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Endocrine Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
There is only one example of an approved antiestrogen agent for breast cancer based on a steroidal structure. This is perhaps surprising given that estrogen, the naturally occurring ligand for the Estrogen Receptor, is a steroid. This agent is fulvestrant (FaslodexTM) (Figure 8.11) which, as well as being classed as a SERM, is also known as a Selective Estrogen Receptor Degrader (SERD) due to its ability to bind to, and then distort, the structure of the ER, thus accelerating its breakdown through normal protein degradation processes. For this reason, it is also referred to as a “third generation SERM”, and the discovery of this novel mechanism led to a search for other agents with SERD activity. There was also interest in discovering inhibitors with oral activity, as fulvestrant must be administered by two concurrent intramuscular injections each month. Examples of agents discovered include elacestrant and brilanestrant (Figure 8.12), although these are not based on a steroidal structure. The development of brilanestrant has been discontinued, although elacestrant is presently in Phase III clinical trials. Fulvestrant, brilanestrant, and elacestrant are described below in more detail. Structure of the steroidal-based ER inhibitor fulvestrant (FaslodexTM).Structures of the experimental Selective Estrogen Receptor Degrader (SERD) agents, brilanestrant (GDC-0810, RO-7056118) and elacestrant (RAD-1901, ER-306323).
Latest generation estrogen receptor degraders for the treatment of hormone receptor-positive breast cancer
Published in Expert Opinion on Investigational Drugs, 2022
Ya-Chi Chen, Jiajie Yu, Ciara Metcalfe, Tom De Bruyn, Thomas Gelzleichter, Vikram Malhi, Pablo D. Perez-Moreno, Xiaojing Wang
The role of hormones as drivers of breast cancer, specifically the steroid hormone estrogen, is well established [8]. Estrogen mediates its effects through nuclear estrogen receptors, particularly ERα [8]. As the majority of HR-positive cancers are dependent on ER signaling for tumor growth and progression, modulating estrogen synthesis and/or ER activity has been a key therapeutic strategy in disease management [9]. Endocrine therapies remain the mainstay of treatment options for HR-positive breast cancer [10–12]. These therapies include compounds which act by reducing the level of endogenous estrogens (e.g. aromatase inhibitors such as anastrozole, letrozole, and exemestane), a selective estrogen receptor modulator (SERM; i.e. tamoxifen) which acts by reducing the effects of estradiol via competitive binding of ER, or a selective estrogen receptor degrader (SERD; i.e. fulvestrant) which acts by fully antagonizing and degrading ER (Figure 1) [9]. Such treatments may also be useful in patients carrying truncating mutations in CHEK2 (e.g. 100delC), which have been associated with positive ER status [13].
Strategies for targeting undruggable targets
Published in Expert Opinion on Drug Discovery, 2022
Gong Zhang, Juan Zhang, Yuting Gao, Yangfeng Li, Yizhou Li
There are also molecular glue degraders functioning as target-specific degraders, promoting the association of E3 ligase with targeted proteins, represented by thalidomide-like anti-cancer drugs. Repositioning E3 ligase CRBN, the thalidomide-like drug induces poly-ubiquitination of transcriptional factors IKZF1 and IKZF3, followed by proteasome-mediated degradation. Likewise, indisulam degrades RBM23 and RBM39 by recruiting E3 ligase DCAF15. By comparison of MOA, molecular glue degrader behaves like PROTAC, but it usually does not contain linker moiety (Figure 1a; Table 2). Molecular glue degrader has a promising outlook for its appropriate molecular weight and pharmacokinetic (PK) property[20]. CC-90009, developed by BMS, is a molecular glue degrader aiming to degrade the GTPases GSPT1 in the clinical study[21]. Fulvestrant, a typical selective estrogen receptor degrader, is to some extent another example of molecule glue degrader that has been approved by FDA[22].
Progestin or anti-estrogen treatment for endometrial cancer: choosing the best option for selected patients
Published in Gynecological Endocrinology, 2021
Marta Caretto, Tommaso Simoncini
Hormonal therapy in endometrial cancer (EC) is an alternative treatment for women with metastatic or recurrent disease without curative options [1] and a strong desire to preserve their fertility. Historically, the most widely applied and still the first line hormonal treatment has been progestin therapy. Currently, there could be an alternative to progestins for EC: the anti-estrogen treatment. This treatment involves the use of several drugs: selective estrogen receptor modulators (SERM), down-regulators (SERD) and aromatase inhibitors. Tamoxifen has both stimulatory and blocking effects on estrogen receptors (ER) in the endometrium, while other SERMs (raloxifene and arzoxifene) only block ER. Fulvestrant is the main SERD and it has antagonistic effects through down regulation of the ER. Aromatase inhibitors (anastrozole, letrozole, and exemestane) reduce the tumor exposure to estrogens produced by aromatase in fat tissue, especially in postmenopausal women [2].