Identification of GDC-0810 (ARN-810), an Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) that Demonstrates Robust Activity in Tamoxifen-Resistant Breast Cancer Xenografts

Abstract

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 11l (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.

Tetrahydroisoquinoline Phenols: Selective Estrogen Receptor Downregulator Antagonists with Oral Bioavailability in Rat

“…We recently reported our initial attempts to develop a coumarin based series of SERDs. 5 Further efforts in this area have resulted in the disclosure of 3 (ARN-810) 6 and 4 (AZD9496), 7 both of which are currently in Phase I clinical trials. Herein we report an investigation, carried out in parallel to the discovery of 4, on a phenolic tetrahydroisoquinoline (THIQ) scaffold with the aim of identifying a potent, orally bioavailable SERD.…”

AZD9496: An Oral Estrogen Receptor Inhibitor That Blocks the Growth of ER-Positive and ESR1-Mutant Breast Tumors in Preclinical Models

“…Achieving oral bioavailability has remained a key challenge in the design of ER downregulators and until now no oral estrogen receptor downregulators, other than GDC-0810 and RAD1901, have progressed into clinical trials, despite encouraging reports from others of preclinical activity in mouse xenograft models (16)(17)(18)(19)(20)(21). Here, we describe a chemically novel, nonsteroidal ERa antagonist and downregulator, AZD9496, that can be administered orally and links increased tumor growth inhibition to enhanced biomarker modulation compared with fulvestrant in a preclinical in vivo model of breast cancer.…”

Aptamer-Enabled Manipulation of the Hsp70 Chaperone System Suggests a Novel Strategy for Targeted Ubiquitination

“…In cancer, a higher level of Hsp70 is often correlated with higher tumor grades and poorer survival [40][41][42]; inhibition of Hsp70 with antisense reagents caused apoptosis of tumor, but not normal cells [25]. In breast cancer, ERa is an important therapeutic target for ER-positive tumors [43,44], and selective ER degradation could be an effective treatment even after they develop resistance to ER antagonists [45,46]. The Hsp70-ERa bifunctional aptamer specifically increased Hsp70-CHIPmediated ubiquitination of the tethered ERa while inhibiting ubiquitination of a nontethered Hsp70 substrate.…”