy options for individuals who have failed or relapsed on current therapies. The overall objective is to identify template-based irreversible ER inhibitors that can bind to the ER with high affinity and form an irreversible covalent C-S bond with the C530 amino acid residue in the ER LBD. The central hypothesis is that a pharmaceutically optimized irreversible ER inhibitor can be obtained by incorporating clinically proven ER- binding motifs and a covalent-bond forming Michael addition moiety in the molecules. This hypothesis is supported by early triphenylethylene-based irreversible ER antagonists exhibiting uterotrophic effects similar to tamoxifen, and prototype compounds from our laboratory with thiophene (Raloxifene-like) core demonstrating lack of such effect but equally potent antagonism in the breast. The central hypothesis will be tested by pursuing three specific aims: 1) Design and synthesis of irreversible ER inhibitors; 2) Determine the impact of the irreversible ER inhibitors on proliferation in breast cancer cells, and 3) Evaluate in vivo pharmacodynamics and anti-tumor therapeutic efficacy of novel irreversible ER inhibitors. Under the first aim, irreversible ER binding inhibitors will be synthesized using cores motifs: triphenylethylenes (tamoxifen-like) and benzothiophenes (raloxifene-like) and are expected to be highly selective, potent, and to exert permanent antagonism. Under aim two, the synthesized compounds will be evaluated in their ability to form a covalent bond with ER C530 and inhibit the growth of breast cancer cells. For the third aim, the lead agent from each structural motif group will be identified for further preclinical studies and efficacy in patient-derived xenograft breast tumor models. The research here is innovative because it focuses on the use of irreversible inhibitors to overcome endocrine resistance and incorporates novel moieties to achieve high drug exposure. This contribution is significant because it will identify a class of irreversible ER inhibitors that display novel antiestrogenic effects, lacks agonist activities, and has high oral bioavailability, offering new opportunities for the development of innovative therapies to treat breast cancer.
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