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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
Elacestrant is a nonsteroidal SERD with complex dose-related ER agonist/antagonist activity that is being developed for HR-positive breast cancer [72,73]. Elacestrant is composed of a tetrahydronaphthalene core and an ethylamine group for its pendent substitution. It is highly basic (pKa: 9.8) and lipophilic (cLogP: 6.8; LogD: 3.6), possessing properties which are closer to those of the first SERM, tamoxifen (pKa: 8.6; cLogP: 6.2; LogD: 4.2), than to those of the recent oral SERDs in development [61]. Elacestrant was identified in screens for compounds that manifest ER agonist activity in the CNS, and was claimed to cross the blood–brain barrier readily [74].
Moving beyond endocrine therapy for luminal metastatic breast cancer in the precision medicine era: looking for new targets
Published in Expert Review of Precision Medicine and Drug Development, 2020
Stefania Morganti, Giuseppe Curigliano
Elacestrant belongs to a new class of hormonal agents called SERD/SERM hybrids (SSH), because of their combined action of ER modulation and downregulation. Elacestrant has reached the phase III [91] of clinical development after demonstrating a significant antitumor activity in preclinical models, including tumors resistant to CDK4/6 inhibitors and fulvestrant and those harboring the ESR1 mutations [92–94].
An evaluation of fulvestrant for the treatment of metastatic breast cancer
Published in Expert Opinion on Pharmacotherapy, 2019
Mohsin Soleja, Ganesh V. Raj, Nisha Unni
Although fulvestrant has shown comparable efficacy to aromatase inhibitors in ER-positive ABC, clinical use may be limited due to intramuscular route of administration. Thus, multiple oral SERDs have been in development to expand the drug class and allow for easier administration. Furthermore, in vivo studies have suggested that newer SERDs have activity in ESR-1 mutated breast cancers [77–80]. AZD9496 is a SERD that has shown significant oral bioavailability that effectively downregulated ER expression and ER-dependent genes similar to that of fulvestrant in preclinical studies [81,82]. A recent phase I study has shown acceptable tolerability and some disease activity in heavily pretreated breast cancer [83]. This drug is further being evaluated in a phase I study to assess a maximum tolerated dose (NCT02248090), a phase I study assessing safety and tolerability of different formulations of AZD9496 (NCT02780713), and an open-label presurgical study assessing ER downregulation compared to fulvestrant (NCT03236974).Elacestrant, formerly RAD1901, is an orally bioavailable nonsteroidal small molecule SERD that showed antiestrogen activity in breast cancer cell lines and xenograft models [84,85]. Currently, elacestrant is under investigation in phase I studies to assess maximum tolerated dose and proposed phase II dosing (NCT02650817, NCT02338349). The EMERALD trial (NCT03778931) is a phase III open-label study assessing elacestrant compared to fulvestrant or aromatase inhibitors in patients with advanced or metastatic HR-positive breast cancer who have progressed on CDK4/6 inhibitor-based therapy.ZB716 in an orally bioavailable SERD that is structurally identical to fulvestrant with the exception of 3-hydroxyl group with a boronic acid moiety [86]. ZB716 has shown anti-tumor activity similar to that of fulvestrant in xenograft models [80]. Development of ZB716 remains in the pre-clinical phase.