ABSTRACT
Potent estrogen receptor ligands typically contain a phenolic hydrogen-bond donor. The indazole of the selective estrogen receptor degrader (SERD) ARN-810 is believed to mimic this. Disclosed herein is the discovery of ARN-810 analogs which lack this hydrogen-bond donor. These SERDs induced tumor regression in a tamoxifen-resistant breast cancer xenograft, demonstrating that the indazole NH is not necessary for robust ER-modulation and anti-tumor activity.
Subject(s)
Antineoplastic Agents/pharmacology , Cinnamates/pharmacology , Drug Resistance, Neoplasm/drug effects , Indazoles/pharmacology , Receptors, Estrogen/antagonists & inhibitors , Selective Estrogen Receptor Modulators/pharmacology , Tamoxifen/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Cell Survival/drug effects , Cinnamates/chemical synthesis , Cinnamates/chemistry , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Female , Indazoles/chemical synthesis , Indazoles/chemistry , Mammary Neoplasms, Experimental/drug therapy , Mammary Neoplasms, Experimental/metabolism , Mammary Neoplasms, Experimental/pathology , Mice , Molecular Structure , Receptors, Estrogen/metabolism , Selective Estrogen Receptor Modulators/chemical synthesis , Selective Estrogen Receptor Modulators/chemistry , Structure-Activity Relationship , Tamoxifen/chemical synthesis , Tamoxifen/chemistryABSTRACT
ER-targeted therapeutics provide valuable treatment options for patients with ER+ breast cancer, however, current relapse and mortality rates emphasize the need for improved therapeutic strategies. The recent discovery of prevalent ESR1 mutations in relapsed tumors underscores a sustained reliance of advanced tumors on ERα signaling, and provides a strong rationale for continued targeting of ERα. Here we describe GDC-0810, a novel, non-steroidal, orally bioavailable selective ER downregulator (SERD), which was identified by prospectively optimizing ERα degradation, antagonism and pharmacokinetic properties. GDC-0810 induces a distinct ERα conformation, relative to that induced by currently approved therapeutics, suggesting a unique mechanism of action. GDC-0810 has robust in vitro and in vivo activity against a variety of human breast cancer cell lines and patient derived xenografts, including a tamoxifen-resistant model and those that harbor ERα mutations. GDC-0810 is currently being evaluated in Phase II clinical studies in women with ER+ breast cancer.
