Endoxifen (Z-isomer)

Endoxifen Z-isomer is an orally active selective PKCβ1 inhibitor with an IC₅₀ of 360 nM against human PKCβ1. Endoxifen Z-isomer also acts as an estrogen receptor modulator and antiestrogen. Endoxifen Z-isomer binds to and blocks ERα, ERβ and PKCβ1, inhibits estrogen and PI3K/AKT/mTORC1 signaling pathways, suppresses the expression of genes associated with cell cycle, cell proliferation and extracellular matrix remodeling, and induces apoptosis, reactive oxygen species (ROS) production and hypoxic features. Endoxifen Z-isomer inhibits tumor growth in breast tumor and glioblastoma models, reduces bone turnover and blood lipid levels, and does not require metabolism via CYP2D6. Endoxifen Z-isomer can be used in research related to ER⁺ breast cancer, invasive breast cancer, glioblastoma multiforme, type I bipolar disorder, desmoid tumor, gynecological malignancies, melanoma and hormone receptor-positive solid tumors^{[1][2][3][4][5][6][7][8][9][10]}. In Vitro:Endoxifen Z-isomer (concentrations matching CYP2D6 extensive metabolizers) is a potent antiestrogen that induces cell-cycle arrest and apoptosis pathways in MCF7 human ER⁺ breast cancer cells, and completely blocks estrogen-stimulated gene expression unlike Tamoxifen (HY-13757A) and its other metabolites^[3].
Endoxifen Z-isomer (0.08-20 μM; 8 days) potently reduces cell proliferation and induces apoptosis in CRT435 GBM cells, with 20 μM endoxifen alone and in combination with 150 μM TMZ (Temozolomide) (HY-17364) demonstrating significantly greater activity than 250 μM TMZ alone^[4].
Endoxifen Z-isomer (2.5-10 μM; 48 h) induces significant dose-dependent apoptosis in estrogen-deprived ERα⁺/HER2^- MCF7AC1 breast cancer cells, with the strongest effect observed at 10 μM^[7].
Endoxifen Z-isomer (0.01-5 μM; 72 h) induces significant apoptosis in estrogen-deprived ERα+/HER2- T47D-LTED breast cancer cells, while lower concentrations (0.01, 0.1 μM) do not^[7].
Endoxifen Z-isomer (5 μM; 24 h) attenuates AKT^Ser473 phosphorylation and induces PARP cleavage in estrogen-deprived ERα+/HER2- T47D-LTED breast cancer cells^[7].
Endoxifen Z-isomer (5 μM; 48 h incubation, after 48 h cumate pretreatment where applicable) has its apoptosis-inducing effect significantly diminished by overexpression of constitutively active AKT in estrogen-deprived ERα+/HER2- MCF7AC1caAKT breast cancer cells^[7].
Endoxifen Z-isomer (10 nM-10000 nM; 7 days) potently inhibits the proliferation of AI-sensitive MCF7AC1 human breast cancer cells in both the presence and absence of Androstenedione^[6].
Endoxifen Z-isomer (10 nM-10000 nM; 7 days) potently inhibits the proliferation of Letrozole (HY-14248)-resistant MCF7LR human breast cancer cells in both the presence and absence of Androstenedione^[6].
Endoxifen Z-isomer (7 days) potently inhibits the proliferation of ER+ human breast cancer cells regardless of HER2 status^[6].
Endoxifen Z-isomer (>5 μM; 7 days) inhibits the proliferation of ER⁻/HER2⁻ MDA-MB-231, MDA-MB-468, and BT20 human breast cancer cells at concentrations greater than 5 μM^[6].
Endoxifen Z-isomer (2.5-10 μM; 48 h) significantly reduces cell viability in estrogen-deprived ERα+/HER2- MCF7AC1 breast cancer cells, with the strongest effect observed at 10 μM^[7].
Endoxifen Z-isomer (0.01-5 μM; 24 h) has a minimal impact on the total proteome of estrogen-deprived ERα+/HER2- MCF7AC1 breast cancer cells but induces robust, concentration-dependent changes to the phosphoproteome at 5 μM, with downregulated phosphosites enriched in the PI3K-AKT signaling pathway^[7].
Endoxifen Z-isomer (0.01-5 μM; 24 h) attenuates AKT^Ser473 phosphorylation and AKT substrate phosphorylation in estrogen-deprived ERα⁺/HER2^- MCF7AC1 breast cancer cells, while lower concentrations (0.01, 0.1 μM) increase AKT^Thr308 phosphorylation without altering AKT^Ser473 or AKT substrate phosphorylation^[7].
Endoxifen Z-isomer (~0.0002-50 μM) potently inhibits purified PKCβ1 kinase activity in vitro with an IC₅₀ of 360 nM^[7].
Endoxifen Z-isomer (0.01-5 μM; 2 h pretreatment, followed by 20 min 200 nM PMA stimulation) reduces total PKCβ1 protein levels and attenuates PMA-stimulated AKT^Ser473 phosphorylation and AKT substrate phosphorylation in serum-starved ERα⁺/HER2^- MCF7AC1 breast cancer cells, while lower concentrations (0.01, 0.1 μM) do not elicit these effects^[7].
Endoxifen Z-isomer (100-1000 nM) inhibits estrogen-induced proliferation in wild-type and ESR1-mutant ER-positive breast cancer cells, with maximum inhibition of ER transcription and estrogen-induced stimulation occurring at concentrations between 100 and 1000 nM, and higher concentrations required for cells with ESR1 mutations or exposed to estradiol concentrations mimicking premenopausal or postmenopausal settings^[9].
Endoxifen Z-isomer (0.1-5 μM; 1 h) inhibits p-Akt and total Akt protein expression in serum-starved MCF7LR human breast cancer cells after 1 hour of treatment^[6]. In Vivo:Endoxifen Z-isomer (5 mg/kg; s.c.; daily; via extended-release pellet replaced every 90 days) significantly increases tumor latency to 111 days, reduces tumor burden by 76%, and reduces tumor multiplicity by 63% in a tamoxifen-insensitive spontaneous aggressive breast cancer mouse model, while downregulating key pathways related to cell proliferation, tumor remodeling, and immune modulation^[2].
Endoxifen Z-isomer (5 mg/kg; s.c.; daily; via extended-release pellet replaced every 90 days) combined with Ulipristal acetate (HY-16508) (16.7 mg/kg/day; s.c.; daily; via extended-release pellet replaced every 30 days) shows no improvement in breast cancer preventive efficacy compared to endoxifen monotherapy; this combination fails to significantly prolong tumor latency, decrease tumor burden, or suppress the expression of critical poor-prognosis genes^[2].
Endoxifen Z-isomer (50 mg/kg; p.o.; daily; 4 weeks) demonstrates superior antitumor activity against Letrozole-resistant ER+ breast cancer xenografts, with potent suppression of proliferation marker Ki-67, ERα target genes, and Akt signaling^[6].
Endoxifen Z-isomer (25-75 mg/kg; p.o.; daily; 28 days), administered as monotherapy or in combination with TMZ, does not significantly reduce tumor volume in a subcutaneous CRT435 GBM PDX athymic nude mouse model, despite being well tolerated^[4].
Endoxifen Z-isomer (25-75 mg/kg; p.o.; daily; 4 weeks) exhibits superior antitumor activity against AI-sensitive ER⁺ breast cancer xenografts, with the 75 mg/kg dose also outperforming letrozole^[6].
Endoxifen Z-isomer (50 mg/kg; p.o.; 5 days a week) exhibits potent, prolonged antitumor activity against Letrozole-resistant ER⁺ breast cancer xenografts^[6].
Endoxifen Z-isomer (10-50 mg/kg) at 10 mg/kg and 50 mg/kg exerts beneficial skeletal effects and modulates uterine gene expression in intact and ovariectomized Sprague-Dawley rats^[7].