Identification of GDC-0810 (ARN-810), an Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) that...

Area of Science:

• Oncology
• Endocrinology
• Medicinal Chemistry

Background:

• Estrogen receptor-alpha (ER-α) positive breast cancer accounts for ~80% of cases, often initially responding to antihormonal therapies like tamoxifen and aromatase inhibitors.
• Resistance to antihormonal therapies frequently emerges, with the ER-α pathway often remaining central, sometimes due to receptor mutations.
• Fulvestrant, an injectable selective estrogen receptor degrader (SERD), is effective but has limitations due to poor pharmaceutical properties and administration route.

Purpose of the Study:

• To identify and characterize novel, orally bioavailable small-molecule selective estrogen receptor degraders (SERDs).
• To prospectively optimize ER-α degrading properties in these new SERDs.
• To evaluate the efficacy of lead compounds in preclinical models of ER-α positive breast cancer.

Main Methods:

• Development and characterization of small-molecule SERDs.
• Optimization of ER-α antagonism and degradation.
• In vitro and in vivo testing in tamoxifen-sensitive and tamoxifen-resistant breast cancer models.

Main Results:

• Identification of a series of potent, orally bioavailable SERDs targeting ER-α.
• The lead compound, 11l (GDC-0810/ARN-810), demonstrated robust activity in both tamoxifen-sensitive and resistant breast cancer models.
• Compound 11l exhibits potent ER-α antagonism and degradation properties.

Conclusions:

• Orally bioavailable small-molecule SERDs represent a promising therapeutic strategy for ER-α positive breast cancer.
• The lead compound 11l shows significant potential and is currently undergoing clinical evaluation.
• These novel SERDs may overcome limitations associated with existing therapies, offering improved treatment for advanced or metastatic breast cancer.