Table 2.

New oral anti-estrogen compounds.

Agent	Agent Class	Mechanism of Action	Pharmacokinetics
Basedoxifene [60,65]	SERM/SERD hybrid	Binds to ERα with high affinity; regulates ERα turnover (“SERD-like” profile)	Major metabolic pathway: Hepatic glucuronidation, Little-to-no cytochrome P450-mediated metabolism Half-life: 30 h Major route of elimination: Gastrointestinal
Brilanestrant [62]	SERD	Degrades ERα and interrupts ERα signaling	No available published data
Lasofoxifene [66,67]	SERM	Binds to ERα, induces conformational changes of ERα, preventing coactivator recruitment	major metabolic pathway: P450-mediated metabolism (CYP2C9) Half-life: 116–150 h Major route of elimination: Gastrointestinal
AZD9496 [68,69]	SERD	Degrades ERα; binds and down-regulates mutant ERα, including D538G and Y537S mutations	Major metabolic pathway: P450-mediated metabolism (CYP2C8) Half-life: Rapid and biphasic decline following peak (0.99–1.99 h) Major route of elimination: Gastrointestinal
SAR439859 [70]	SERD	Binds ERα, inducing a conformational change that results in ERα degradation	No available published data
Elacestrant [71]	SERD	Dose-dependent ER degrader, inhibits estradiol-dependent induction of ER target gene transcription and cell proliferation in BC cells with wild-type and Y537S, D538G mutant ERα.	No available published data
H3b-5942 [72]	SERCA	Inactivates both wild-type and Y537S-mutated ERα by targeting Cys530, inducing a unique antagonist conformation	No available published data

Abbreviations: SERM, selective estrogen receptor modulator; SERD, selective estrogen receptor down-regulator; SERCA, selective estrogen receptor covalent antagonists; SERM/SERD hybrid, ERα, estrogen receptor alpha; BC, breast cancer.