Design and Synthesis of Basic Selective Estrogen Receptor Degraders for Endocrine Therapy Resistant Breast Cancer

Abstract

The clinical steroidal selective estrogen receptor (ER) degrader (SERD), fulvestrant, is effective in metastatic breast cancer, but limited by poor pharmacokinetics, prompting the development of orally bioavailable, nonsteroidal SERDs, currently in clinical trials. These trials address local breast cancer as well as peripheral metastases, but patients with brain metastases are generally excluded because of the lack of blood–brain barrier penetration. A novel family of benzothiophene SERDs with a basic amino side arm (B-SERDs) was synthesized. Proteasomal degradation of ERα was induced by B-SERDs that achieved the objectives of oral and brain bioavailability, while maintaining high affinity binding to ERα and both potency and efficacy comparable to fulvestrant in cell lines resistant to endocrine therapy or bearing ESR1 mutations. A novel 3-oxyazetidine side chain was designed, leading to 37d, a B-SERD that caused endocrine-resistant ER+ tumors to regress in a mouse orthotopic xenograft model.

Oral Selective Estrogen Receptor Degraders (SERDs) as a Novel Breast Cancer Therapy: Present and Future from a Clinical Perspective

“…C domain is the DNA-binding region, while D domain is a flexible hinge region containing the nuclear localization signal and links the C to E domain. Finally, E domain harbors the hormone-binding site [19].…”

“…Furthermore, there are alternative noncanonical ER signaling pathways. For example, ER can interact with other transcription factors, such as AP-1 and Sp1, which will bind with non-ERE genes [19]. In addition, ER can also do its functions in the plasma membrane, where participates in the activation of different signaling cascade such as PI3K or MAPK [23,24].…”

“…Compared to acrylic-acid-containing oral SERDs that do not degrade ER equally in different ER+ cell lines, basic SERDs were optimized to deliver maximal ERα degradation across multiple ER+ cell lines, a feature possessed by fulvestrant. This new SERDs has oral and brain bioavailability, while maintaining high-affinity binding to ERα and both potency and efficacy comparable to fulvestrant in ET-resistant or ESR1-mutated cell lines [19,68]. (Figure 3) 3.2.4.…”

The Quest for Orally Available Selective Estrogen Receptor Degraders (SERDs)

“…Thatcher and co-workers, who developed and optimized the benzothiophene core in compound 17 [22] (Table 1), have recently disclosed a variety of basic chain replacements of the acrylic acid motif. [80] The goal of this chemical transformation was to achieve adequate blood-brain barrier penetration in order to address brain metastases, which is often associated with extremely poor prognosis. [81][82][83] The design of the amine side chain considered its ability to interact with Asp351 of h3, amine basicity and susceptibility to oxidation.…”

Discovery of GNE-149 as a Full Antagonist and Efficient Degrader of Estrogen Receptor alpha for ER+ Breast Cancer

“…However, fulvestrant is not orally bioavailable and its clinical efficacy is believed to be limited by incomplete ERα occupancy in human . This led to a surge of interest in recent years to discover orally bioavailable SERD, − and several such compounds have entered human clinical trials, including GDC-0810 ( 2 ), AZD9496 ( 3 ), LSZ102 ( 4 ), GDC-0927 ( 5 ), and SAR430859 …”