Tolebrutinib
drug drugOn this page
Also known as PRN-2246PRN2246SAR-442168Sar442168
Summary
Tolebrutinib (CHEMBL4650323) is a phase-3 clinical-stage small molecule targeting BTK; indicated across 4 conditions including primary progressive multiple sclerosis and secondary progressive multiple sclerosis.
At a glance
- Status: Max clinical phase 3 (not approved)
- Modality: Small molecule
- Targets: 1 (BTK)
- Indications: 4 conditions
- Clinical trials: 13
- Chemistry: 455.5 Da · C26H25N5O3
Identifiers
Drug identity and classification
| Field | Value |
|---|---|
| ChEMBL ID | CHEMBL4650323 |
| Name | Tolebrutinib |
| Type | Small molecule |
| Max phase | 3 |
| FDA approved | no |
| PubChem CID | 124111565 |
| Molecular formula | C26H25N5O3 |
| Molecular weight | 455.5 |
| InChIKey | KOEUOFPEZFUWRF-LJQANCHMSA-N |
SMILES: C=CC(=O)N1CCC[C@H](C1)N2C3=C(C(=NC=C3)N)N(C2=O)C4=CC=C(C=C4)OC5=CC=CC=C5
IUPAC name: 4-amino-3-(4-phenoxyphenyl)-1-[(3R)-1-prop-2-enoylpiperidin-3-yl]imidazo[4,5-c]pyridin-2-one
Also known as: PRN-2246, PRN2246, SAR-442168, Sar442168, SAR442168, Tolebrutinib, TOLEBRUTINIB
Patent coverage: 152 distinct patent families (371 SureChEMBL compound mentions), from 2 matched compound structure(s). One matched structure accounts for 347 (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 |
|---|---|---|---|---|---|
| BTK | Bruton tyrosine kinase | Inhibition | 7.67 | 0.7% | Q06187 |
Broader ChEMBL bioactivity targets: 4 (assay-derived). Sample: Epidermal growth factor receptor, Early activation antigen CD69, Tyrosine-protein kinase Tec, Tyrosine-protein kinase BTK.
Bioactivity
ChEMBL activities: 9 potent at pChembl ≥ 5 of 9 total. Top 100 by potency (10 = 0.1 nM, 6 = 1 µM):
| Target | pChembl | Type | Value | Unit | Activity ID |
|---|---|---|---|---|---|
| BTK | 9.15 | IC50 | 0.7 | nM | CHEMBL_ACT_22813281 |
| BTK | 9 | IC50 | 1 | nM | CHEMBL_ACT_24398441 |
| BTK | 8.92 | IC50 | 1.2 | nM | CHEMBL_ACT_24861805 |
| BTK | 8.85 | Kd | 1.4 | nM | CHEMBL_ACT_24398656 |
| BTK | 8.85 | Kd | 1.4 | nM | CHEMBL_ACT_25838082 |
| BTK | 8.21 | IC50 | 6.2 | nM | CHEMBL_ACT_25067006 |
| TEC | 8.11 | IC50 | 7.8 | nM | CHEMBL_ACT_25067063 |
| EGFR | 7.13 | IC50 | 74 | nM | CHEMBL_ACT_25067053 |
| CD69 | 6.7 | IC50 | 200 | nM | CHEMBL_ACT_24398498 |
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
4 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 |
|---|---|---|---|
| primary progressive multiple sclerosis | 3 | MONDO:0000451 | EFO:0008520 |
| secondary progressive multiple sclerosis | 3 | MONDO:0000450 | EFO:0008522 |
| multiple sclerosis | 3 | MONDO:0005301 | MONDO:0005301 |
| kidney disorder | 1 | MONDO:0005240 | EFO:0003086 |
Clinical trials
Total trials: 13.
Phase distribution
| Phase | Trials |
|---|---|
| PHASE3 | 5 |
| PHASE1 | 5 |
| PHASE2 | 3 |
Top trials by phase / activity
| NCT | Phase | Status | Title |
|---|---|---|---|
| NCT06372145 | PHASE3 | ACTIVE_NOT_RECRUITING | A Study to Investigate Long-term Safety and Tolerability of Tolebrutinib in Participants With Multiple Sclerosis. |
| NCT04410978 | PHASE3 | COMPLETED | Relapsing Forms of Multiple Sclerosis (RMS) Study of Bruton’s Tyrosine Kinase (BTK) Inhibitor Tolebrutinib (SAR442168) (GEMINI 1) |
| NCT04410991 | PHASE3 | COMPLETED | Relapsing Forms of Multiple Sclerosis (RMS) Study of Bruton’s Tyrosine Kinase (BTK) Inhibitor Tolebrutinib (SAR442168) (GEMINI 2) |
| NCT04411641 | PHASE3 | COMPLETED | Nonrelapsing Secondary Progressive Multiple Sclerosis (NRSPMS) Study of Bruton’s Tyrosine Kinase (BTK) Inhibitor Tolebrutinib (SAR442168) (HERCULES) |
| NCT04458051 | PHASE3 | COMPLETED | Primary Progressive Multiple Sclerosis (PPMS) Study of Bruton’s Tyrosine Kinase (BTK) Inhibitor Tolebrutinib (SAR442168) (PERSEUS) |
| NCT03889639 | PHASE2 | COMPLETED | Dose-finding Study for SAR442168 in Relapsing Multiple Sclerosis |
| NCT03996291 | PHASE2 | COMPLETED | Long Term Safety and Efficacy Study of Tolebrutinib (SAR442168) in Participants With Relapsing Multiple Sclerosis |
| NCT04742400 | PHASE2 | UNKNOWN | Tolebrutinib, a Brain-penetrant Bruton’s Tyrosine Kinase Inhibitor, for the Modulation of Chronically Inflamed White Matter Lesions in Multiple Sclerosis |
| NCT04171310 | PHASE1 | COMPLETED | Study of Excretion Balance and Pharmacokinetics of [14C]-SAR442168 in Healthy Male Subjects |
| NCT05282030 | PHASE1 | COMPLETED | Study to Assess the Plasma Concentration of Tolebrutinib Given as a Tablet to Adult Participants With Renal Impairment Compared to Healthy Participants. |
| NCT05283915 | PHASE1 | COMPLETED | Study to Assess the Plasma Concentration of Tolebrutinib Given as a Tablet to Adult Participants With Mild Hepatic Impairment Compared to Participants With Normal Hepatic Function |
| NCT06064539 | PHASE1 | COMPLETED | Study of Drug-drug Interaction of the Effects of Gemfibrozil and Rifampicin on SAR442168 in Healthy Adult Subjects |
| NCT06106074 | PHASE1 | COMPLETED | Study of the Tolerability and Pharmacokinetics of Oral Doses of SAR442168 With a Food Effect Investigation in Healthy Adult Participants |
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 |
| TIRABRUTINIB | 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 |
| 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: primary progressive multiple sclerosis, secondary progressive multiple sclerosis, multiple sclerosis
- Drugs: Crizotinib, Ritlecitinib, Acalabrutinib, Bosutinib, Brigatinib, Ceritinib, Dasatinib, Entrectinib, Fedratinib, Futibatinib, Ibrutinib, Mitoxantrone, Neratinib, Nintedanib, Olmutinib, Osimertinib, Pirtobrutinib, Ponatinib, Sunitinib, Tirabrutinib, Vandetanib, Zanubrutinib, Abivertinib, Alisertib, Canertinib, Cediranib, Dovitinib, Entospletinib, Evobrutinib, Fenebrutinib, Lestaurtinib, Nemtabrutinib, Orelabrutinib, Poziotinib, Pyrotinib, Remibrutinib, Rilzabrutinib, Rociletinib, Saracatinib, Tesevatinib, Afatinib, belumosudil, Binimetinib, dacomitinib, Fostamatinib, Idelalisib, Mobocertinib, Pazopanib, regorafenib, Selumetinib, Trametinib