3 research outputs found
Transposition of Three Amino Acids Transforms the Human Metabotropic Glutamate Receptor (mGluR)-3-Positive Allosteric Modulation Site to mGluR2, and Additional Characterization of the mGluR2-Positive Allosteric Modulation Site
Identification of GDC-0810 (ARN-810), an Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) that Demonstrates Robust Activity in Tamoxifen-Resistant Breast Cancer Xenografts
Approximately
80% of breast cancers are estrogen receptor alpha
(ER-α) positive, and although women typically initially respond
well to antihormonal therapies such as tamoxifen and aromatase inhibitors,
resistance often emerges. Although a variety of resistance mechanism
may be at play in this state, there is evidence that in many cases
the ER still plays a central role, including mutations in the ER leading
to constitutively active receptor. Fulvestrant is a steroid-based,
selective estrogen receptor degrader (SERD) that both antagonizes
and degrades ER-α and is active in patients who have progressed
on antihormonal agents. However, fulvestrant suffers from poor pharmaceutical
properties and must be administered by intramuscular injections that
limit the total amount of drug that can be administered and hence
lead to the potential for incomplete receptor blockade. We describe
the identification and characterization of a series of small-molecule,
orally bioavailable SERDs which are potent antagonists and degraders
of ER-α and in which the ER-α degrading properties were
prospectively optimized. The lead compound <b>11l</b> (GDC-0810
or ARN-810) demonstrates robust activity in models of tamoxifen-sensitive
and tamoxifen-resistant breast cancer, and is currently in clinical
trials in women with locally advanced or metastatic estrogen receptor-positive
breast cancer