ABSTRACT
In breast cancer, estrogen receptor alpha (ERα) positive cancer accounts for approximately 74% of all diagnoses, and in these settings, it is a primary driver of cell proliferation. Treatment of ERα positive breast cancer has long relied on endocrine therapies such as selective estrogen receptor modulators, aromatase inhibitors, and selective estrogen receptor degraders (SERDs). The steroid-based anti-estrogen fulvestrant (5), the only approved SERD, is effective in patients who have not previously been treated with endocrine therapy as well as in patients who have progressed after receiving other endocrine therapies. Its efficacy, however, may be limited due to its poor physicochemical properties. We describe the design and synthesis of a series of potent benzothiophene-containing compounds that exhibit oral bioavailability and preclinical activity as SERDs. This article culminates in the identification of LSZ102 (10), a compound in clinical development for the treatment of ERα positive breast cancer.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Estrogen Receptor alpha/drug effects , Selective Estrogen Receptor Modulators/chemical synthesis , Selective Estrogen Receptor Modulators/pharmacology , Thiophenes/chemical synthesis , Thiophenes/pharmacology , Animals , Antineoplastic Agents/pharmacokinetics , Biological Availability , Drug Design , Drug Discovery , Female , Humans , MCF-7 Cells , Mice , Mice, Nude , Rats , Rats, Sprague-Dawley , Rats, Wistar , Selective Estrogen Receptor Modulators/pharmacokinetics , Thiophenes/chemistry , Thiophenes/pharmacokinetics , Xenograft Model Antitumor AssaysABSTRACT
Tetrahydroisoquinoline 40 has been identified as a potent ERα antagonist and selective estrogen receptor degrader (SERD), exhibiting good oral bioavailability, antitumor efficacy, and SERD activity in vivo. We outline the discovery and chemical optimization of the THIQ scaffold leading to THIQ 40 and showcase the racemization of the scaffold, pharmacokinetic studies in preclinical species, and the in vivo efficacy of THIQ 40 in a MCF-7 human breast cancer xenograft model.