Afimoxifene

Summary

Afimoxifene (CHEMBL489) is a phase-3 clinical-stage small-molecule antineoplastic agent targeting GPER1, ESR1, and ESR2; indicated across 3 conditions including ductal breast carcinoma in situ and breast neoplasm.

At a glance

• Status: Max clinical phase 3 (not approved)
• Modality: Small molecule
• Targets: 4 (GPER1, ESR1, ESR2…)
• Indications: 3 conditions
• Clinical trials: 12
• Chemistry: 387.5 Da · C26H29NO2

Identifiers

Drug identity and classification

Field	Value
ChEMBL ID	CHEMBL489
Name	Afimoxifene
Type	Small molecule
Max phase	3
FDA approved	no
PubChem CID	449459
ChEBI	CHEBI:44616
Molecular formula	C26H29NO2
Molecular weight	387.5
InChIKey	TXUZVZSFRXZGTL-QPLCGJKRSA-N

SMILES: CC/C(=C(\C1=CC=C(C=C1)O)/C2=CC=C(C=C2)OCCN(C)C)/C3=CC=CC=C3

IUPAC name: 4-[(Z)-1-[4-[2-(dimethylamino)ethoxy]phenyl]-2-phenylbut-1-enyl]phenol

ChEBI definition: A tertiary amino compound that is tamoxifen in which the phenyl group which is in a Z- relationship to the ethyl substituent is hydroxylated at the para- position. It is the active metabolite of tamoxifen.

Pharmacological roles (ChEBI): antineoplastic agent, estrogen receptor antagonist.

Other ChEBI roles (chemical / environmental): metabolite.

Also known as: Afimoxifene, Afimoxifeno, Tamogel, SID11532960, SID17389512, SID56422185, SID26757818, AFIMOXIFENE, SID99357276, SID144208141, SID144213959, hydroxy-tamoxifen

Patent coverage: 6,096 distinct patent families (25,119 SureChEMBL compound mentions), from 1 matched compound structure(s). Mentions count patents naming the compound (not distinct inventions), so promiscuous / reference molecules inflate the mention figure — families are the dedup metric.

Targets

Targets

Primary targets (GtoPdb curated mechanism): the Cancer dependency column is the DepMap CRISPR fitness signal (% of screened cell lines dependent on the target).

Gene	Target	Action	pAffinity	Cancer dependency	UniProt
GPER1	GPER	Agonist		0.2%	Q99527
ESR1	Estrogen receptor-α	Agonist	9.85	1.7%	P03372
ESR2	Estrogen receptor-β	Antagonist	10.6	0.2%	Q92731
ESRRG	Estrogen-related receptor-γ	Inverse agonist	7.46	0.4%	P62508

Broader ChEMBL bioactivity targets: 15 (assay-derived). Sample: Microtubule-associated protein tau, Lysine-specific demethylase 4E, Nuclear receptor ROR-gamma, Prelamin-A/C, 4’-phosphopantetheinyl transferase ffp, Ferritin light chain, Estrogen receptor, Menin/Histone-lysine N-methyltransferase MLL, Estrogen receptor beta, Cytochrome P450 3A4.

Bioactivity

ChEMBL activities: 27 potent at pChembl ≥ 5 of 42 total. Top 30 by potency (10 = 0.1 nM, 6 = 1 µM):

Target	pChembl	Type	Value	Unit	Activity ID
ESR1	10.01	EC50	0.1	nM	CHEMBL_ACT_25477468
ESR1	9.28	IC50	0.53	nM	CHEMBL_ACT_16843645
ESR1	9.1	IC50	0.79	nM	CHEMBL_ACT_19211881
ESR2	9	IC50	1	nM	CHEMBL_ACT_24503388
ESR1	8.95	IC50	1.12	nM	CHEMBL_ACT_24751370
ESR1	8.87	IC50	1.36	nM	CHEMBL_ACT_23232650
ESR2	8.78	IC50	1.68	nM	CHEMBL_ACT_24503284
ESR1	8.68	IC50	2.1	nM	CHEMBL_ACT_19211872
ESR1	8.65	IC50	2.24	nM	CHEMBL_ACT_24503266
ESR1	8.64	IC50	2.3	nM	CHEMBL_ACT_24503370
ESR1	8.52	IC50	3	nM	CHEMBL_ACT_18113316
ESR2	8.44	IC50	3.61	nM	CHEMBL_ACT_24751408
ESR1	8.42	IC50	3.8	nM	CHEMBL_ACT_25522261
ESR1	8.25	IC50	5.6	nM	CHEMBL_ACT_18340177
ESR1	8.12	IC50	7.5	nM	CHEMBL_ACT_24506350
ESR1	8	IC50	10	nM	CHEMBL_ACT_16392065
ESR1	7.99	IC50	10.2	nM	CHEMBL_ACT_18113486
ESR1	7.7	Ki	20	nM	CHEMBL_ACT_25534826
ESR2	7.4	EC50	40	nM	CHEMBL_ACT_29242928
ESR1	7.16	IC50	70	nM	CHEMBL_ACT_16392057
ESR2	7.16	Ki	70	nM	CHEMBL_ACT_25534852
ESR1	7.1	EC50	80	nM	CHEMBL_ACT_29242917
ESR2	6.28	IC50	520	nM	CHEMBL_ACT_29242954
ESR1	5.92	IC50	1190	nM	CHEMBL_ACT_29242939
MAPT	5.05	Potency	8912	nM	CHEMBL_ACT_3967420
MEN1	5	Potency	10000	nM	CHEMBL_ACT_4554647
NPSR1	5	Potency	10000	nM	CHEMBL_ACT_4884926

Target pathways

Aggregated over 4 target gene(s): GPER1, ESR1, ESR2, ESRRG.

Top Reactome pathways

20 total, by targets touching each:

Pathway	Targets	Genes
Nuclear Receptor transcription pathway	3	ESR1, ESR2, ESRRG
PIP3 activates AKT signaling	2	ESR1, ESR2
Constitutive Signaling by Aberrant PI3K in Cancer	2	ESR1, ESR2
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	2	ESR1, ESR2
ESR-mediated signaling	2	ESR1, ESR2
Extra-nuclear estrogen signaling	2	ESR1, ESR2
Nuclear signaling by ERBB4	1	ESR1
Peptide ligand-binding receptors	1	GPER1
SUMOylation of intracellular receptors	1	ESR1
G alpha (i) signalling events	1	GPER1
Ovarian tumor domain proteases	1	ESR1
TFAP2 (AP-2) family regulates transcription of growth factors and their receptors	1	ESR1
RUNX1 regulates estrogen receptor mediated transcription	1	ESR1
RUNX1 regulates transcription of genes involved in WNT signaling	1	ESR1
Regulation of RUNX2 expression and activity	1	ESR1
Estrogen-dependent gene expression	1	ESR1
GPER1 signaling	1	GPER1
Mitochondrial unfolded protein response (UPRmt)	1	ESR1
Developmental Lineage of Mammary Gland Luminal Epithelial Cells	1	ESR1
Developmental Lineage of Mammary Gland Alveolar Cells	1	ESR1

Dominant GO biological processes

GO term	Targets
positive regulation of transcription by RNA polymerase II	4
nuclear receptor-mediated steroid hormone signaling pathway	3
cellular response to estradiol stimulus	3
signal transduction	3
regulation of DNA-templated transcription	3
regulation of transcription by RNA polymerase II	3
positive regulation of DNA-templated transcription	3
positive regulation of cytosolic calcium ion concentration	2
negative regulation of gene expression	2
steroid hormone receptor signaling pathway	2
negative regulation of transcription by RNA polymerase II	2
estrogen receptor signaling pathway	2
obsolete positive regulation of DNA-binding transcription factor activity	2
cellular response to oxygen-containing compound	2
positive regulation of protein phosphorylation	1

Indications & clinical

Indications

3 indications (0 at ChEMBL trial phase 4). Phase below is the highest clinical-trial phase recorded for this drug against each disease — not the molecule’s overall approval status (that is in the Summary).

Indication	Trial phase	MONDO	EFO
ductal breast carcinoma in situ	2	MONDO:0005023	EFO:0000432
breast neoplasm	2	MONDO:0021100	MONDO:0007254

1 further indication record had no mapped disease name (EFO/MeSH-only) or were duplicates, and are omitted.

Clinical trials

Total trials: 12.

Phase distribution

Phase	Trials
PHASE2	8
PHASE1	2
PHASE3	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04315792	PHASE3	COMPLETED	Evaluate Efficacy and Safety of Endoxifen in Bipolar I Disorder Patients
NCT01042379	PHASE2	RECRUITING	I-SPY TRIAL: Neoadjuvant and Personalized Adaptive Novel Agents to Treat Breast Cancer
NCT02311933	PHASE2	ACTIVE_NOT_RECRUITING	Tamoxifen Citrate or Z-Endoxifen Hydrochloride in Treating Patients With Locally Advanced or Metastatic, Estrogen Receptor-Positive, HER2-Negative Breast Cancer
NCT04009044	PHASE2	ACTIVE_NOT_RECRUITING	Topical Afimoxifene in Treating Patients With Breast Cancer Who Have Undergone Radiation Therapy on One Breast
NCT00272714	PHASE2	COMPLETED	Study of Afimoxifene Gel to Treat Cyclic Mastalgia in Premenopausal Women
NCT00952731	PHASE2	COMPLETED	4-Hydroxytamoxifen or Tamoxifen Citrate in Treating Women With Newly Diagnosed Ductal Breast Carcinoma in Situ
NCT02993159	PHASE2	COMPLETED	Testing an Active Form of Tamoxifen (4-hydroxytamoxifen) Delivered Through Breast Skin to Control Ductal Carcinoma in Situ (DCIS) of the Breast
NCT03063619	PHASE2	COMPLETED	Afimoxifene in Reducing the Risk of Breast Cancer in Women With Mammographically Dense Breast
NCT04616430	PHASE2	COMPLETED	Topical Endoxifen in Women
NCT01327781	PHASE1	ACTIVE_NOT_RECRUITING	Z-Endoxifen Hydrochloride in Treating Patients With Metastatic or Locally Recurrent Estrogen Receptor-Positive Breast Cancer
NCT03317405	PHASE1	ACTIVE_NOT_RECRUITING	Phase I Trial of Endoxifen Gel Versus Placebo in Women Undergoing Breast Surgery
NCT00084344	Not specified	COMPLETED	Effect of 4-Hydroxytamoxifen Gel on Breast Density, Salivary Sex Steroids, and Quality of Life in Premenopausal Women

Clinical evidence (CIViC)

No CIViC predictive evidence (expected for non-precision-medicine drugs).

Pharmacology

Pharmacogenomics

No CPIC/DPWG dosing guideline, but PharmGKB curates 0 clinical and 24 variant annotation(s) for this drug (gene-keyed; see PharmGKB).

Related molecules

Related molecules

Molecules sharing ≥1 of this drug’s curated primary targets, merged from two biobtree sources and ranked by shared-target count, then clinical phase: ChEMBL clinical-stage candidates (development phase ≥2) and PubChem drug-class bioactivity (approved / known drugs acting on the target). Deduplicated by drug name; the drug’s own salt forms are excluded. Note: for a drug with few primary targets a shared-target match can reflect off-target / promiscuous binding rather than the same therapeutic mechanism — the phase ordering surfaces bona-fide therapeutics first.

178 molecules share ≥1 primary target. Top 60 by shared-target count:

Molecule	Source	Status	Shared targets
ESTRADIOL	ChEMBL + PubChem	Phase 4 (approved)	ESR1, ESR2, ESRRG, GPER1
Tamoxifen	ChEMBL + PubChem	Phase 4 (approved)	ESR1, ESR2, ESRRG, GPER1
DIETHYLSTILBESTROL	ChEMBL + PubChem	Phase 4 (approved)	ESR1, ESR2, ESRRG
Fulvestrant	ChEMBL + PubChem	Phase 4 (approved)	ESR1, ESR2, GPER1
Raloxifene	ChEMBL + PubChem	Phase 4 (approved)	ESR1, ESR2, GPER1
GENISTEIN	ChEMBL + PubChem	Phase 2 (approved)	ESR1, ESR2, ESRRG
BAZEDOXIFENE	ChEMBL	Phase 4 (approved)	ESR1, ESR2
BITHIONOL	ChEMBL	Phase 4 (approved)	ESR1, ESR2
CISPLATIN	ChEMBL	Phase 4 (approved)	ESR1, ESR2
ELACESTRANT	ChEMBL	Phase 4 (approved)	ESR1, ESR2
ESTETROL	ChEMBL	Phase 4 (approved)	ESR1, ESR2
ESTRIOL	ChEMBL	Phase 4 (approved)	ESR1, ESR2
ESTRONE	ChEMBL	Phase 4 (approved)	ESR1, ESR2
ETHINYL ESTRADIOL	ChEMBL	Phase 4 (approved)	ESR1, ESR2
HEXACHLOROPHENE	ChEMBL	Phase 4 (approved)	ESR1, ESR2
LASOFOXIFENE	ChEMBL	Phase 4 (approved)	ESR1, ESR2
MEDROXYPROGESTERONE	ChEMBL	Phase 4 (approved)	ESR1, ESR2
MIFEPRISTONE	ChEMBL	Phase 4 (approved)	ESR1, ESR2
PHENOLPHTHALEIN	ChEMBL	Phase 4 (approved)	ESR1, ESR2
SPIRONOLACTONE	ChEMBL	Phase 4 (approved)	ESR1, ESR2
ACOLBIFENE	ChEMBL	Phase 3	ESR1, ESR2
AMCENESTRANT	ChEMBL	Phase 3	ESR1, ESR2
ARZOXIFENE	ChEMBL	Phase 3	ESR1, ESR2
BENSERAZIDE	ChEMBL	Phase 3	ESR1, ESR2
ALFATRADIOL	ChEMBL	Phase 2	ESR1, ESR2
AUS-131	ChEMBL	Phase 2	ESR1, ESR2
BRILANESTRANT	ChEMBL	Phase 2	ESR1, ESR2
DAIDZEIN	ChEMBL	Phase 2	ESR1, ESR2
ERTEBEREL	ChEMBL	Phase 2	ESR1, ESR2
GTX-758	ChEMBL	Phase 2	ESR1, ESR2
IDOXIFENE	ChEMBL	Phase 2	ESR1, ESR2
LEVORMELOXIFENE	ChEMBL	Phase 2	ESR1, ESR2
MOXESTROL	ChEMBL	Phase 2	ESR1, ESR2
PIPENDOXIFENE	ChEMBL	Phase 2	ESR1, ESR2
PRINABEREL	ChEMBL	Phase 2	ESR1, ESR2
STALLIMYCIN	ChEMBL	Phase 2	ESR1, ESR2
Bosentan	PubChem	Approved	ESR1, ESR2
Dihydroergotamine	PubChem	Approved	ESR1, ESR2
Fidaxomicin	PubChem	Approved	ESR1, ESR2
Propoxyphene	PubChem	Approved	ESR1, ESR2
Pyrazinamide	PubChem	Approved	ESR1, ESR2
ACETOPHENAZINE	ChEMBL	Phase 4 (approved)	ESR1
ALECTINIB	ChEMBL	Phase 4 (approved)	ESR1
APOMORPHINE	ChEMBL	Phase 4 (approved)	ESR1
ARIPIPRAZOLE	ChEMBL	Phase 4 (approved)	ESR1
ASPIRIN	ChEMBL	Phase 4 (approved)	ESR1
AZTREONAM	ChEMBL	Phase 4 (approved)	ESR1
BELINOSTAT	ChEMBL	Phase 4 (approved)	ESR1
BENZBROMARONE	ChEMBL	Phase 4 (approved)	ESR1
BEXAROTENE	ChEMBL	Phase 4 (approved)	ESR1
BISACODYL	ChEMBL	Phase 4 (approved)	ESR1
BROMOCRIPTINE	ChEMBL	Phase 4 (approved)	ESR1
BUTOCONAZOLE	ChEMBL	Phase 4 (approved)	ESR1
CANDESARTAN CILEXETIL	ChEMBL	Phase 4 (approved)	ESR1
CASPOFUNGIN	ChEMBL	Phase 4 (approved)	ESR1
CEFADROXIL	ChEMBL	Phase 4 (approved)	ESR1
CEFEPIME	ChEMBL	Phase 4 (approved)	ESR1
CEFTAZIDIME	ChEMBL	Phase 4 (approved)	ESR1
CERIVASTATIN	ChEMBL	Phase 4 (approved)	ESR1
CHLOROTRIANISENE	ChEMBL	Phase 4 (approved)	ESR1