The race to develop oral SERDs and other novel estrogen receptor inhibitors: recent clinical trial results and impact on treatment options

Abstract

Hormonal therapy plays a vital part in the treatment of estrogen receptor–positive (ER +) breast cancer. ER can be activated in a ligand-dependent and independent manner. Currently available ER-targeting agents include selective estrogen receptor modulators (SERMs), selective estrogen receptor degraders (SERDs), and aromatase inhibitors (AIs). Estrogen receptor mutation (ESR1 mutation) is one of the common mechanisms by which breast cancer becomes resistant to additional therapies from SERMs or AIs. These tumors remain sensitive to SERDs such as fulvestrant. Fulvestrant is limited in clinical utilization by its intramuscular formulation and once-monthly injection in large volumes. Oral SERDs are being rapidly developed to replace fulvestrant with the potential of higher efficacy and lower toxicities. Elacestrant is the first oral SERD that went through a randomized phase III trial showing increased efficacy, especially in tumors bearing ESR1 mutation, and good tolerability. Two other oral SERDs recently failed to achieve the primary endpoints of longer progression-free survival (PFS). They targeted tumors previously treated with several lines of prior therapies untested for ESR1 mutation. Initial clinical trial data demonstrated that tumors without the ESR1 mutation are less likely to benefit from the SERDs and may still respond to SERMs or AIs, including tumors previously exposed to hormonal therapy. Testing for ESR1 mutation in ongoing clinical trials and in hormonal therapy for breast cancer is highly recommended. Novel protein degradation technologies such as proteolysis-targeting chimera (PROTACS), molecular glue degrader (MGD), and lysosome-targeting chimeras (LYTACS) may result in more efficient ER degradation, while ribonuclease-targeting chimeras (RIBOTAC) and small interfering RNA (siRNA) may inhibit the production of ER protein.

Selenium Analogue of LSZ102 as a Highly Potent ER‐α Binder

“…The crude product was purified by silica gel flash column chromatography using a mixture of petroleum ether and EtOAc (1:0!20 : 1) as an eluent to give 18 (1.54 g) in 40 % yield as a white amorphous solid. Mp = 91-92 °C; 1 H NMR (400 MHz, DMSO-d 6 ): δ = 7.99 (dd, 3 J (H,F) = 9.0 Hz, 4 J (H,H) = 2.4 Hz, 1H), 7.71 (dd, 3 J (H,H) = 8.8 Hz, 4 J (H,F) = 5.2 Hz, 1H), 7.28 (ddd, 3 J (H,F) = 9.0 Hz, 3 J (H,H) = 9.0 Hz, 4 J (H,H) = 2.5 Hz, 1H), 7.14-7.01 (m, 5H), 5.43-5.37 (m, 1H), 3.83-3.73 (m, 1H), 3.59-3.50 (m, 1H), 1.93-1.45 ppm (m, 6H); 13 (2-(1,1-difluoroethyl)-4fluorophenyl)boronic acid (0.588 mmol, 120 mg), and K 2 CO 3 (1.76 mmol, 243 mg) under argon was added dioxane (2.0 ml) and water (0.8 ml) and the reaction mixture was purged with argon for 5 min. Then, the reaction mixture was placed in microwave reactor to stir at 150 °C for 45 min.…”

“…Furthermore, due to its steroidal structure and consequently poor physicochemical properties, it requires intramuscular injection which limits its efficacy [12d] . Therefore, the development of new orally available SERD or SERM/SERD hybrid (SSH) drugs is actively pursued [13] . Giredestrant or GDC‐9545 ( 7 ) [14] is probably the best oral SERD to date, but numerous other compounds have shown high potency and have entered clinical trials, including benzo[ b ]thiophene based rintodestrant or G1T48 ( 8 ) and LSZ102 ( 10 ) [14b] …”

“…[12d] Therefore, the development of new orally available SERD or SERM/SERD hybrid (SSH) drugs is actively pursued. [13] Giredestrant or GDC-9545 (7) [14] is probably the best oral SERD to date, but numerous other compounds have shown high potency and have entered clinical trials, including benzo[b]thiophene based rintodestrant or G1T48 (8) and LSZ102 (10). [14b] Wide range of different cyclic systems have served as molecular platforms for the construction of the SERD activity possessing compounds; those include indole, [14,15] indazole, [16] 1,3,5-triazine, [17] 1,2,3,4-tetrahydronaphthalene, [18] 2Hchromene, [3] 8,9-dihydro-7H-benzo [7]annulene, [19] benzo[b]thiophene, [20] and others.…”

An overview of PROTACs: a promising drug discovery paradigm

“…Nevertheless, ERα has been verified to be primarily responsible for converting the estrogen signaling in the female reproductive system and mammary tissue [ 126 , 127 ]. Most selective estrogen receptor degraders (SERD) were designed to target ERα to treat ER + breast cancer [ 128 ]. SERD is a class of small molecules that bind with ERα and subsequently degraded by proteasome.…”

Discovery of a Novel Class of PROTACs as Potent and Selective Estrogen Receptor α Degraders to Overcome Endocrine-Resistant Breast Cancer In Vitro and In Vivo

“…Fulvestrant (Figure ) is the first SERD approved by the FDA for the treatment of metastatic ER + BC but is limited by poor drug-like properties and an inconvenient administration method. This gave impetus to research efforts into a new generation of orally bioavailable SERDs with greater potency, and a number of new oral SERDs have progressed into clinical trials over the past few years. − In 2023, elacestrant was approved by the FDA as the first oral SERD for the treatment of patients with advanced or metastatic ER + BC . The clinical success of SERDs suggests that the strategy of degrading ERα protein can provide an effective way for the treatment of ER + BC including endocrine-resistant ones.…”