Lonafarnib
drugOn this page
Also known as SarasarSCH 66336SCH-66336SCH66336ZokinvyLonafranibLONAFARNIB (SCH66336)LonarfarnibIonafarnib
Summary
Lonafarnib (CHEMBL298734) is an approved small-molecule antineoplastic agent (ATC A16AX20) targeting HRAS, NRAS, and KRAS; indicated across 21 conditions including progeroid syndrome and laminopathy; with CIViC clinical evidence for 1 variant-indication association (e.g. FNTB RS11623866 in ovarian cancer).
At a glance
- Status: Approved (max clinical phase 4)
- Modality: Small molecule
- ATC class: A16AX20
- Targets: 3 (HRAS, NRAS, KRAS)
- Indications: 21 conditions
- Clinical trials: 34
- Precision-oncology evidence (CIViC): 1 variant–indication association
- Chemistry: 638.8 Da · C27H31Br2ClN4O2
Identifiers
Drug identity and classification
| Field | Value |
|---|---|
| ChEMBL ID | CHEMBL298734 |
| Name | Lonafarnib |
| Type | Small molecule |
| Max phase | 4 |
| FDA approved | yes |
| PubChem CID | 148195 |
| ChEBI | CHEBI:47097 |
| ATC | A16AX20 |
| Molecular formula | C27H31Br2ClN4O2 |
| Molecular weight | 638.8 |
| InChIKey | DHMTURDWPRKSOA-RUZDIDTESA-N |
SMILES: C1CN(CCC1CC(=O)N2CCC(CC2)[C@@H]3C4=C(CCC5=C3N=CC(=C5)Br)C=C(C=C4Br)Cl)C(=O)N
IUPAC name: 4-[2-[4-[(2R)-6,15-dibromo-13-chloro-4-azatricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,12,14-hexaen-2-yl]piperidin-1-yl]-2-oxoethyl]piperidine-1-carboxamide
ChEBI definition: A 4-{2-[4-(3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)piperidin-1-yl]-2-oxoethyl}piperidine-1-carboxamide that has R configuration. It is used as oral farnesyltransferase inhibitor.
Pharmacological roles (ChEBI): antineoplastic agent, EC 2.5.1.58 (protein farnesyltransferase) inhibitor.
Also known as: Lonafarnib, Sarasar, SCH 66336, SCH-66336, SCH66336, Zokinvy, lonafarnib, LONAFARNIB, Lonafranib, LONAFARNIB (SCH66336), Lonafarnib (SCH66336), Lonarfarnib
Patent coverage: 3,356 distinct patent families (12,801 SureChEMBL compound mentions), from 2 matched compound structure(s). One matched structure accounts for 12,776 (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 |
|---|---|---|---|---|---|
| HRAS | HRAS | Inhibition | 8.72 | 3.5% | P01112 |
| NRAS | NRAS | Inhibition | 8.55 | 7.8% | P01111 |
| KRAS | KRAS | Inhibition | 8.28 | 52.4% | P01116 |
Broader ChEMBL bioactivity targets: 7 (assay-derived). Sample: Protein farnesyltransferase, Protein farnesyltransferase, Protein farnesyltransferase, Protein farnesyltransferase, GTPase HRas, GTPase KRas, ATP-dependent translocase ABCB1.
Bioactivity
ChEMBL activities: 19 potent at pChembl ≥ 5 of 19 total. Top 30 by potency (10 = 0.1 nM, 6 = 1 µM):
| Target | pChembl | Type | Value | Unit | Activity ID |
|---|---|---|---|---|---|
| FNTA | 8.72 | IC50 | 1.9 | nM | CHEMBL_ACT_1183092 |
| FNTA | 8.72 | IC50 | 1.9 | nM | CHEMBL_ACT_14546343 |
| FNTA | 8.72 | IC50 | 1.9 | nM | CHEMBL_ACT_156353 |
| Q02293 | 8.72 | IC50 | 1.9 | nM | CHEMBL_ACT_18483963 |
| FNTA | 8.72 | IC50 | 1.9 | nM | CHEMBL_ACT_649099 |
| FNTA | 8.72 | IC50 | 1.9 | nM | CHEMBL_ACT_670218 |
| FNTA | 8.72 | IC50 | 1.9 | nM | CHEMBL_ACT_99705 |
| FNTA | 8.7 | IC50 | 2 | nM | CHEMBL_ACT_1460870 |
| FNTA | 8.7 | IC50 | 2 | nM | CHEMBL_ACT_442755 |
| P29702 | 8.11 | IC50 | 7.8 | nM | CHEMBL_ACT_1228558 |
| P29702 | 8.08 | IC50 | 8.3 | nM | CHEMBL_ACT_1452757 |
| P29702 | 8.08 | IC50 | 8.3 | nM | CHEMBL_ACT_1499224 |
| FNTA | 8 | IC50 | 10 | nM | CHEMBL_ACT_3526147 |
| FNTA | 8 | IC50 | 10 | nM | CHEMBL_ACT_649100 |
| FNTA | 8 | IC50 | 10 | nM | CHEMBL_ACT_670219 |
| KRAS | 7.4 | IC50 | 40 | nM | CHEMBL_ACT_25500523 |
| HRAS | 7.16 | IC50 | 70 | nM | CHEMBL_ACT_670232 |
| Q61239 | 7 | EC50 | 100 | nM | CHEMBL_ACT_1452759 |
| ABCB1 | 5.57 | IC50 | 2700 | nM | CHEMBL_ACT_11001324 |
Target pathways
Aggregated over 3 target gene(s): HRAS, NRAS, KRAS.
Top Reactome pathways
73 total, by targets touching each:
| Pathway | Targets | Genes |
|---|---|---|
| SOS-mediated signalling | 3 | HRAS, KRAS, NRAS |
| Activation of RAS in B cells | 3 | HRAS, KRAS, NRAS |
| Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants | 3 | HRAS, KRAS, NRAS |
| SHC1 events in ERBB2 signaling | 3 | HRAS, KRAS, NRAS |
| SHC1 events in ERBB4 signaling | 3 | HRAS, KRAS, NRAS |
| Signaling by SCF-KIT | 3 | HRAS, KRAS, NRAS |
| Signalling to RAS | 3 | HRAS, KRAS, NRAS |
| p38MAPK events | 3 | HRAS, KRAS, NRAS |
| GRB2 events in EGFR signaling | 3 | HRAS, KRAS, NRAS |
| SHC1 events in EGFR signaling | 3 | HRAS, KRAS, NRAS |
| Downstream signal transduction | 3 | HRAS, KRAS, NRAS |
| GRB2 events in ERBB2 signaling | 3 | HRAS, KRAS, NRAS |
| Tie2 Signaling | 3 | HRAS, KRAS, NRAS |
| EGFR Transactivation by Gastrin | 3 | HRAS, KRAS, NRAS |
| DAP12 signaling | 3 | HRAS, KRAS, NRAS |
| SHC-related events triggered by IGF1R | 3 | HRAS, KRAS, NRAS |
| FCERI mediated MAPK activation | 3 | HRAS, KRAS, NRAS |
| NCAM signaling for neurite out-growth | 3 | HRAS, KRAS, NRAS |
| Ras activation upon Ca2+ influx through NMDA receptor | 3 | HRAS, KRAS, NRAS |
| VEGFR2 mediated cell proliferation | 3 | HRAS, KRAS, NRAS |
| CD209 (DC-SIGN) signaling | 3 | HRAS, KRAS, NRAS |
| Constitutive Signaling by EGFRvIII | 3 | HRAS, KRAS, NRAS |
| SHC-mediated cascade:FGFR1 | 3 | HRAS, KRAS, NRAS |
| FRS-mediated FGFR1 signaling | 3 | HRAS, KRAS, NRAS |
| SHC-mediated cascade:FGFR2 | 3 | HRAS, KRAS, NRAS |
| FRS-mediated FGFR2 signaling | 3 | HRAS, KRAS, NRAS |
| SHC-mediated cascade:FGFR3 | 3 | HRAS, KRAS, NRAS |
| FRS-mediated FGFR3 signaling | 3 | HRAS, KRAS, NRAS |
| FRS-mediated FGFR4 signaling | 3 | HRAS, KRAS, NRAS |
| SHC-mediated cascade:FGFR4 | 3 | HRAS, KRAS, NRAS |
Dominant GO biological processes
| GO term | Targets |
|---|---|
| MAPK cascade | 3 |
| signal transduction | 3 |
| Ras protein signal transduction | 3 |
| negative regulation of neuron apoptotic process | 2 |
| regulation of long-term neuronal synaptic plasticity | 2 |
| neuron apoptotic process | 2 |
| positive regulation of gene expression | 2 |
| regulation of transcription by RNA polymerase II | 1 |
| endocytosis | 1 |
| chemotaxis | 1 |
| cell surface receptor signaling pathway | 1 |
| positive regulation of cell population proliferation | 1 |
| negative regulation of cell population proliferation | 1 |
| insulin receptor signaling pathway | 1 |
| animal organ morphogenesis | 1 |
Indications & clinical
Indications
21 indications (3 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 |
|---|---|---|---|
| progeroid syndrome | 4 | MONDO:0015333 | MONDO:0020732 |
| laminopathy | 4 | MONDO:0021106 | |
| hepatitis D virus infection | 3 | MONDO:0005789 | EFO:0007304 |
| non-small cell lung carcinoma | 3 | MONDO:0005233 | EFO:0003060 |
| myelodysplastic syndrome | 3 | MONDO:0018881 | EFO:0000198 |
| chronic myelomonocytic leukemia | 3 | MONDO:0020311 | EFO:1001779 |
| chronic myeloid leukemia | 2 | MONDO:0011996 | EFO:0000339 |
| breast neoplasm | 2 | MONDO:0021100 | MONDO:0007254 |
| ovarian cancer | 2 | MONDO:0008170 | MONDO:0008170 |
| lymphoma | 1 | MONDO:0005062 | EFO:0000574 |
| anaplastic astrocytoma | 1 | MONDO:0016684 | EFO:0002499 |
| head and neck cancer | 1 | MONDO:0005627 | EFO:0006859 |
| gliosarcoma | 1 | MONDO:0016681 | EFO:1001465 |
| central nervous system neoplasm | 1 | MONDO:0006130 | EFO:1000158 |
| glioblastoma | 1 | MONDO:0018177 | EFO:0000519 |
| colorectal neoplasm | 1 | MONDO:0005335 | MONDO:0005575 |
5 further indication records had no mapped disease name (EFO/MeSH-only) or were duplicates, and are omitted.
Clinical trials
Total trials: 34.
Phase distribution
| Phase | Trials |
|---|---|
| PHASE2 | 17 |
| PHASE1 | 11 |
| PHASE3 | 4 |
| PHASE1/PHASE2 | 1 |
| Not specified | 1 |
Top trials by phase / activity
| NCT | Phase | Status | Title |
|---|---|---|---|
| NCT00050336 | PHASE3 | TERMINATED | Study of Lonafarnib in Combination With Paclitaxel and Carboplatin in Patients With Non-Small Cell Lung Cancer (Study P01901)(TERMINATED) |
| NCT00109538 | PHASE3 | TERMINATED | Study of Lonafarnib Versus Placebo in Subjects With Either Myelodysplastic Syndrome (MDS) or Chronic Myelomonocytic Leukemia (CMML) (Study P02978AM3)(TERMINATED) |
| NCT03719313 | PHASE3 | COMPLETED | Study of the Efficacy and Safety of Lonafarnib / Ritonavir With and Without Pegylated Interferon -Alfa-2a |
| NCT05229991 | PHASE3 | COMPLETED | Once Daily Dosing of Lonafarnib Co-administered With Ritonavir for Treatment of Chronic Hepatitis D Virus Infection |
| NCT02579044 | PHASE1/PHASE2 | ENROLLING_BY_INVITATION | Phase I/II Trial of Everolimus in Combination With Lonafarnib in Progeria |
| NCT06775041 | PHASE2 | ACTIVE_NOT_RECRUITING | Study to Determine Optimal Dose and Evaluate Safety, Tolerability, and Pharmacokinetics of Progerinin in Patients With Hutchinson-Gilford Progeria Syndrome (HGPS) |
| NCT00006351 | PHASE2 | COMPLETED | SCH 66336 Plus Gemcitabine in Treating Patients With Advanced Cancer of the Urinary Tract |
| NCT00020774 | PHASE2 | WITHDRAWN | SCH 66336 With or Without Gemcitabine Followed by Surgery Compared With Surgery Alone in Treating Patients With Primary Liver Cancer |
| NCT00038493 | PHASE2 | COMPLETED | Temozolomide and SCH66336 for Recurrent Glioblastoma Multiforme |
| NCT00038597 | PHASE2 | COMPLETED | Phase II Study of SCH66336, A Farnesyltransferase Inhibitor in Chronic Myelogenous Leukemia (CML) |
| NCT00081510 | PHASE2 | COMPLETED | Anastrozole Plus Lonafarnib (SCH 66336) or Plus Placebo for the Treatment of Advanced Breast Cancer (P03480) |
| NCT00281515 | PHASE2 | COMPLETED | Comparison of Paclitaxel/Carboplatin and Lonafarnib to Paclitaxel/Carboplatin for First-line Treatment of Ovarian Cancer |
| NCT00425607 | PHASE2 | COMPLETED | Phase II Trial of Lonafarnib (a Farnesyltransferase Inhibitor) for Progeria |
| NCT00773474 | PHASE2 | TERMINATED | Lonafarnib in Metastatic Breast Cancer |
| NCT00879034 | PHASE2 | COMPLETED | A Study of Zoledronic Acid, Pravastatin, and Lonafarnib for Patients With Progeria |
| NCT01495585 | PHASE2 | COMPLETED | Lonafarnib for Chronic Hepatitis D |
| NCT02430181 | PHASE2 | COMPLETED | Lonafarnib With and Without Ritonavir in HDV (LOWR-1) |
| NCT02430194 | PHASE2 | COMPLETED | Lonafarnib Boosted With Ritonavir With and Without Peginterferon Alfa-2a (PEG IFN-a) in HDV (LOWR-2) |
| NCT02511431 | PHASE2 | COMPLETED | Treatment of Chronic Delta Hepatitis With Lonafarnib and Ritonavir |
| NCT02527707 | PHASE2 | COMPLETED | Titrating-Dose of Lonafarnib in Combination With Ritonavir |
| NCT02968641 | PHASE2 | WITHDRAWN | A Study of Lonafarnib With or Without Ritonavir in Patients With HDV |
| NCT03600714 | PHASE2 | COMPLETED | Treatment of Chronic Delta Hepatitis With Lonafarnib, Ritonavir and Lambda Interferon |
| NCT00102648 | PHASE1 | ACTIVE_NOT_RECRUITING | Lonafarnib and Temozolomide in Treating Patients with Glioblastoma Multiforme That is Recurrent or Did Not Respond to Previous Treatment with Temozolomide |
| NCT00003956 | PHASE1 | COMPLETED | Combination Chemotherapy in Treating Patients With Advanced Cancer |
| NCT00005030 | PHASE1 | WITHDRAWN | SCH 66336 Before Surgery in Treating Patients With Colorectal Cancer That Has Metastasized to the Liver |
| NCT00015899 | PHASE1 | COMPLETED | SCH 66336 in Treating Children With Recurrent or Progressive Brain Tumors |
| NCT00038584 | PHASE1 | COMPLETED | A Phase IB Study Of Oral SCH 66336 Preoperatively In Patients With Head And Neck Squamous Cell Cancer |
| NCT00047502 | PHASE1 | COMPLETED | Study of Lonafarnib and Gleevec in Chronic Myelogenous Leukemia |
| NCT00068757 | PHASE1 | COMPLETED | Lonafarnib, Trastuzumab, and Paclitaxel in Treating Patients With HER2/Neu-Overexpressing Stage IIIB, Stage IIIC, or Stage IV Breast Cancer |
| NCT00083096 | PHASE1 | UNKNOWN | Lonafarnib and Temozolomide in Treating Patients With Recurrent Primary Supratentorial Gliomas |
| NCT00102635 | PHASE1 | TERMINATED | 4-HPR and FTI in Head and Neck Squamous Cell Carcinoma (HNSCC) |
| NCT00288444 | PHASE1 | TERMINATED | Interaction of Docetaxel and Lonafarnib in Patients With Advanced Cancer |
| NCT00612651 | PHASE1 | COMPLETED | PH I Addition of Farnesyl Transferase Inhibitor to Temozolomide for Pts w Gr 3 & 4 Malignant Gliomas |
| NCT03895528 | Not specified | APPROVED_FOR_MARKETING | Lonafarnib for Patients With Hutchinson-Gilford Progeria Syndrome or Progeroid Laminopathy |
Clinical evidence (CIViC)
Variant × indication × effect (1 predictive associations from 1 curated evidence items):
| Variant | Indication | Effect | Therapy | Level | CIViC |
|---|---|---|---|---|---|
| FNTB RS11623866 | Ovarian Cancer | Resistance | Lonafarnib | CIViC B | EID815 |
Pharmacology
Pharmacogenomics
No CPIC/DPWG dosing guideline, but PharmGKB curates 1 clinical and 1 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.
8 molecules share ≥1 primary target. Top 8 by shared-target count:
| Molecule | Source | Status | Shared targets |
|---|---|---|---|
| ADAGRASIB | ChEMBL + PubChem | Phase 4 (approved) | KRAS |
| SOTORASIB | ChEMBL + PubChem | Phase 4 (approved) | KRAS |
| DABRAFENIB | ChEMBL | Phase 4 (approved) | KRAS |
| VEMURAFENIB | ChEMBL | Phase 4 (approved) | KRAS |
| OPNURASIB | ChEMBL | Phase 3 | KRAS |
| DIVARASIB | ChEMBL | Phase 2 | KRAS |
| GLECIRASIB | ChEMBL | Phase 2 | KRAS |
| STALLIMYCIN | ChEMBL | Phase 2 | HRAS |
Related Atlas pages
- Genes: HRAS, NRAS, KRAS
- Diseases: progeroid syndrome, laminopathy, hepatitis D virus infection, non-small cell lung carcinoma, myelodysplastic syndrome, chronic myelomonocytic leukemia, ovarian carcinoma
- Drugs: Adagrasib, Sotorasib, Dabrafenib, Vemurafenib, Opnurasib
- Biomarker genes: FNTB