Lasofoxifene

Summary

Lasofoxifene (CHEMBL328190) is an approved small-molecule antineoplastic agent (ATC G03XC03) targeting ESR1 and ESR2; indicated across 4 conditions including osteoporosis and breast neoplasm; with CIViC clinical evidence for 1 variant-indication association (e.g. ESR1 D538G OR ESR1 Y537C OR ESR1 Y537N OR ESR1 Y537S OR ESR1 E380Q OR ESR1 Mutation in breast cancer).

At a glance

• Status: Approved (max clinical phase 4)
• Modality: Small molecule
• ATC class: G03XC03
• Targets: 2 (ESR1, ESR2)
• Indications: 4 conditions
• Clinical trials: 7
• Precision-oncology evidence (CIViC): 1 variant–indication association
• Chemistry: 413.5 Da · C28H31NO2

Identifiers

Drug identity and classification

Field	Value
ChEMBL ID	CHEMBL328190
Name	Lasofoxifene
Type	Small molecule
Max phase	4
FDA approved	no
PubChem CID	216416
ChEBI	CHEBI:135938
ATC	G03XC03
Molecular formula	C28H31NO2
Molecular weight	413.5
InChIKey	GXESHMAMLJKROZ-IAPPQJPRSA-N

SMILES: C1CCN(C1)CCOC2=CC=C(C=C2)[C@H]3[C@H](CCC4=C3C=CC(=C4)O)C5=CC=CC=C5

IUPAC name: (5R,6S)-6-phenyl-5-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalen-2-ol

ChEBI definition: A member of the class of tetralins that is 5,6,7,8-tetrahydronaphthalen-2-ol in which the hydrogens at positions 5 and 6 are replaced by 4-[2-(pyrrolidin-1-yl)ethoxy]phenyl and phenyl groups, respectively (the 5R,6S-stereoisomer). It is a selective estrogen receptor modulator indicated for the prevention and treatment of osteoporosis in post-menopausal women.

Pharmacological roles (ChEBI): antineoplastic agent, cardioprotective agent, estrogen receptor agonist, estrogen receptor antagonist, bone density conservation agent.

Also known as: Lasofoxifene, Lasofoxifeno, LASOFOXIFENE, LASOFOXIFENE (TARTRATE), lasofoxifene, Lasofoxifene (Tartrate)

Parent form; salt/anhydrous children: CHEMBL2113354, CHEMBL5307767, CHEMBL6067998

Patent coverage: 2,518 distinct patent families (10,617 SureChEMBL compound mentions), from 2 matched compound structure(s). One matched structure accounts for 10,576 (100%) of the total. 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
ESR1	Estrogen receptor-α	Partial agonist	8.51	1.7%	P03372
ESR2	Estrogen receptor-β	Partial agonist	7.89	0.2%	Q92731

Broader ChEMBL bioactivity targets: 38 (assay-derived). Sample: Vasopressin V2 receptor, 5-hydroxytryptamine receptor 2B, Alpha-2A adrenergic receptor, Alpha-2C adrenergic receptor, Alpha-2B adrenergic receptor, Glucocorticoid receptor, Estrogen receptor, Estrogen receptor, Estrogen receptor, Muscarinic acetylcholine receptor M2, Beta-1 adrenergic receptor, Muscarinic acetylcholine receptor M1, D(2) dopamine receptor, Motilin receptor, Sodium-dependent noradrenaline transporter, 5-hydroxytryptamine receptor 2A, 5-hydroxytryptamine receptor 2C, Sodium-dependent serotonin transporter, Alpha-1A adrenergic receptor, Prostaglandin G/H synthase 2.

Bioactivity

ChEMBL activities: 37 potent at pChembl ≥ 5 of 50 total. Top 100 by potency (10 = 0.1 nM, 6 = 1 µM):

Target	pChembl	Type	Value	Unit	Activity ID
ESR1	10	IC50	0.1	nM	CHEMBL_ACT_1432222
ESR1	9.7	Ki	0.2	nM	CHEMBL_ACT_29105258
ESR1	8.89	IC50	1.3	nM	CHEMBL_ACT_1432220
ESR1	8.85	IC50	1.4	nM	CHEMBL_ACT_1654175
ESR2	8.74	IC50	1.8	nM	CHEMBL_ACT_1432221
ESR2	8.74	IC50	1.8	nM	CHEMBL_ACT_1654176
ESR1	8.64	IC50	2.3	nM	CHEMBL_ACT_1514343
ESR1	8.51	IC50	3.1	nM	CHEMBL_ACT_1514341
ESR1	8.4	IC50	4	nM	CHEMBL_ACT_1514236
P06211	7.96	IC50	11.1	nM	CHEMBL_ACT_753150
P06211	7.95	IC50	11.3	nM	CHEMBL_ACT_753152
ESR2	7.89	IC50	13	nM	CHEMBL_ACT_1514340
ESR2	7.62	IC50	24	nM	CHEMBL_ACT_1514342
ESR1	7.41	AC50	39	nM	CHEMBL_ACT_25167323
ESR1	7.35	AC50	45	nM	CHEMBL_ACT_25116337
OPRK1	7.07	AC50	84.9	nM	CHEMBL_ACT_25129436
SLC6A3	6.93	AC50	116.8	nM	CHEMBL_ACT_25123967
HTR2B	6.57	AC50	272	nM	CHEMBL_ACT_25164117
KCNH2	6.14	AC50	730	nM	CHEMBL_ACT_25117889
HRH3	6	AC50	990	nM	CHEMBL_ACT_25200607
ADRA2C	5.8	AC50	1600	nM	CHEMBL_ACT_25147891
SLC6A4	5.8	AC50	1600	nM	CHEMBL_ACT_25150350
NR1I2	5.8	AC50	1600	nM	CHEMBL_ACT_25188187
SLC6A2	5.7	AC50	2000	nM	CHEMBL_ACT_25145017
DRD3	5.66	AC50	2200	nM	CHEMBL_ACT_25193542
MLNR	5.54	AC50	2900	nM	CHEMBL_ACT_25189201
Q63921	5.3	AC50	5000	nM	CHEMBL_ACT_25174413
HTR2C	5.28	AC50	5300	nM	CHEMBL_ACT_25131822
GHSR	5.28	AC50	5200	nM	CHEMBL_ACT_25172769
ADORA3	5.24	AC50	5800	nM	CHEMBL_ACT_25134226
OPRD1	5.14	AC50	7200	nM	CHEMBL_ACT_25154083
ADRA2B	5.09	AC50	8200	nM	CHEMBL_ACT_25143716
DRD2	5.07	AC50	8600	nM	CHEMBL_ACT_25140349
NR3C1	5.03	AC50	9300	nM	CHEMBL_ACT_25175858
HTR2B	5.02	AC50	9487	nM	CHEMBL_ACT_25227537
ADRB1	5	AC50	10000	nM	CHEMBL_ACT_25121792
ADRA2A	5	AC50	10000	nM	CHEMBL_ACT_25221102

Target pathways

Aggregated over 2 target gene(s): ESR1, ESR2.

Top Reactome pathways

17 total, by targets touching each:

Pathway	Targets	Genes
PIP3 activates AKT signaling	2	ESR1, ESR2
Constitutive Signaling by Aberrant PI3K in Cancer	2	ESR1, ESR2
Nuclear Receptor transcription pathway	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
SUMOylation of intracellular receptors	1	ESR1
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
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
negative regulation of transcription by RNA polymerase II	2
regulation of DNA-templated transcription	2
regulation of transcription by RNA polymerase II	2
signal transduction	2
estrogen receptor signaling pathway	2
positive regulation of DNA-templated transcription	2
positive regulation of transcription by RNA polymerase II	2
obsolete positive regulation of DNA-binding transcription factor activity	2
cellular response to estradiol stimulus	2
cellular response to oxygen-containing compound	2
antral ovarian follicle growth	1
epithelial cell development	1
chromatin remodeling	1
phospholipase C-activating G protein-coupled receptor signaling pathway	1
positive regulation of cytosolic calcium ion concentration	1

Indications & clinical

Indications

3 diseases in clinical trials (phase 1–3, investigational — not approved indications). Highest ChEMBL trial phase per disease; a non-cancer approved use is occasionally logged at phase 3 here.

Disease (in trials)	Phase	MONDO	EFO
osteoporosis	3	MONDO:0005298	EFO:0003882
breast neoplasm	3	MONDO:0021100	MONDO:0007254
angiosarcoma	2	MONDO:0016982	EFO:0003968

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

Clinical trials

Total trials: 7.

Phase distribution

Phase	Trials
PHASE2	5
PHASE3	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00141323	PHASE3	COMPLETED	Postmenopausal Evaluation and Risk-reduction With Lasofoxifene (PEARL)
NCT00163137	PHASE3	COMPLETED	Comparison of Raloxifene and Lasofoxifene - A Randomized, Blinded Study of These Drugs and Placebo on Bone Loss
NCT01042379	PHASE2	RECRUITING	I-SPY TRIAL: Neoadjuvant and Personalized Adaptive Novel Agents to Treat Breast Cancer
NCT00143273	PHASE2	COMPLETED	Dose Response Study of Lasofoxifene in Postmenopausal Women With Osteoporosis - Japanese Asian Dose Evaluation
NCT00674453	PHASE2	COMPLETED	The Prevention Of Postmenopausal Osteoporosis With Lasofoxifene And Cytokine Evaluation
NCT03781063	PHASE2	COMPLETED	Evaluation of Lasofoxifene Versus Fulvestrant in Advanced or Metastatic ER+/HER2- Breast Cancer With an ESR1 Mutation
NCT04432454	PHASE2	COMPLETED	Evaluation of Lasofoxifene Combined With Abemaciclib in Advanced or Metastatic ER+/HER2- Breast Cancer With an ESR1 Mutation

Clinical evidence (CIViC)

Variant × indication × effect (1 predictive associations from 1 curated evidence items):

Variant	Indication	Effect	Therapy	Level	CIViC
ESR1 D538G OR ESR1 Y537C OR ESR1 Y537N OR ESR1 Y537S OR ESR1 E380Q OR ESR1 Mutation	Breast Cancer	Sensitivity/Response	Lasofoxifene	CIViC A	EID12934

Pharmacology

Pharmacogenomics

No PharmGKB pharmacogenomic data curated for this drug.

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 100 by shared-target count:

Molecule	Source	Status	Shared targets
FULVESTRANT	ChEMBL + PubChem	Phase 4 (approved)	ESR1, ESR2
BAZEDOXIFENE	ChEMBL	Phase 4 (approved)	ESR1, ESR2
BITHIONOL	ChEMBL	Phase 4 (approved)	ESR1, ESR2
CISPLATIN	ChEMBL	Phase 4 (approved)	ESR1, ESR2
DIETHYLSTILBESTROL	ChEMBL	Phase 4 (approved)	ESR1, ESR2
ELACESTRANT	ChEMBL	Phase 4 (approved)	ESR1, ESR2
ESTETROL	ChEMBL	Phase 4 (approved)	ESR1, ESR2
ESTRADIOL	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
MEDROXYPROGESTERONE	ChEMBL	Phase 4 (approved)	ESR1, ESR2
MIFEPRISTONE	ChEMBL	Phase 4 (approved)	ESR1, ESR2
PHENOLPHTHALEIN	ChEMBL	Phase 4 (approved)	ESR1, ESR2
RALOXIFENE	ChEMBL	Phase 4 (approved)	ESR1, ESR2
SPIRONOLACTONE	ChEMBL	Phase 4 (approved)	ESR1, ESR2
TAMOXIFEN	ChEMBL	Phase 4 (approved)	ESR1, ESR2
ACOLBIFENE	ChEMBL	Phase 3	ESR1, ESR2
AFIMOXIFENE	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
GENISTEIN	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
CLOFAZIMINE	ChEMBL	Phase 4 (approved)	ESR1
CLOMIPHENE	ChEMBL	Phase 4 (approved)	ESR1
CYCLOFENIL	ChEMBL	Phase 4 (approved)	ESR1
DANAZOL	ChEMBL	Phase 4 (approved)	ESR1
DAUNORUBICIN	ChEMBL	Phase 4 (approved)	ESR1
DEMECLOCYCLINE	ChEMBL	Phase 4 (approved)	ESR2
DEQUALINIUM	ChEMBL	Phase 4 (approved)	ESR1
DESOGESTREL	ChEMBL	Phase 4 (approved)	ESR1
DIENESTROL	ChEMBL	Phase 4 (approved)	ESR1
DINOPROSTONE	ChEMBL	Phase 4 (approved)	ESR1
DOXORUBICIN	ChEMBL	Phase 4 (approved)	ESR1
DRONEDARONE	ChEMBL	Phase 4 (approved)	ESR1
ERGOCALCIFEROL	ChEMBL	Phase 4 (approved)	ESR1
ERTAPENEM	ChEMBL	Phase 4 (approved)	ESR1
ESTRADIOL CYPIONATE	ChEMBL	Phase 4 (approved)	ESR1
ESTRADIOL VALERATE	ChEMBL	Phase 4 (approved)	ESR1
ESTRAMUSTINE	ChEMBL	Phase 4 (approved)	ESR1
ETHYLESTRENOL	ChEMBL	Phase 4 (approved)	ESR1
ETHYNODIOL DIACETATE	ChEMBL	Phase 4 (approved)	ESR1
ETONOGESTREL	ChEMBL	Phase 4 (approved)	ESR1
ETRAVIRINE	ChEMBL	Phase 4 (approved)	ESR1
FLUPIRTINE	ChEMBL	Phase 4 (approved)	ESR1
HEXESTROL	ChEMBL	Phase 4 (approved)	ESR1
IBUPROFEN	ChEMBL	Phase 4 (approved)	ESR1
ISOCONAZOLE	ChEMBL	Phase 4 (approved)	ESR1
LENVATINIB	ChEMBL	Phase 4 (approved)	ESR1
LEVONORGESTREL	ChEMBL	Phase 4 (approved)	ESR1
LUSUTROMBOPAG	ChEMBL	Phase 4 (approved)	ESR1
LYMECYCLINE	ChEMBL	Phase 4 (approved)	ESR1
MASOPROCOL	ChEMBL	Phase 4 (approved)	ESR1
MEMANTINE	ChEMBL	Phase 4 (approved)	ESR1
MESTRANOL	ChEMBL	Phase 4 (approved)	ESR1
METHYSERGIDE	ChEMBL	Phase 4 (approved)	ESR2
MICAFUNGIN	ChEMBL	Phase 4 (approved)	ESR1
MIFAMURTIDE ACID	ChEMBL	Phase 4 (approved)	ESR1
MILTEFOSINE	ChEMBL	Phase 4 (approved)	ESR1
MITOXANTRONE	ChEMBL	Phase 4 (approved)	ESR1
MOLSIDOMINE	ChEMBL	Phase 4 (approved)	ESR1
MONTELUKAST	ChEMBL	Phase 4 (approved)	ESR1
NORETHINDRONE	ChEMBL	Phase 4 (approved)	ESR1