Tivantinib

Summary

Tivantinib (CHEMBL2103882) is a phase-3 clinical-stage small molecule targeting MET; indicated across 19 conditions including hepatocellular carcinoma and non-small cell lung carcinoma.

At a glance

• Status: Max clinical phase 3 (not approved)
• Modality: Small molecule
• Targets: 1 (MET)
• Indications: 19 conditions
• Clinical trials: 38
• Chemistry: 369.4 Da · C23H19N3O2

Identifiers

Drug identity and classification

Field	Value
ChEMBL ID	CHEMBL2103882
Name	Tivantinib
Type	Small molecule
Max phase	3
FDA approved	no
PubChem CID	11494412
Molecular formula	C23H19N3O2
Molecular weight	369.4
InChIKey	UCEQXRCJXIVODC-PMACEKPBSA-N

SMILES: C1CC2=C3C(=CC=C2)C(=CN3C1)[C@H]4[C@@H](C(=O)NC4=O)C5=CNC6=CC=CC=C65

IUPAC name: (3R,4R)-3-(1-azatricyclo[6.3.1.04,12]dodeca-2,4,6,8(12)-tetraen-3-yl)-4-(1H-indol-3-yl)pyrrolidine-2,5-dione

Also known as: ARQ 197, Arq-197, ARQ-197, Tivantinib, TIVANTINIB

Patent coverage: 1,042 distinct patent families (2,741 SureChEMBL compound mentions), from 2 matched compound structure(s). One matched structure accounts for 2,615 (95%) 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
MET	MET proto-oncogene, receptor tyrosine kinase	Inhibition	6.45	2.4%	P08581

Broader ChEMBL bioactivity targets: 4 (assay-derived). Sample: Heme oxygenase 2, Hepatocyte growth factor receptor, Dynamin-like GTPase OPA1, mitochondrial, Eukaryotic translation initiation factor 5B.

Bioactivity

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

Target	pChembl	Type	Value	Unit	Activity ID
OPA1	7.77	Kd	17	nM	CHEMBL_ACT_17923160
HMOX2	6.92	Kd	119	nM	CHEMBL_ACT_17906076
EIF5B	6.63	Kd	232	nM	CHEMBL_ACT_17899043
MET	6.47	Ki	335	nM	CHEMBL_ACT_25898561
MET	6.45	Ki	355	nM	CHEMBL_ACT_16466227
MET	6.45	Ki	355	nM	CHEMBL_ACT_16844180
MET	6.45	Ki	355	nM	CHEMBL_ACT_25595714
MET	6.45	Ki	355	nM	CHEMBL_ACT_29282140
MET	6.44	IC50	360	nM	CHEMBL_ACT_24754919
MET	6.29	Kd	511	nM	CHEMBL_ACT_17919130

Target pathways

Aggregated over 1 target gene(s): MET.

Top Reactome pathways

44 total, by targets touching each:

Pathway	Targets	Genes
PIP3 activates AKT signaling	1	MET
Developmental Biology	1	MET
Signal Transduction	1	MET
Disease	1	MET
Negative regulation of the PI3K/AKT network	1	MET
Generic Transcription Pathway	1	MET
PI3K/AKT Signaling in Cancer	1	MET
Constitutive Signaling by Aberrant PI3K in Cancer	1	MET
Semaphorin interactions	1	MET
Sema4D in semaphorin signaling	1	MET
Sema4D mediated inhibition of cell attachment and migration	1	MET
Axon guidance	1	MET
Diseases of signal transduction by growth factor receptors and second messengers	1	MET
Infectious disease	1	MET
RAF/MAP kinase cascade	1	MET
MAPK family signaling cascades	1	MET
MAPK1/MAPK3 signaling	1	MET
Signaling by MET	1	MET
MET Receptor Activation	1	MET
Negative regulation of MET activity	1	MET
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	1	MET
RNA Polymerase II Transcription	1	MET
Gene expression (Transcription)	1	MET
MET activates RAS signaling	1	MET
MET activates PI3K/AKT signaling	1	MET
MET activates PTPN11	1	MET
MET activates PTK2 signaling	1	MET
InlB-mediated entry of Listeria monocytogenes into host cell	1	MET
MET interacts with TNS proteins	1	MET
MET activates RAP1 and RAC1	1	MET

Dominant GO biological processes

GO term	Targets
endothelial cell morphogenesis	1
liver development	1
cell surface receptor signaling pathway	1
cell surface receptor protein tyrosine kinase signaling pathway	1
negative regulation of autophagy	1
neuron differentiation	1
pancreas development	1
positive regulation of transcription by RNA polymerase II	1
hepatocyte growth factor receptor signaling pathway	1
branching morphogenesis of an epithelial tube	1
positive chemotaxis	1
excitatory postsynaptic potential	1
semaphorin-plexin signaling pathway	1
negative regulation of hydrogen peroxide-mediated programmed cell death	1
positive regulation of endothelial cell chemotaxis	1

Indications & clinical

Indications

19 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
hepatocellular carcinoma	3	MONDO:0007256	EFO:0000182
non-small cell lung carcinoma	3	MONDO:0005233	EFO:0003060
papillary renal cell carcinoma	2	MONDO:0017884	EFO:0000640
small cell lung carcinoma	2	MONDO:0008433	EFO:0000702
germ cell tumor	2	MONDO:0005040	EFO:0000514
malignant pleural mesothelioma	2	MONDO:0005112	EFO:0000770
plasma cell myeloma	2	MONDO:0009693	EFO:0001378
prostate adenocarcinoma	2	MONDO:0005082	EFO:0000673
pancreatic neoplasm	2	MONDO:0021040	EFO:0003860
head and neck squamous cell carcinoma	2	MONDO:0010150	EFO:0000181
gastric neoplasm	2	MONDO:0021085	MONDO:0001056
triple-negative breast carcinoma	2	MONDO:0005494	EFO:0005537
breast carcinoma	2	MONDO:0004989	EFO:0000305
mesothelioma	2	MONDO:0005065	EFO:0000588
prostate carcinoma	2	MONDO:0005159	EFO:0001663
neoplasm	1	MONDO:0005070	EFO:0000616

3 further indication records had no mapped disease name (EFO/MeSH-only) or were duplicates, and are omitted.

Clinical trials

Total trials: 38.

Phase distribution

Phase	Trials
PHASE1	17
PHASE2	14
PHASE1/PHASE2	4
PHASE3	3

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01244191	PHASE3	TERMINATED	Tivantinib Plus Erlotinib Versus Placebo Plus Erlotinib for the Treatment of Non-squamous, Non-small-cell Lung Cancer
NCT01377376	PHASE3	TERMINATED	A Phase 3, Randomized, Double-Blinded, Placebo-Controlled Study of ARQ 197 Plus Erlotinib Versus Placebo Plus Erlotinib
NCT01755767	PHASE3	COMPLETED	Study of Tivantinib in Subjects With Inoperable Hepatocellular Carcinoma (HCC) Who Have Been Treated With One Prior Therapy
NCT00557609	PHASE2	COMPLETED	Phase 2 Study in Patients With MiT Tumors
NCT00558207	PHASE2	COMPLETED	A Randomized Phase 2 Study of ARQ 197 Versus Gemcitabine in Treatment-Naïve Patients With Unresectable Locally Advanced or Metastatic Pancreatic Adenocarcinoma
NCT00777309	PHASE2	COMPLETED	A Randomized Phase 2 Study of Erlotinib + ARQ 197 Versus Erlotinib + Placebo in Previously Treated Patients With Locally Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC)
NCT00988741	PHASE2	COMPLETED	Trial of ARQ 197 in Patients With Unresectable Hepatocellular Carcinoma (HCC) Who Have Failed One Prior Systemic Therapy
NCT01070290	PHASE2	WITHDRAWN	A Study of ARQ 197 Versus Investigator’s Choice of Second-Line Chemotherapy in Patients With Locally Advanced or Metastatic Gastric Cancer Who Have Progressive Neoplastic Disease Following Treatment With One Prior Chemotherapy Regimen
NCT01075048	PHASE1/PHASE2	COMPLETED	ARQ 197 in Combination With Chemotherapy in Patients With Metastatic Colorectal Cancer
NCT01152645	PHASE2	COMPLETED	Study of ARQ 197 Monotherapy
NCT01178411	PHASE1/PHASE2	COMPLETED	An Extension Protocol for Subjects Who Were Previously Enrolled in Other Tivantinib (ARQ 197) Protocols
NCT01447914	PHASE2	COMPLETED	Tivantinib in Treating Patients With Relapsed, or Relapsed and Refractory Multiple Myeloma
NCT01519414	PHASE2	COMPLETED	Tivantinib in Treating Patients With Metastatic Prostate Cancer
NCT01575522	PHASE2	COMPLETED	Tivantinib in Treating Patients With Recurrent or Metastatic Breast Cancer
NCT01580735	PHASE2	COMPLETED	ARQ 197 Plus Erlotinib in Patient With Locally Advanced or Metastatic EGFR Mutation-positive Non-small-cell Lung Cancer
NCT01611857	PHASE1/PHASE2	COMPLETED	Phase I/II Trial of Tivantinib With FOLFOX for the Treatment of Advanced Solid Tumors and Previously Untreated Metastatic Adenocarcinoma of the Distal Esophagus, Gastroesophageal Junction or Stomach
NCT01688973	PHASE2	COMPLETED	Tivantinib With or Without Erlotinib Hydrochloride in Treating Patients With Metastatic or Locally Advanced Kidney Cancer That Cannot Be Removed by Surgery
NCT01696955	PHASE2	COMPLETED	Cetuximab With or Without Tivantinib in Treating Patients With Head and Neck Cancer That Is Recurrent, Metastatic, or Cannot Be Removed by Surgery
NCT01861301	PHASE2	TERMINATED	Tivantinib in Treating Patients With Previously Treated Malignant Mesothelioma
NCT01892527	PHASE2	COMPLETED	Study of Tivantinib (ARQ 197) Plus Cetuximab in EGFR Inhibitor-Resistant MET High Subjects
NCT02049060	PHASE1/PHASE2	COMPLETED	Study of the Combination of Tivantinib Plus Pemetrexed and Carboplatin
NCT00302172	PHASE1	COMPLETED	ARQ 197 in Subjects With Metastatic Solid Tumors
NCT00612209	PHASE1	COMPLETED	A Phase 1 Study of ARQ 197 in Adult Patients With Advanced Solid Tumors
NCT00612703	PHASE1	COMPLETED	A Phase 1 Study of ARQ 197 in Adult Patients With Advanced Solid Tumors
NCT00651638	PHASE1	COMPLETED	A Study of ARQ 197 in Healthy Volunteers to Assess the Pharmacokinetic (PK) Profile in Extensive and Poor Metabolizers as Defined by Cytochrome P450 2C19 (CYP 2C19) Genotype
NCT00658554	PHASE1	COMPLETED	Bioequivalence Study of ARQ 197 Amorphous and Crystalline Polymorphs A and B in Normal Healthy Volunteers
NCT00802555	PHASE1	COMPLETED	Safety Study of ARQ 197 in Cirrhotic Patients With Hepatocellular Carcinoma (HCC)
NCT01069757	PHASE1	COMPLETED	A Study of ARQ 197 in Combination With Erlotinib
NCT01251796	PHASE1	COMPLETED	A Study of ARQ 197 in Combination With Erlotinib
NCT01468922	PHASE1	COMPLETED	Pazopanib and ARQ 197 for Advanced Solid Tumors
NCT01517399	PHASE1	COMPLETED	Drug-drug Interaction Study of Tivantinib (ARQ 197) With Omeprazole, S-warfarin, Caffeine, Midazolam, and Digoxin in Cancer Subjects
NCT01625156	PHASE1	COMPLETED	Tivantinib and Temsirolimus in Treating Patients With Solid Tumors That is Metastatic or Cannot be Removed by Surgery
NCT01654965	PHASE1	COMPLETED	Tivantinib and Topotecan Hydrochloride in Treating Patients With Advanced or Metastatic Solid Tumors
NCT01656265	PHASE1	COMPLETED	Study of ARQ 197 in Hepatocellular Carcinoma (HCC)
NCT01699061	PHASE1	COMPLETED	Effect of Tivantinib on the QTC Interval in Cancer Subjects
NCT01725191	PHASE1	COMPLETED	Tivantinib in Treating Younger Patients With Relapsed or Refractory Solid Tumors
NCT01749384	PHASE1	COMPLETED	Tivantinib and Bevacizumab in Treating Patients With Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery
NCT02150733	PHASE1	COMPLETED	Pharmacokinetics of Tivantinib in Subjects With Advanced Solid Tumors and Hepatic Impairment

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.

83 molecules share ≥1 primary target. Top 60 by shared-target count:

Molecule	Source	Status	Shared targets
AFATINIB	ChEMBL + PubChem	Phase 4 (approved)	MET
CRIZOTINIB	ChEMBL + PubChem	Phase 4 (approved)	MET
PAZOPANIB	ChEMBL + PubChem	Phase 4 (approved)	MET
AFATINIB DIMALEATE	ChEMBL	Phase 4 (approved)	MET
AXITINIB	ChEMBL	Phase 4 (approved)	MET
BOSUTINIB	ChEMBL	Phase 4 (approved)	MET
BRIGATINIB	ChEMBL	Phase 4 (approved)	MET
CABOZANTINIB	ChEMBL	Phase 4 (approved)	MET
CABOZANTINIB S-MALATE	ChEMBL	Phase 4 (approved)	MET
CAPMATINIB	ChEMBL	Phase 4 (approved)	MET
CERITINIB	ChEMBL	Phase 4 (approved)	MET
DABRAFENIB	ChEMBL	Phase 4 (approved)	MET
ENSARTINIB	ChEMBL	Phase 4 (approved)	MET
ENTRECTINIB	ChEMBL	Phase 4 (approved)	MET
ERLOTINIB	ChEMBL	Phase 4 (approved)	MET
FEDRATINIB	ChEMBL	Phase 4 (approved)	MET
GEFITINIB	ChEMBL	Phase 4 (approved)	MET
INFIGRATINIB	ChEMBL	Phase 4 (approved)	MET
MIDOSTAURIN	ChEMBL	Phase 4 (approved)	MET
NERATINIB	ChEMBL	Phase 4 (approved)	MET
NINTEDANIB	ChEMBL	Phase 4 (approved)	MET
PALBOCICLIB	ChEMBL	Phase 4 (approved)	MET
SORAFENIB	ChEMBL	Phase 4 (approved)	MET
SUNITINIB	ChEMBL	Phase 4 (approved)	MET
TEPOTINIB	ChEMBL	Phase 4 (approved)	MET
TIVOZANIB	ChEMBL	Phase 4 (approved)	MET
VANDETANIB	ChEMBL	Phase 4 (approved)	MET
CANERTINIB	ChEMBL	Phase 3	MET
CEDIRANIB	ChEMBL	Phase 3	MET
DACTOLISIB	ChEMBL	Phase 3	MET
ENZASTAURIN	ChEMBL	Phase 3	MET
EPIGALOCATECHIN GALLATE	ChEMBL	Phase 3	MET
LESTAURTINIB	ChEMBL	Phase 3	MET
LINIFANIB	ChEMBL	Phase 3	MET
LINSITINIB	ChEMBL	Phase 3	MET
POZIOTINIB	ChEMBL	Phase 3	MET
QUERCETIN	ChEMBL	Phase 3	MET
RIGOSERTIB	ChEMBL	Phase 3	MET
SAVOLITINIB	ChEMBL	Phase 3	MET
SITRAVATINIB	ChEMBL	Phase 3	MET
ALTIRATINIB	ChEMBL	Phase 2	MET
AMG-208	ChEMBL	Phase 2	MET
AMG-337	ChEMBL	Phase 2	MET
AT-9283	ChEMBL	Phase 2	MET
BEMCENTINIB	ChEMBL	Phase 2	MET
BI-2536	ChEMBL	Phase 2	MET
BMS-754807	ChEMBL	Phase 2	MET
BMS-777607	ChEMBL	Phase 2	MET
CENISERTIB	ChEMBL	Phase 2	MET
CEP-32496	ChEMBL	Phase 2	MET
DALMELITINIB	ChEMBL	Phase 2	MET
DECERNOTINIB	ChEMBL	Phase 2	MET
DEFOSBARASERTIB	ChEMBL	Phase 2	MET
ELLAGIC ACID	ChEMBL	Phase 2	MET
ELZOVANTINIB	ChEMBL	Phase 2	MET
ENVONALKIB	ChEMBL	Phase 2	MET
FORETINIB	ChEMBL	Phase 2	MET
GLESATINIB	ChEMBL	Phase 2	MET
GOLVATINIB	ChEMBL	Phase 2	MET
GUMARONTINIB	ChEMBL	Phase 2	MET