ABSTRACT
The further optimization of ER-α degradation efficacy of a series of ER modulators by refining side-chain substitution led to efficacious selective estrogen receptor degraders (SERDs). A fluoromethyl azetidine group was found to be preferred and resulted in the identification of bis-phenol chromene 17ha. In a tamoxifen-resistant breast cancer xenograft model, 17ha (ER-α degradation efficacy = 97%) demonstrated tumor regression, together with robust reduction of intratumoral ER-α levels. However, despite superior oral exposure, 5a (ER-α degradation efficacy = 91%) had inferior activity. This result suggests that optimizing ER-α degradation efficacy leads to compounds with robust effects in a model of tamoxifen-resistant breast cancer. Compound 17ha (GDC-0927) was evaluated in clinical trials in women with metastatic estrogen receptor-positive breast cancer.
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.
Subject(s)
Antineoplastic Agents/administration & dosage , Breast Neoplasms/drug therapy , Cinnamates/administration & dosage , Indazoles/administration & dosage , Receptors, Estrogen/administration & dosage , Animals , Cell Line, Tumor , Disease Models, Animal , Heterografts , Humans , Mice , Prospective Studies , Rats , Treatment OutcomeABSTRACT
Selective estrogen receptor degraders (SERDs) have shown promise for the treatment of ER+ breast cancer. Disclosed herein is the continued optimization of our indazole series of SERDs. Exploration of ER degradation and antagonism in vitro followed by in vivo antagonism and oral exposure culminated in the discovery of indazoles 47 and 56, which induce tumor regression in a tamoxifen-resistant breast cancer xenograft.
Subject(s)
Antineoplastic Agents/therapeutic use , Breast Neoplasms/drug therapy , Estrogen Receptor Antagonists/therapeutic use , Indazoles/therapeutic use , Tamoxifen/therapeutic use , Animals , Antineoplastic Agents/chemistry , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cinnamates/therapeutic use , Drug Resistance, Neoplasm , Estrogen Receptor Antagonists/metabolism , Female , Indazoles/chemistry , Rats , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
SAR studies on the quinolone carboxylic acid class of HIV-1 integrase inhibitors focused on improving the metabolic stability and led to the discovery of 27 and 38.
Subject(s)
HIV Integrase Inhibitors/metabolism , HIV Integrase Inhibitors/pharmacology , HIV-1/enzymology , Microsomes, Liver/metabolism , Quinolines/metabolism , Quinolines/pharmacology , Animals , Dogs , HIV Infections/drug therapy , HIV Integrase Inhibitors/chemistry , HIV Integrase Inhibitors/pharmacokinetics , Haplorhini , Humans , Naphthyridines/chemistry , Naphthyridines/metabolism , Naphthyridines/pharmacokinetics , Naphthyridines/pharmacology , Quinolines/chemistry , Quinolines/pharmacokinetics , Rats , Structure-Activity RelationshipABSTRACT
Structure-activity relationship studies leading to the discovery of novel mGlu5 receptor antagonists are described. These compounds show high in vitro potency, have good in vivo receptor occupancy, and a reasonable intravenous pharmacokinetic profile.
Subject(s)
Excitatory Amino Acid Antagonists/pharmacology , Pyridines/pharmacology , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Excitatory Amino Acid Antagonists/pharmacokinetics , Pyridines/pharmacokinetics , Receptor, Metabotropic Glutamate 5ABSTRACT
Pyrimidine methyl anilines as potent and selective mGlu2 potentiators are described. Findings from the structure-activity-relationship investigations are discussed.
