Lumacaftor

Summary

Lumacaftor (CHEMBL2103870) is an approved small-molecule CFTR potentiator targeting CFTR; indicated across 2 conditions including cystic fibrosis and liver disorder.

At a glance

• Status: Approved (max clinical phase 4)
• Modality: Small molecule
• Targets: 1 (CFTR)
• Indications: 2 conditions
• Clinical trials: 13
• Chemistry: 452.4 Da · C24H18F2N2O5

Identifiers

Drug identity and classification

Field	Value
ChEMBL ID	CHEMBL2103870
Name	Lumacaftor
Type	Small molecule
Max phase	4
FDA approved	no
PubChem CID	16678941
ChEBI	CHEBI:90951
Molecular formula	C24H18F2N2O5
Molecular weight	452.4
InChIKey	UFSKUSARDNFIRC-UHFFFAOYSA-N

SMILES: CC1=C(N=C(C=C1)NC(=O)C2(CC2)C3=CC4=C(C=C3)OC(O4)(F)F)C5=CC(=CC=C5)C(=O)O

IUPAC name: 3-[6-[[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarbonyl]amino]-3-methyl-2-pyridinyl]benzoic acid

ChEBI definition: An aromatic amide obtained by formal condensation of the carboxy group of 1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropane-1-carboxylic acid with the aromatic amino group of 3-(6-amino-3-methylpyridin-2-yl)benzoic acid. Used for the treatment of cystic fibrosis.

Pharmacological roles (ChEBI): CFTR potentiator, orphan drug.

Also known as: Lumacaftor, Lumacaftor component of orkambi, VRT 826809, VRT-826809, VRT826809, VX 809, VX-809, VX809, LUMACAFTOR, VX-809 (LUMACAFTOR), LumacaftorÊ, VX-809 (Lumacaftor)

Patent coverage: 845 distinct patent families (2,367 SureChEMBL compound mentions), from 4 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
CFTR	CFTR	Binding	5.59	0.1%	P13569

Broader ChEMBL bioactivity targets: 7 (assay-derived). Sample: Alpha-1A adrenergic receptor, Adenosine receptor A3, 3’,5’-cyclic-AMP phosphodiesterase 4D, Cytochrome P450 2C9, Nuclear receptor subfamily 1 group I member 2, Cytochrome P450 2C8, Cystic fibrosis transmembrane conductance regulator.

Bioactivity

ChEMBL activities: 7 potent at pChembl ≥ 5 of 14 total. Top 30 by potency (10 = 0.1 nM, 6 = 1 µM):

Target	pChembl	Type	Value	Unit	Activity ID
CFTR	7.1	EC50	80	nM	CHEMBL_ACT_29226432
NR1I2	6.7	AC50	200	nM	CHEMBL_ACT_25224653
CFTR	5.59	EC50	2570	nM	CHEMBL_ACT_18382038
CFTR	5.58	EC50	2600	nM	CHEMBL_ACT_16424758
CFTR	5.58	EC50	2600	nM	CHEMBL_ACT_18382033
CFTR	5.58	EC50	2600	nM	CHEMBL_ACT_19098847
NR1I2	5.24	AC50	5800	nM	CHEMBL_ACT_25188637

Target pathways

Aggregated over 1 target gene(s): CFTR.

Top Reactome pathways

11 total, by targets touching each:

Pathway	Targets	Genes
ABC-family protein mediated transport	1	CFTR
RHO GTPases regulate CFTR trafficking	1	CFTR
Defective CFTR causes cystic fibrosis	1	CFTR
Ub-specific processing proteases	1	CFTR
Cargo recognition for clathrin-mediated endocytosis	1	CFTR
Clathrin-mediated endocytosis	1	CFTR
RHOQ GTPase cycle	1	CFTR
Chaperone Mediated Autophagy	1	CFTR
Late endosomal microautophagy	1	CFTR
Aggrephagy	1	CFTR
Developmental Lineage of Pancreatic Ductal Cells	1	CFTR

Dominant GO biological processes

GO term	Targets
cholesterol biosynthetic process	1
water transport	1
bicarbonate transport	1
cholesterol transport	1
response to endoplasmic reticulum stress	1
transepithelial water transport	1
sperm capacitation	1
multicellular organismal-level water homeostasis	1
intracellular pH elevation	1
establishment of localization in cell	1
transmembrane transport	1
membrane hyperpolarization	1
positive regulation of enamel mineralization	1
cellular response to cAMP	1
amelogenesis	1

Indications & clinical

Indications

2 indications (1 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
cystic fibrosis	4	MONDO:0009061	MONDO:0009061
liver disorder	1	MONDO:0005154	EFO:0001421

Clinical trials

Total trials: 13.

Phase distribution

Phase	Trials
PHASE1	5
PHASE3	3
PHASE2	3
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01897233	PHASE3	COMPLETED	Study of Lumacaftor in Combination With Ivacaftor in Subjects 6 Through 11 Years of Age With Cystic Fibrosis, Homozygous for the F508del-CFTR Mutation
NCT02390219	PHASE3	COMPLETED	Study to Evaluate Lumacaftor and Ivacaftor Combination Therapy in Subjects 12 Years and Older With Advanced Lung Disease
NCT02514473	PHASE3	COMPLETED	A Study to Evaluate the Efficacy and Safety of Lumacaftor in Combination With Ivacaftor in Subjects With CF, Homozygous for the F508del-CFTR Mutation
NCT00865904	PHASE2	COMPLETED	Study of VX-809 in Cystic Fibrosis Subjects With the ∆F508-CFTR Gene Mutation
NCT01225211	PHASE2	COMPLETED	Study of VX-809 Alone and in Combination With VX-770 in Cystic Fibrosis (CF) Patients Homozygous or Heterozygous for the F508del-CFTR Mutation
NCT04581408	PHASE2	COMPLETED	Mutation-specific Therapy for the Long QT Syndrome
NCT00966602	PHASE1	COMPLETED	Drug-Drug Interaction Study of VX-809 and VX-770 in Healthy Subjects
NCT01216046	PHASE1	COMPLETED	Drug-Drug Interaction Study of VX-770 and VX-809 in Healthy Subjects
NCT01768663	PHASE1	COMPLETED	A Phase 1 Study to Examine the Drug-Drug Interaction of Ciprofloxacin, Itraconazole, and Rifampin on the Combination of Lumacaftor With Ivacaftor in Healthy Adult Subjects
NCT01899105	PHASE1	COMPLETED	A Phase 1 Study to Investigate the Food Effect of Lumacaftor in Combination With Ivacaftor
NCT01910415	PHASE1	COMPLETED	Phase 1, QT/QTC Interval Study in Healthy Subjects
NCT03475381	Not specified	COMPLETED	Real-life Follow-up of Cystic Fibrosis Patients Treated With Ivacaftor+Lumacaftor (Orkambi*)
NCT04623879	Not specified	COMPLETED	Real Life Evaluation of the Multi-organ Effects of Lumacaftor/Ivacaftor on F508del Homozygous Cystic Fibrosis Patients.

Clinical evidence (CIViC)

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

Pharmacology

Pharmacogenomics

No CPIC/DPWG dosing guideline, but PharmGKB curates 2 clinical and 18 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.

14 molecules share ≥1 primary target. Top 14 by shared-target count:

Molecule	Source	Status	Shared targets
IVACAFTOR	ChEMBL + PubChem	Phase 4 (approved)	CFTR
ELEXACAFTOR	ChEMBL	Phase 4 (approved)	CFTR
GLYBURIDE	ChEMBL	Phase 4 (approved)	CFTR
TEZACAFTOR	ChEMBL	Phase 4 (approved)	CFTR
BAMOCAFTOR	ChEMBL	Phase 3	CFTR
QUERCETIN	ChEMBL	Phase 3	CFTR
RUTIN	ChEMBL	Phase 3	CFTR
GALICAFTOR	ChEMBL	Phase 2	CFTR
GENISTEIN	ChEMBL	Phase 2	CFTR
GLPG-2737	ChEMBL	Phase 2	CFTR
ICENTICAFTOR	ChEMBL	Phase 2	CFTR
NAVOCAFTOR	ChEMBL	Phase 2	CFTR
RISELCAFTOR	ChEMBL	Phase 2	CFTR
Tadalafil	PubChem	Approved	CFTR