Discovery of LSZ102, a Potent, Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) for the Treatment of Estrogen Receptor Positive Breast Cancer

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.

Eucalyptol as a Bio-Based Solvent for Buchwald-Hartwig Reaction on O,S,N-Heterocycles

“…Catalysts 2019, 9, 840 8 of 12 similar compounds and found Buchwald-Hartwig studies using dioxane and 2,4,6-collidine as solvents in reaction on benzo[b]thiophene [42][43][44][45]. In this case, the average yields were given on two reactions for each solvent and, as can be seen from Chart 4, they were very low: 15% in dioxane and 5% in 2,4,6-collidine.…”

“…In order to have a comparison point and to be able to view the comportment of thieno-fused derivatives, we looked for To the best of our knowledge, there is no report in the literature to date on the use of 7-Bromo-6-phenylthieno [2,3-b]pyrazine and 3-Bromo-2-phenylthieno[3,2-b]pyridine as the starting material involved in pallado-catalyzed coupling reactions of the Buchwald-Hartwig type. In order to have a comparison point and to be able to view the comportment of thieno-fused derivatives, we looked for similar compounds and found Buchwald-Hartwig studies using dioxane and 2,4,6-collidine as solvents in reaction on benzo[b]thiophene [42][43][44][45]. In this case, the average yields were given on two reactions for each solvent and, as can be seen from Chart 4, they were very low: 15% in dioxane and 5% in 2,4,6-collidine.…”

Nickel‐Catalyzed 1,1‐Difluoroethylation of (Hetero)aryl Halides with 1,1‐Difluoroethyl Chloride (CH3CF2Cl)

“…Among a variety of fluorinated moieties, the 1,1‐difluoroethyl group (CF 2 CH 3 ) can function as a bioisostere of the methoxy group, which often result in favorable effects to the parent compounds . For instance, UT‐B inhibitor and LSZ102 show prominent advantages in the aspect of potency and metabolic stability (Scheme A). The traditional method for synthesis of difluoroethylated compounds is via nucleophilic fluorination of ketones or their derivatives with N , N ‐diethylaminosulfur trifluoride (DAST) or other fluorination reagents .…”

G1T48, an oral selective estrogen receptor degrader, and the CDK4/6 inhibitor lerociclib inhibit tumor growth in animal models of endocrine-resistant breast cancer

“…Novel ER antagonists with SERD activity have recently been described, but clinical development of these compounds has thus far been limited due to unanticipated side effects or for undisclosed reasons [29][30][31][32][33][34][35][36]. We sought to identify an orally bioavailable SERD using the chemical backbone of raloxifene as a starting point, since this SERM has demonstrated a favorable safety profile in the clinical setting of breast cancer prevention and osteoporosis treatment [37,38].…”

“…G1T48 incorporates an acrylic acid side chain ( Fig. 1a) [29,31,32,34,39,40], and was the product of structure-guided investigations, driven by activity in breast cancer cell lines [24]. G1T48 was first assessed for its ability to downregulate ER when compared to several benchmark SERMs and SERDs including fulvestrant [12,41].…”