Cilofexor
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Also known as GS 9674Gs-9674PX-104PX104Cliofexor
Summary
Cilofexor (CHEMBL4297613) is a phase-3 clinical-stage small molecule targeting EPHA2 and NR1H4; indicated across 4 conditions including sclerosing cholangitis and metabolic dysfunction-associated steatohepatitis.
At a glance
- Status: Max clinical phase 3 (not approved)
- Modality: Small molecule
- Targets: 2 (EPHA2, NR1H4)
- Indications: 4 conditions
- Clinical trials: 9
- Chemistry: 586.8 Da · C28H22Cl3N3O5
Identifiers
Drug identity and classification
| Field | Value |
|---|---|
| ChEMBL ID | CHEMBL4297613 |
| Name | Cilofexor |
| Type | Small molecule |
| Max phase | 3 |
| FDA approved | no |
| PubChem CID | 71228883 |
| Molecular formula | C28H22Cl3N3O5 |
| Molecular weight | 586.8 |
| InChIKey | KZSKGLFYQAYZCO-UHFFFAOYSA-N |
SMILES: C1CC1C2=C(C(=NO2)C3=C(C=CC=C3Cl)Cl)COC4=CC(=C(C=C4)C5(CN(C5)C6=NC=CC(=C6)C(=O)O)O)Cl
IUPAC name: 2-[3-[2-chloro-4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]phenyl]-3-hydroxyazetidin-1-yl]pyridine-4-carboxylic acid
Also known as: Cilofexor, GS 9674, Gs-9674, GS-9674, PX-104, PX104, CILOFEXOR, Cliofexor
Patent coverage: 461 distinct patent families (1,374 SureChEMBL compound mentions), from 3 matched compound structure(s). One matched structure accounts for 1,293 (94%) 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 |
|---|---|---|---|---|---|
| EPHA2 | EPH receptor A2 | Inhibition | 5.07 | 0.1% | P29317 |
| NR1H4 | Farnesoid X receptor | Agonist | 7.6 | 0.7% | Q96RI1 |
Broader ChEMBL bioactivity targets: 2 (assay-derived). Sample: Bile acid receptor, 17-beta-hydroxysteroid dehydrogenase 13.
Bioactivity
ChEMBL activities: 5 potent at pChembl ≥ 5 of 5 total. Top 30 by potency (10 = 0.1 nM, 6 = 1 µM):
| Target | pChembl | Type | Value | Unit | Activity ID |
|---|---|---|---|---|---|
| NR1H4 | 7.82 | EC50 | 15 | nM | CHEMBL_ACT_19005356 |
| NR1H4 | 7.4 | EC50 | 40 | nM | CHEMBL_ACT_26335959 |
| NR1H4 | 7.39 | EC50 | 41 | nM | CHEMBL_ACT_19005357 |
| NR1H4 | 7.24 | EC50 | 58 | nM | CHEMBL_ACT_29190970 |
| HSD17B13 | 5.02 | IC50 | 9470 | nM | CHEMBL_ACT_29190945 |
Target pathways
Aggregated over 2 target gene(s): EPHA2, NR1H4.
Top Reactome pathways
20 total, by targets touching each:
| Pathway | Targets | Genes |
|---|---|---|
| Recycling of bile acids and salts | 1 | NR1H4 |
| Synthesis of bile acids and bile salts | 1 | NR1H4 |
| Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol | 1 | NR1H4 |
| Synthesis of bile acids and bile salts via 27-hydroxycholesterol | 1 | NR1H4 |
| PPARA activates gene expression | 1 | NR1H4 |
| Endogenous sterols | 1 | NR1H4 |
| EPH-Ephrin signaling | 1 | EPHA2 |
| Nuclear Receptor transcription pathway | 1 | NR1H4 |
| EPHA-mediated growth cone collapse | 1 | EPHA2 |
| EPH-ephrin mediated repulsion of cells | 1 | EPHA2 |
| SUMOylation of intracellular receptors | 1 | NR1H4 |
| RAC1 GTPase cycle | 1 | EPHA2 |
| RAC2 GTPase cycle | 1 | EPHA2 |
| RHOG GTPase cycle | 1 | EPHA2 |
| RHOU GTPase cycle | 1 | EPHA2 |
| RAC3 GTPase cycle | 1 | EPHA2 |
| RHOV GTPase cycle | 1 | EPHA2 |
| RND3 GTPase cycle | 1 | EPHA2 |
| RND2 GTPase cycle | 1 | EPHA2 |
| RND1 GTPase cycle | 1 | EPHA2 |
Dominant GO biological processes
| GO term | Targets |
|---|---|
| inflammatory response | 2 |
| cell differentiation | 2 |
| skeletal system development | 1 |
| angiogenesis | 1 |
| vasculogenesis | 1 |
| osteoblast differentiation | 1 |
| blood vessel endothelial cell proliferation involved in sprouting angiogenesis | 1 |
| cell adhesion | 1 |
| cell surface receptor protein tyrosine kinase signaling pathway | 1 |
| intrinsic apoptotic signaling pathway in response to DNA damage | 1 |
| regulation of lamellipodium assembly | 1 |
| notochord formation | 1 |
| cell migration | 1 |
| negative regulation of angiogenesis | 1 |
| neural tube development | 1 |
Indications & clinical
Indications
4 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 |
|---|---|---|---|
| sclerosing cholangitis | 3 | MONDO:0018646 | EFO:0004268 |
| metabolic dysfunction-associated steatohepatitis | 2 | MONDO:0007027 | EFO:1001249 |
| primary biliary cholangitis | 2 | MONDO:0005388 | EFO:1001486 |
| metabolic dysfunction-associated steatotic liver disease | 2 | MONDO:0013209 | EFO:0003095 |
Clinical trials
Total trials: 9.
Phase distribution
| Phase | Trials |
|---|---|
| PHASE2 | 5 |
| PHASE1 | 3 |
| PHASE3 | 1 |
Top trials by phase / activity
| NCT | Phase | Status | Title |
|---|---|---|---|
| NCT03890120 | PHASE3 | TERMINATED | Study of Cilofexor in Adults With Primary Sclerosing Cholangitis |
| NCT01999101 | PHASE2 | COMPLETED | Safety Pilot Study of Farnesoid X Receptor (FXR) Agonist in Non-alcoholic Fatty Liver Disease (NAFLD) Patients |
| NCT02854605 | PHASE2 | COMPLETED | Evaluating the Safety, Tolerability, and Efficacy of GS-9674 in Participants With Nonalcoholic Steatohepatitis (NASH) |
| NCT02943447 | PHASE2 | TERMINATED | Study to Evaluate the Safety, Tolerability, and Efficacy of Cilofexor in Adults With Primary Biliary Cholangitis Without Cirrhosis |
| NCT02943460 | PHASE2 | COMPLETED | Study to Evaluate the Safety, Tolerability, and Efficacy of Cilofexor in Adults With Primary Sclerosing Cholangitis Without Cirrhosis |
| NCT03987074 | PHASE2 | COMPLETED | Safety, Tolerability, and Efficacy of Monotherapy and Combination Regimens in Participants With Nonalcoholic Steatohepatitis (NASH) |
| NCT02654002 | PHASE1 | COMPLETED | Study in Healthy Volunteers to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GS-9674 (Cilofexor), and the Effect of Food on GS-9674 Pharmacokinetics and Pharmacodynamics |
| NCT02808312 | PHASE1 | COMPLETED | Pharmacokinetics and Pharmacodynamics of Cilofexor in Adults With Normal and Impaired Hepatic Function |
| NCT04060147 | PHASE1 | TERMINATED | Safety and Tolerability of Cilofexor in Participants With Primary Sclerosing Cholangitis (PSC) and Compensated Cirrhosis |
Clinical evidence (CIViC)
No CIViC predictive evidence (expected for non-precision-medicine drugs).
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.
90 molecules share ≥1 primary target. Top 60 by shared-target count:
| Molecule | Source | Status | Shared targets |
|---|---|---|---|
| REGORAFENIB | ChEMBL + PubChem | Phase 4 (approved) | EPHA2, NR1H4 |
| CHENODIOL | ChEMBL + PubChem | Phase 4 (approved) | NR1H4 |
| CRIZOTINIB | ChEMBL + PubChem | Phase 4 (approved) | EPHA2 |
| FEDRATINIB | ChEMBL + PubChem | Phase 4 (approved) | EPHA2 |
| FULVESTRANT | ChEMBL + PubChem | Phase 4 (approved) | NR1H4 |
| ACETAMINOPHEN | ChEMBL | Phase 4 (approved) | NR1H4 |
| ATORVASTATIN | ChEMBL | Phase 4 (approved) | NR1H4 |
| BENZBROMARONE | ChEMBL | Phase 4 (approved) | NR1H4 |
| BOSUTINIB | ChEMBL | Phase 4 (approved) | EPHA2 |
| CABOZANTINIB | ChEMBL | Phase 4 (approved) | EPHA2 |
| CHOLIC ACID | ChEMBL | Phase 4 (approved) | NR1H4 |
| CLOFAZIMINE | ChEMBL | Phase 4 (approved) | NR1H4 |
| CLOTRIMAZOLE | ChEMBL | Phase 4 (approved) | NR1H4 |
| CYCLOSPORINE | ChEMBL | Phase 4 (approved) | NR1H4 |
| DASATINIB | ChEMBL | Phase 4 (approved) | EPHA2 |
| DEOXYCHOLIC ACID | ChEMBL | Phase 4 (approved) | NR1H4 |
| DICLOFENAC | ChEMBL | Phase 4 (approved) | NR1H4 |
| EPALRESTAT | ChEMBL | Phase 4 (approved) | NR1H4 |
| FELODIPINE | ChEMBL | Phase 4 (approved) | NR1H4 |
| FLUTRIMAZOLE | ChEMBL | Phase 4 (approved) | NR1H4 |
| IVERMECTIN | ChEMBL | Phase 4 (approved) | NR1H4 |
| KETOCONAZOLE | ChEMBL | Phase 4 (approved) | NR1H4 |
| LEVOTHYROXINE | ChEMBL | Phase 4 (approved) | NR1H4 |
| LORATADINE | ChEMBL | Phase 4 (approved) | NR1H4 |
| NILOTINIB | ChEMBL | Phase 4 (approved) | EPHA2 |
| NIMODIPINE | ChEMBL | Phase 4 (approved) | NR1H4 |
| NINTEDANIB | ChEMBL | Phase 4 (approved) | EPHA2 |
| OBETICHOLIC ACID | ChEMBL | Phase 4 (approved) | NR1H4 |
| ODEVIXIBAT | ChEMBL | Phase 4 (approved) | NR1H4 |
| PONATINIB | ChEMBL | Phase 4 (approved) | EPHA2 |
| PRANLUKAST | ChEMBL | Phase 4 (approved) | NR1H4 |
| RALOXIFENE | ChEMBL | Phase 4 (approved) | NR1H4 |
| REPAGLINIDE | ChEMBL | Phase 4 (approved) | NR1H4 |
| RIMONABANT | ChEMBL | Phase 4 (approved) | NR1H4 |
| SIMVASTATIN | ChEMBL | Phase 4 (approved) | NR1H4 |
| SORAFENIB | ChEMBL | Phase 4 (approved) | EPHA2 |
| SULCONAZOLE | ChEMBL | Phase 4 (approved) | NR1H4 |
| SUNITINIB | ChEMBL | Phase 4 (approved) | NR1H4 |
| TAURURSODIOL | ChEMBL | Phase 4 (approved) | NR1H4 |
| TIVOZANIB | ChEMBL | Phase 4 (approved) | EPHA2 |
| TOVORAFENIB | ChEMBL | Phase 4 (approved) | EPHA2 |
| TROGLITAZONE | ChEMBL | Phase 4 (approved) | NR1H4 |
| VANDETANIB | ChEMBL | Phase 4 (approved) | EPHA2 |
| ZAFIRLUKAST | ChEMBL | Phase 4 (approved) | NR1H4 |
| ALISERTIB | ChEMBL | Phase 3 | EPHA2 |
| ALVOCIDIB | ChEMBL | Phase 3 | EPHA2 |
| ANDROGRAPHOLIDE | ChEMBL | Phase 3 | NR1H4 |
| ELOBIXIBAT | ChEMBL | Phase 3 | NR1H4 |
| LESTAURTINIB | ChEMBL | Phase 3 | EPHA2 |
| LINIFANIB | ChEMBL | Phase 3 | EPHA2 |
| SARACATINIB | ChEMBL | Phase 3 | EPHA2 |
| TESEVATINIB | ChEMBL | Phase 3 | EPHA2 |
| VIDOFLUDIMUS | ChEMBL | Phase 3 | NR1H4 |
| AT-9283 | ChEMBL | Phase 2 | EPHA2 |
| BAFETINIB | ChEMBL | Phase 2 | EPHA2 |
| BMS-754807 | ChEMBL | Phase 2 | EPHA2 |
| CEP-32496 | ChEMBL | Phase 2 | EPHA2 |
| DANUSERTIB | ChEMBL | Phase 2 | EPHA2 |
| DORAMAPIMOD | ChEMBL | Phase 2 | EPHA2 |
| FORETINIB | ChEMBL | Phase 2 | EPHA2 |
Related Atlas pages
- Genes: EPHA2, NR1H4
- Diseases: sclerosing cholangitis
- Drugs: Regorafenib, Chenodiol, Crizotinib, Fedratinib, Fulvestrant, Acetaminophen, Atorvastatin, Benzbromarone, Bosutinib, Cabozantinib, Cholic Acid, Clofazimine, Clotrimazole, Cyclosporine, Dasatinib, Deoxycholic Acid, Diclofenac, Epalrestat, Felodipine, Flutrimazole, Ivermectin, Ketoconazole, Levothyroxine, Loratadine, Nilotinib, Nimodipine, Nintedanib, Obeticholic Acid, Odevixibat, Ponatinib, Pranlukast, Raloxifene, Repaglinide, Rimonabant, Simvastatin, Sorafenib, Sulconazole, Sunitinib, Taurursodiol, Tivozanib, Tovorafenib, Troglitazone, Vandetanib, Zafirlukast, Alisertib, Alvocidib, Andrographolide, Elobixibat, Lestaurtinib, Linifanib, Saracatinib, Tesevatinib, Vidofludimus