Tirabrutinib
drug drugOn this page
Also known as Gs-4059Ono-4059ONO-4059(FREE BASE)Velexbru
Summary
Tirabrutinib (CHEMBL4071161) is an approved small molecule (ATC L01EL06) targeting BTK; indicated across 7 conditions including b-cell chronic lymphocytic leukemia and sjogren syndrome.
At a glance
- Status: Approved (max clinical phase 4)
- Modality: Small molecule
- ATC class: L01EL06
- Targets: 1 (BTK)
- Indications: 7 conditions
- Clinical trials: 14
- Chemistry: 454.5 Da · C25H22N6O3
Identifiers
Drug identity and classification
| Field | Value |
|---|---|
| ChEMBL ID | CHEMBL4071161 |
| Name | Tirabrutinib |
| Type | Small molecule |
| Max phase | 4 |
| FDA approved | no |
| PubChem CID | 54755438 |
| ATC | L01EL06 |
| Molecular formula | C25H22N6O3 |
| Molecular weight | 454.5 |
| InChIKey | SEJLPXCPMNSRAM-GOSISDBHSA-N |
SMILES: CC#CC(=O)N1CC[C@H](C1)N2C3=NC=NC(=C3N(C2=O)C4=CC=C(C=C4)OC5=CC=CC=C5)N
IUPAC name: 6-amino-9-[(3R)-1-but-2-ynoylpyrrolidin-3-yl]-7-(4-phenoxyphenyl)purin-8-one
Also known as: Gs-4059, GS-4059, Ono-4059, ONO-4059, ONO-4059(FREE BASE), Tirabrutinib, Velexbru, TIRABRUTINIB
Parent form; salt/anhydrous children: CHEMBL5314600
Patent coverage: 779 distinct patent families (2,170 SureChEMBL compound mentions), from 2 matched compound structure(s). One matched structure accounts for 1,878 (87%) 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 |
|---|---|---|---|---|---|
| BTK | Bruton tyrosine kinase | Inhibition | 8.4 | 0.7% | Q06187 |
Broader ChEMBL bioactivity targets: 9 (assay-derived). Sample: Receptor tyrosine-protein kinase erbB-2, Tyrosine-protein kinase Blk, Tyrosine-protein kinase Lck, Receptor tyrosine-protein kinase erbB-4, Platelet glycoprotein VI, Cytoplasmic tyrosine-protein kinase BMX, Tyrosine-protein kinase Tec, Tyrosine-protein kinase TXK, Tyrosine-protein kinase BTK.
Bioactivity
ChEMBL activities: 25 potent at pChembl ≥ 5 of 25 total. Top 100 by potency (10 = 0.1 nM, 6 = 1 µM):
| Target | pChembl | Type | Value | Unit | Activity ID |
|---|---|---|---|---|---|
| BMX | 8.37 | IC50 | 4.3 | nM | CHEMBL_ACT_24773291 |
| BTK | 8.28 | IC50 | 5.2 | nM | CHEMBL_ACT_19061026 |
| BTK | 8.25 | IC50 | 5.6 | nM | CHEMBL_ACT_24773271 |
| BMX | 8.22 | IC50 | 6 | nM | CHEMBL_ACT_29287531 |
| TEC | 8.21 | Kd | 6.2 | nM | CHEMBL_ACT_19061195 |
| BTK | 8.15 | IC50 | 7 | nM | CHEMBL_ACT_29287532 |
| BTK | 7.85 | Kd | 14 | nM | CHEMBL_ACT_19061183 |
| TEC | 7.84 | IC50 | 14.3 | nM | CHEMBL_ACT_25067060 |
| BTK | 7.58 | IC50 | 26 | nM | CHEMBL_ACT_19061056 |
| BTK | 7.54 | IC50 | 29 | nM | CHEMBL_ACT_25067003 |
| BMX | 7.33 | Kd | 47 | nM | CHEMBL_ACT_19061189 |
| TEC | 7.11 | IC50 | 77 | nM | CHEMBL_ACT_24773279 |
| BTK | 6.99 | IC50 | 103 | nM | CHEMBL_ACT_18109184 |
| TXK | 6.94 | IC50 | 116 | nM | CHEMBL_ACT_24773287 |
| BTK | 6.88 | IC50 | 132 | nM | CHEMBL_ACT_19061084 |
| BTK | 6.5 | IC50 | 312.3 | nM | CHEMBL_ACT_18109384 |
| BTK | 6.44 | IC50 | 363 | nM | CHEMBL_ACT_19061323 |
| LCK | 6.43 | IC50 | 375 | nM | CHEMBL_ACT_17722944 |
| ERBB2 | 6.21 | Kd | 610 | nM | CHEMBL_ACT_19061213 |
| ERBB4 | 6 | IC50 | 991 | nM | CHEMBL_ACT_24773303 |
| BTK | 5.98 | IC50 | 1057 | nM | CHEMBL_ACT_17722945 |
| BLK | 5.95 | IC50 | 1133 | nM | CHEMBL_ACT_24773307 |
| GP6 | 5.92 | IC50 | 1200 | nM | CHEMBL_ACT_22480800 |
| BTK | 5.78 | IC50 | 1662 | nM | CHEMBL_ACT_17722946 |
| BTK | 5.17 | IC50 | 6800 | nM | CHEMBL_ACT_26191694 |
Target pathways
Aggregated over 1 target gene(s): BTK.
Top Reactome pathways
45 total, by targets touching each:
| Pathway | Targets | Genes |
|---|---|---|
| ER-Phagosome pathway | 1 | BTK |
| Antigen processing-Cross presentation | 1 | BTK |
| Adaptive Immune System | 1 | BTK |
| Signal Transduction | 1 | BTK |
| Disease | 1 | BTK |
| Toll Like Receptor 4 (TLR4) Cascade | 1 | BTK |
| MyD88:MAL(TIRAP) cascade initiated on plasma membrane | 1 | BTK |
| Toll Like Receptor TLR1:TLR2 Cascade | 1 | BTK |
| Toll Like Receptor TLR6:TLR2 Cascade | 1 | BTK |
| Innate Immune System | 1 | BTK |
| Immune System | 1 | BTK |
| Toll-like Receptor Cascades | 1 | BTK |
| Toll Like Receptor 2 (TLR2) Cascade | 1 | BTK |
| Signaling by Rho GTPases | 1 | BTK |
| RHO GTPase Effectors | 1 | BTK |
| Fcgamma receptor (FCGR) dependent phagocytosis | 1 | BTK |
| Regulation of actin dynamics for phagocytic cup formation | 1 | BTK |
| DAP12 interactions | 1 | BTK |
| DAP12 signaling | 1 | BTK |
| Fc epsilon receptor (FCERI) signaling | 1 | BTK |
| FCERI mediated Ca+2 mobilization | 1 | BTK |
| Signaling by GPCR | 1 | BTK |
| GPCR downstream signalling | 1 | BTK |
| G-protein beta:gamma signalling | 1 | BTK |
| G alpha (q) signalling events | 1 | BTK |
| G alpha (12/13) signalling events | 1 | BTK |
| Diseases of Immune System | 1 | BTK |
| Diseases associated with the TLR signaling cascade | 1 | BTK |
| MyD88 deficiency (TLR2/4) | 1 | BTK |
| IRAK4 deficiency (TLR2/4) | 1 | BTK |
| Infectious disease | 1 | BTK |
| RHO GTPases Activate WASPs and WAVEs | 1 | BTK |
| G beta:gamma signalling through BTK | 1 | BTK |
| Leishmania infection | 1 | BTK |
| Parasite infection | 1 | BTK |
| Leishmania phagocytosis | 1 | BTK |
| FCGR3A-mediated phagocytosis | 1 | BTK |
| Potential therapeutics for SARS | 1 | BTK |
| SARS-CoV Infections | 1 | BTK |
| Signaling by Rho GTPases, Miro GTPases and RHOBTB3 | 1 | BTK |
| Parasitic Infection Pathways | 1 | BTK |
| Viral Infection Pathways | 1 | BTK |
| Class I MHC mediated antigen processing & presentation | 1 | BTK |
| Antigen activates B Cell Receptor (BCR) leading to generation of second messengers | 1 | BTK |
| Signaling by the B Cell Receptor (BCR) | 1 | BTK |
Dominant GO biological processes
| GO term | Targets |
|---|---|
| neutrophil homeostasis | 1 |
| positive regulation of type III hypersensitivity | 1 |
| positive regulation of type I hypersensitivity | 1 |
| adaptive immune response | 1 |
| B cell affinity maturation | 1 |
| histamine secretion by mast cell | 1 |
| positive regulation of immunoglobulin production | 1 |
| regulation of B cell cytokine production | 1 |
| MyD88-dependent toll-like receptor signaling pathway | 1 |
| regulation of B cell apoptotic process | 1 |
| mesoderm development | 1 |
| peptidyl-tyrosine phosphorylation | 1 |
| calcium-mediated signaling | 1 |
| proteoglycan catabolic process | 1 |
| negative regulation of B cell proliferation | 1 |
Indications & clinical
Indications
5 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 |
|---|---|---|---|
| B-cell chronic lymphocytic leukemia | 2 | MONDO:0004948 | EFO:0000095 |
| Sjogren syndrome | 2 | MONDO:0010030 | EFO:0000699 |
| neoplasm | 2 | MONDO:0005070 | EFO:0000616 |
| rheumatoid arthritis | 1 | MONDO:0008383 | EFO:0000685 |
| non-Hodgkin lymphoma | 1 | MONDO:0018908 | EFO:0005952 |
2 further indication records had no mapped disease name (EFO/MeSH-only) or were duplicates, and are omitted.
Clinical trials
Total trials: 14.
Phase distribution
| Phase | Trials |
|---|---|
| PHASE2 | 6 |
| PHASE1 | 6 |
| PHASE3 | 2 |
Top trials by phase / activity
| NCT | Phase | Status | Title |
|---|---|---|---|
| NCT06696716 | PHASE3 | RECRUITING | ONO-4059 Study in Patients With Steroid-resistant Pemphigus |
| NCT07104032 | PHASE3 | RECRUITING | IGNITE: Study of Tirabrutinib vs Rituximab/Temozolomide for Relapsed/Refractory Primary Central Nervous System Lymphoma (PCNSL) |
| NCT04947319 | PHASE2 | ACTIVE_NOT_RECRUITING | Study of Tirabrutinib (ONO-4059) in Patients With Primary Central Nervous System Lymphoma (PROSPECT Study) |
| NCT06940791 | PHASE2 | RECRUITING | Tirabrutinib Maintenance Versus Placebo in Patients With Primary CNS Lymphoma in Complete Remission (JCOG2104) |
| NCT02968563 | PHASE2 | COMPLETED | Study to Evaluate the Safety and Efficacy of the Combination of Tirabrutinib and Idelalisib With and Without Obinutuzumab in Adults With Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) |
| NCT02983617 | PHASE2 | COMPLETED | Safety and Efficacy of the Combination of Tirabrutinib and Entospletinib With and Without Obinutuzumab in Adults With Chronic Lymphocytic Leukemia (CLL) |
| NCT03100942 | PHASE2 | COMPLETED | Study to Assess Safety and Efficacy of Filgotinib, Lanraplenib and Tirabrutinib in Adults With Active Sjogren’s Syndrome |
| NCT04827589 | PHASE2 | WITHDRAWN | Study to Evaluate the Efficacy, Safety, and Tolerability of Tirabrutinib in Participants With Antihistamine-Resistant Chronic Spontaneous Urticaria |
| NCT06541665 | PHASE1 | ACTIVE_NOT_RECRUITING | Phase I Study Evaluating Tolerability, Safety, Pharmacokinetics, and Efficacy of Combined ONO-4059 and R-MPV Therapy for PCNSL |
| NCT07198087 | PHASE1 | ACTIVE_NOT_RECRUITING | A Study to Investigate the Pharmacokinetics of Tirabrutinib in Participants With Mild, Moderate, and Severe Hepatic Impairment Compared to Healthy Participants |
| NCT01659255 | PHASE1 | COMPLETED | Study to Evaluate the Safety and Tolerability of Tirabrutinib (ONO/GS-4059) Given as Monotherapy in Participants With Relapsed/Refractory NHL and CLL |
| NCT02457559 | PHASE1 | COMPLETED | Study to Assess the Long-term Safety and Efficacy of Tirabrutinib in Adults With Relapsed/Refractory B-cell Malignancies |
| NCT02457598 | PHASE1 | TERMINATED | Dose Escalation and Dose Expansion Study of Tirabrutinib in Combination With Other Targeted Anti-cancer Therapies in Adults With B-cell Malignancies |
| NCT02626026 | PHASE1 | COMPLETED | Study to Evaluate Safety and Pharmacokinetics of GS-4059 (Tirabrutinib) in Healthy Volunteers and Participants With Rheumatoid Arthritis (RA) |
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.
80 molecules share ≥1 primary target. Top 80 by shared-target count:
| Molecule | Source | Status | Shared targets |
|---|---|---|---|
| CRIZOTINIB | ChEMBL + PubChem | Phase 4 (approved) | BTK |
| RITLECITINIB | ChEMBL + PubChem | Phase 4 (approved) | BTK |
| ACALABRUTINIB | ChEMBL | Phase 4 (approved) | BTK |
| BOSUTINIB | ChEMBL | Phase 4 (approved) | BTK |
| BRIGATINIB | ChEMBL | Phase 4 (approved) | BTK |
| CERITINIB | ChEMBL | Phase 4 (approved) | BTK |
| DASATINIB | ChEMBL | Phase 4 (approved) | BTK |
| ENTRECTINIB | ChEMBL | Phase 4 (approved) | BTK |
| FEDRATINIB | ChEMBL | Phase 4 (approved) | BTK |
| FUTIBATINIB | ChEMBL | Phase 4 (approved) | BTK |
| IBRUTINIB | ChEMBL | Phase 4 (approved) | BTK |
| MITOXANTRONE | ChEMBL | Phase 4 (approved) | BTK |
| NERATINIB | ChEMBL | Phase 4 (approved) | BTK |
| NINTEDANIB | ChEMBL | Phase 4 (approved) | BTK |
| OLMUTINIB | ChEMBL | Phase 4 (approved) | BTK |
| OSIMERTINIB | ChEMBL | Phase 4 (approved) | BTK |
| PIRTOBRUTINIB | ChEMBL | Phase 4 (approved) | BTK |
| PONATINIB | ChEMBL | Phase 4 (approved) | BTK |
| SUNITINIB | ChEMBL | Phase 4 (approved) | BTK |
| VANDETANIB | ChEMBL | Phase 4 (approved) | BTK |
| ZANUBRUTINIB | ChEMBL | Phase 4 (approved) | BTK |
| ABIVERTINIB | ChEMBL | Phase 3 | BTK |
| ALISERTIB | ChEMBL | Phase 3 | BTK |
| CANERTINIB | ChEMBL | Phase 3 | BTK |
| CEDIRANIB | ChEMBL | Phase 3 | BTK |
| DOVITINIB | ChEMBL | Phase 3 | BTK |
| ENTOSPLETINIB | ChEMBL | Phase 3 | BTK |
| EVOBRUTINIB | ChEMBL | Phase 3 | BTK |
| FENEBRUTINIB | ChEMBL | Phase 3 | BTK |
| LESTAURTINIB | ChEMBL | Phase 3 | BTK |
| NEMTABRUTINIB | ChEMBL | Phase 3 | BTK |
| ORELABRUTINIB | ChEMBL | Phase 3 | BTK |
| POZIOTINIB | ChEMBL | Phase 3 | BTK |
| PYROTINIB | ChEMBL | Phase 3 | BTK |
| REMIBRUTINIB | ChEMBL | Phase 3 | BTK |
| RILZABRUTINIB | ChEMBL | Phase 3 | BTK |
| ROCILETINIB | ChEMBL | Phase 3 | BTK |
| SARACATINIB | ChEMBL | Phase 3 | BTK |
| TESEVATINIB | ChEMBL | Phase 3 | BTK |
| TOLEBRUTINIB | ChEMBL | Phase 3 | BTK |
| APITOLISIB | ChEMBL | Phase 2 | BTK |
| AT-9283 | ChEMBL | Phase 2 | BTK |
| ATUZABRUTINIB | ChEMBL | Phase 2 | BTK |
| BIIB-091 | ChEMBL | Phase 2 | BTK |
| BMS-754807 | ChEMBL | Phase 2 | BTK |
| BMS-919373 | ChEMBL | Phase 2 | BTK |
| BMS-986142 | ChEMBL | Phase 2 | BTK |
| BRANEBRUTINIB | ChEMBL | Phase 2 | BTK |
| CENISERTIB | ChEMBL | Phase 2 | BTK |
| CEP-11981 | ChEMBL | Phase 2 | BTK |
| DANUSERTIB | ChEMBL | Phase 2 | BTK |
| DEFOSBARASERTIB | ChEMBL | Phase 2 | BTK |
| EDRALBRUTINIB | ChEMBL | Phase 2 | BTK |
| ELSUBRUTINIB | ChEMBL | Phase 2 | BTK |
| FORETINIB | ChEMBL | Phase 2 | BTK |
| ILORASERTIB | ChEMBL | Phase 2 | BTK |
| MILREBRUTINIB | ChEMBL | Phase 2 | BTK |
| PELITINIB | ChEMBL | Phase 2 | BTK |
| POSELTINIB | ChEMBL | Phase 2 | BTK |
| R-406 | ChEMBL | Phase 2 | BTK |
| REBASTINIB | ChEMBL | Phase 2 | BTK |
| SOFNOBRUTINIB | ChEMBL | Phase 2 | BTK |
| SOQUELITINIB | ChEMBL | Phase 2 | BTK |
| SPEBRUTINIB | ChEMBL | Phase 2 | BTK |
| SU-014813 | ChEMBL | Phase 2 | BTK |
| TOZASERTIB | ChEMBL | Phase 2 | BTK |
| UCN-01 | ChEMBL | Phase 2 | BTK |
| VECABRUTINIB | ChEMBL | Phase 2 | BTK |
| ZELEBRUDOMIDE | ChEMBL | Phase 2 | BTK |
| Afatinib | PubChem | Approved | BTK |
| belumosudil | PubChem | Approved | BTK |
| Binimetinib | PubChem | Approved | BTK |
| dacomitinib | PubChem | Approved | BTK |
| Fostamatinib | PubChem | Approved | BTK |
| Idelalisib | PubChem | Approved | BTK |
| Mobocertinib | PubChem | Approved | BTK |
| Pazopanib | PubChem | Approved | BTK |
| regorafenib | PubChem | Approved | BTK |
| Selumetinib | PubChem | Approved | BTK |
| Trametinib | PubChem | Approved | BTK |
Related Atlas pages
- Genes: BTK
- In clinical trials for: B-cell chronic lymphocytic leukemia, Sjogren syndrome, neoplasm
- Drugs: Crizotinib, Ritlecitinib, Acalabrutinib, Bosutinib, Brigatinib, Ceritinib, Dasatinib, Entrectinib, Fedratinib, Futibatinib, Ibrutinib, Mitoxantrone, Neratinib, Nintedanib, Olmutinib, Osimertinib, Pirtobrutinib, Ponatinib, Sunitinib, Vandetanib, Zanubrutinib, Abivertinib, Alisertib, Canertinib, Cediranib, Dovitinib, Entospletinib, Evobrutinib, Fenebrutinib, Lestaurtinib, Nemtabrutinib, Orelabrutinib, Poziotinib, Pyrotinib, Remibrutinib, Rilzabrutinib, Rociletinib, Saracatinib, Tesevatinib, Tolebrutinib, Afatinib, belumosudil, Binimetinib, dacomitinib, Fostamatinib, Idelalisib, Mobocertinib, Pazopanib, regorafenib, Selumetinib, Trametinib