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.