Tucatinib

Summary

Tucatinib (CHEMBL3989868) is an approved small molecule (ATC L01EH03) targeting EGFR, ERBB4, and ERBB2; indicated across 17 conditions including her2 positive breast carcinoma and breast neoplasm; with CIViC clinical evidence for 2 variant-indication associations (e.g. ERBB2 Amplification in breast cancer).

At a glance

• Status: Approved (max clinical phase 4)
• Modality: Small molecule
• ATC class: L01EH03
• Targets: 3 (EGFR, ERBB4, ERBB2)
• Indications: 17 conditions
• Clinical trials: 60
• Precision-oncology evidence (CIViC): 2 variant–indication associations
• Chemistry: 480.5 Da · C26H24N8O2

Identifiers

Drug identity and classification

Field	Value
ChEMBL ID	CHEMBL3989868
Name	Tucatinib
Type	Small molecule
Max phase	4
FDA approved	yes
PubChem CID	51039094
ATC	L01EH03
Molecular formula	C26H24N8O2
Molecular weight	480.5
InChIKey	SDEAXTCZPQIFQM-UHFFFAOYSA-N

SMILES: CC1=C(C=CC(=C1)NC2=NC=NC3=C2C=C(C=C3)NC4=NC(CO4)(C)C)OC5=CC6=NC=NN6C=C5

IUPAC name: 6-N-(4,4-dimethyl-5H-1,3-oxazol-2-yl)-4-N-[3-methyl-4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)phenyl]quinazoline-4,6-diamine

Also known as: ARRY-380, Irbinitinib, MK-7119, Ont-380, ONT-380, Tucatinib, Tukysa, TUCATINIB, Tucatinib; Tukysa, US10822334, Compound ONT380

Patent coverage: 1,522 distinct patent families (3,159 SureChEMBL compound mentions), from 5 matched compound structure(s). One matched structure accounts for 2,486 (79%) 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
EGFR	epidermal growth factor receptor	Inhibition	6.35	17.5%	P00533
ERBB4	erb-b2 receptor tyrosine kinase 4	Inhibition	6.51	0.7%	Q15303
ERBB2	erb-b2 receptor tyrosine kinase 2	Inhibition	8.16	17.7%	P04626

Broader ChEMBL bioactivity targets: 6 (assay-derived). Sample: Receptor-interacting serine/threonine-protein kinase 3, Receptor tyrosine-protein kinase erbB-2, Epidermal growth factor receptor, Ferrochelatase, mitochondrial, Ribosyldihydronicotinamide dehydrogenase [quinone], Myosin-14.

Bioactivity

ChEMBL activities: 13 potent at pChembl ≥ 5 of 13 total. Top 30 by potency (10 = 0.1 nM, 6 = 1 µM):

Target	pChembl	Type	Value	Unit	Activity ID
ERBB2	8.7	IC50	2	nM	CHEMBL_ACT_28170569
ERBB2	8.16	IC50	6.9	nM	CHEMBL_ACT_24833554
ERBB2	8.16	IC50	6.9	nM	CHEMBL_ACT_24907893
ERBB2	8.15	IC50	7	nM	CHEMBL_ACT_25870153
ERBB2	8.1	IC50	8	nM	CHEMBL_ACT_29092467
ERBB2	7.85	IC50	14	nM	CHEMBL_ACT_24862047
MYH14	6.73	Kd	188	nM	CHEMBL_ACT_17919789
EGFR	6.35	IC50	449	nM	CHEMBL_ACT_24833555
EGFR	6.35	IC50	449	nM	CHEMBL_ACT_24907896
RIPK3	5.97	Kd	1065	nM	CHEMBL_ACT_17935642
NQO2	5.61	Kd	2463	nM	CHEMBL_ACT_17922354
EGFR	5.6	Kd	2534	nM	CHEMBL_ACT_17898383
FECH	5.41	Kd	3912	nM	CHEMBL_ACT_17902472

Target pathways

Aggregated over 3 target gene(s): EGFR, ERBB4, ERBB2.

Top Reactome pathways

59 total, by targets touching each:

Pathway	Targets	Genes
Signaling by ERBB2	3	EGFR, ERBB2, ERBB4
SHC1 events in ERBB2 signaling	3	EGFR, ERBB2, ERBB4
PIP3 activates AKT signaling	3	EGFR, ERBB2, ERBB4
GRB2 events in ERBB2 signaling	3	EGFR, ERBB2, ERBB4
PI3K events in ERBB2 signaling	3	EGFR, ERBB2, ERBB4
Constitutive Signaling by Aberrant PI3K in Cancer	3	EGFR, ERBB2, ERBB4
RAF/MAP kinase cascade	3	EGFR, ERBB2, ERBB4
ERBB2 Regulates Cell Motility	3	EGFR, ERBB2, ERBB4
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	3	EGFR, ERBB2, ERBB4
ERBB2 Activates PTK6 Signaling	3	EGFR, ERBB2, ERBB4
Downregulation of ERBB2 signaling	3	EGFR, ERBB2, ERBB4
Signaling by ERBB2 KD Mutants	3	EGFR, ERBB2, ERBB4
Signaling by ERBB2 TMD/JMD mutants	3	EGFR, ERBB2, ERBB4
Signaling by ERBB4	2	EGFR, ERBB4
PLCG1 events in ERBB2 signaling	2	EGFR, ERBB2
TFAP2 (AP-2) family regulates transcription of growth factors and their receptors	2	EGFR, ERBB2
Signaling by ERBB2 ECD mutants	2	EGFR, ERBB2
Developmental Lineage of Mammary Gland Myoepithelial Cells	2	EGFR, ERBB2
Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants	1	EGFR
PI3K events in ERBB4 signaling	1	ERBB4
SHC1 events in ERBB4 signaling	1	ERBB4
Nuclear signaling by ERBB4	1	ERBB4
Downregulation of ERBB4 signaling	1	ERBB4
GRB7 events in ERBB2 signaling	1	ERBB2
Downregulation of ERBB2:ERBB3 signaling	1	ERBB2
Signaling by EGFR	1	EGFR
GRB2 events in EGFR signaling	1	EGFR
GAB1 signalosome	1	EGFR
SHC1 events in EGFR signaling	1	EGFR
EGFR downregulation	1	EGFR

Dominant GO biological processes

GO term	Targets
signal transduction	3
cell surface receptor signaling pathway	3
epidermal growth factor receptor signaling pathway	3
neuron differentiation	3
negative regulation of apoptotic process	3
positive regulation of MAPK cascade	3
positive regulation of epithelial cell proliferation	3
cellular response to epidermal growth factor stimulus	3
protein phosphorylation	3
cell surface receptor protein tyrosine kinase signaling pathway	3
positive regulation of protein phosphorylation	2
positive regulation of cell population proliferation	2
positive regulation of cell growth	2
ERBB2-EGFR signaling pathway	2
phosphatidylinositol 3-kinase/protein kinase B signal transduction	2

Indications & clinical

Indications

17 indications (9 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
HER2 positive breast carcinoma	4	MONDO:0006244	EFO:1000294
breast neoplasm	4	MONDO:0021100	MONDO:0007254
breast carcinoma	4	MONDO:0004989	EFO:0000305
neoplasm	4	MONDO:0005070	EFO:0000616
colorectal neoplasm	4	MONDO:0005335	EFO:0004142
colorectal carcinoma	4	MONDO:0024331	EFO:1001951
angiosarcoma	2	MONDO:0016982	EFO:0003968
gastric neoplasm	2	MONDO:0021085	MONDO:0001056
colon carcinoma	2	MONDO:0002032	EFO:1001950
liver disorder	1	MONDO:0005154	EFO:0001421
chronic myeloid leukemia	1	MONDO:0011996	EFO:0000339
non-small cell lung carcinoma	1	MONDO:0005233	EFO:0003060
hepatocellular carcinoma	1	MONDO:0007256	EFO:0000182
lung neoplasm	1	MONDO:0021117	MONDO:0008903

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

Clinical trials

Total trials: 60.

Phase distribution

Phase	Trials
PHASE2	26
PHASE1	16
PHASE1/PHASE2	8
PHASE3	4
Not specified	3
PHASE2/PHASE3	2
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03975647	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Tucatinib vs. Placebo in Combination With Ado-trastuzumab Emtansine (T-DM1) for Patients With Advanced or Metastatic HER2+ Breast Cancer
NCT04457596	PHASE3	ACTIVE_NOT_RECRUITING	T-DM1 and Tucatinib Compared With T-DM1 Alone in Preventing Relapses in People With High Risk HER2-Positive Breast Cancer, the CompassHER2 RD Trial
NCT05132582	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Tucatinib or Placebo With Trastuzumab and Pertuzumab for Metastatic HER2+ Breast Cancer
NCT05253651	PHASE3	RECRUITING	A Study of Tucatinib With Trastuzumab and mFOLFOX6 Versus Standard of Care Treatment in First-line HER2+ Metastatic Colorectal Cancer
NCT07413939	PHASE2/PHASE3	RECRUITING	RO7771950 Versus Tucatinib in Combination With Trastuzumab and Capecitabine in People With Locally Advanced or Metastatic Breast Cancer That is Human Epidermal Growth Factor Receptor 2 (HER2)-Positive
NCT04499924	PHASE2/PHASE3	COMPLETED	Tucatinib, Trastuzumab, Ramucirumab, and Paclitaxel Versus Paclitaxel and Ramucirumab in Previously Treated HER2+ Gastroesophageal Cancer
NCT03297606	PHASE2	RECRUITING	Canadian Profiling and Targeted Agent Utilization Trial (CAPTUR)
NCT04430738	PHASE2	ACTIVE_NOT_RECRUITING	Tucatinib Plus Trastuzumab and Oxaliplatin-based Chemotherapy or Pembrolizumab-containing Combinations for HER2+ Gastrointestinal Cancers
NCT04538742	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Phase 1b/2 Study of T-DXd Combinations in HER2-positive Metastatic Breast Cancer
NCT04579380	PHASE2	ACTIVE_NOT_RECRUITING	Basket Study of Tucatinib and Trastuzumab in Solid Tumors With HER2 Alterations
NCT04721977	PHASE2	ACTIVE_NOT_RECRUITING	A Study of Tucatinib (MK-7119) in Combination With Trastuzumab and Capecitabine in Participants With Previously Treated Locally Advanced Unresectable or Metastatic Human Epidermal Growth Factor Receptor 2 Positive (HER2+) Breast Carcinoma (MK-7119-001)
NCT05041842	PHASE2	ACTIVE_NOT_RECRUITING	Treatment With Tucatinib in Patients With an Isolated Brain Progression of a Metastatic Breast Cancer
NCT05230810	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Clinical Trial of Alpelisb and Tucatinib in Patients With PIK3CA-Mutant HER2+ Metastatic Breast Cancer.
NCT05319873	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Ribociclib, Tucatinib, and Trastuzumab for the Treatment of HER2 Positive Breast Cancer
NCT05323955	PHASE2	ACTIVE_NOT_RECRUITING	Secondary BRain Metastases Prevention After Isolated Intracranial Progression on Trastuzumab/Pertuzumab or T-DM1 in Patients With aDvanced Human Epidermal Growth Factor Receptor 2+ brEast Cancer With the Addition of Tucatinib
NCT05458674	PHASE2	RECRUITING	Tucatinib+Trastuzumab+Eribulin in HER2+ MBC
NCT05672524	PHASE2	RECRUITING	A Study of Tucatinib and Trastuzumab in People With Rectal Cancer
NCT05673928	PHASE2	RECRUITING	A Phase II Study of Tucatinib and Ado-trastuzumab Emtansine (T-DM1) in Patients With HER2-positive Metastatic Solid Tumors and Metastases to Brain (TUCATEMEB)
NCT05748834	PHASE2	RECRUITING	Study of Tucatinib and Doxil in Participants With Human Epidermal Growth Factor Receptor 2 Positive (HER2+) Metastatic Breast Cancer
NCT05800275	PHASE2	RECRUITING	Capecitabine, Tucatinib, and Intrathecal Trastuzumab for Breast Cancer Patients With Leptomeningeal Disease
NCT05892068	PHASE2	ACTIVE_NOT_RECRUITING	A Study of Tucatinib Given Before Surgery to People With HER2+ Cancers That Have Spread to the Brain
NCT06016387	PHASE2	RECRUITING	Tucatinib, Trastuzumab and Capecitabine With Brain and/or Spinal Radiotherapy (XRT) in Patients With HER2+, HER2 Mutated and/or HER2-amplified Metastatic Breast Cancer and Leptomeningeal Disease: A Multi-centre Phase II, Single Arm Feasibility Study
NCT06157892	PHASE2	RECRUITING	A Study of Disitamab Vedotin With Other Anticancer Drugs in Solid Tumors
NCT06439693	PHASE2	RECRUITING	The SAPPHO Study: Sequential Therapy With Curative Intent in de Novo HER2+ Metastatic Breast Cancer
NCT06686394	PHASE1/PHASE2	RECRUITING	Study of Patritumab Deruxtecan With Other Anticancer Agents in Participants With HER2 Positive Breast Cancer That Has Spread and Cannot Be Surgically Removed (MK-1022-009)
NCT07193394	PHASE2	RECRUITING	Tucatinib and Trastuzumab in HER3-mutant and HER2-not Amplified Metastatic Breast Cancer
NCT07494448	PHASE1/PHASE2	NOT_YET_RECRUITING	Phase Ib/II Study of Zanidatamab Plus Tucatinib and Chemotherapy in HER2-Positive Advanced Breast Cancer
NCT02614794	PHASE2	COMPLETED	A Study of Tucatinib vs. Placebo in Combination With Capecitabine & Trastuzumab in Patients With Advanced HER2+ Breast Cancer
NCT03043313	PHASE2	COMPLETED	Tucatinib Plus Trastuzumab in Patients With HER2+ Colorectal Cancer
NCT03501979	PHASE2	TERMINATED	Tucatinib, Trastuzumab, and Capecitabine for the Treatment of HER2+ LMD
NCT04512261	PHASE1/PHASE2	WITHDRAWN	TOPAZ: Tucatinib in COmbination With Pembrolizumab And TrastuZumab in Patients With HER2-Positive Breast Cancer Brain Metastases
NCT04539938	PHASE2	COMPLETED	A Study of Tucatinib Plus Trastuzumab Deruxtecan in HER2+ Breast Cancer
NCT04632992	PHASE2	COMPLETED	A Study Evaluating Targeted Therapies in Participants Who Have Advanced Solid Tumors With Genomic Alterations or Protein Expression Patterns Predictive of Response
NCT04789096	PHASE2	TERMINATED	Tucatinib Together With Pembrolizumab and Trastuzumab
NCT04896320	PHASE1/PHASE2	WITHDRAWN	Tucatinib With Chemotherapy and Trastuzumab in Advanced Her-2-neu Overexpressing, Previously Treated Breast Cancer.
NCT05062889	PHASE2	SUSPENDED	Exploiting Circulating Tumour DNA to Intensify the Postoperative Treatment Resected Colon Cancer Patients
NCT05091528	PHASE1/PHASE2	TERMINATED	A Safety and Activity Study of SBT6050 in Combination With Other HER2-directed Therapies for HER2-positive Cancers
NCT05227131	PHASE2	WITHDRAWN	Margetuximab Plus Tucatinib and Capecitabine in HER2-positive Metastatic Breast Cancer
NCT05356897	PHASE2	WITHDRAWN	Tucatinib Combined with Trastuzumab and TAS-102 for the Treatment of HER2 Positive Metastatic Colorectal Cancer in Molecularly Selected Patients, 3T Study
NCT05583110	PHASE2	TERMINATED	Efficacy and Safety of the Combination of Trastuzumab Plus TUCAtinib Plus viNorelbine in Patients With HER2-positive Non-resectable Locally Advanced or Metastatic Breast Cancer

Clinical evidence (CIViC)

Variant × indication × effect (2 predictive associations from 2 curated evidence items):

Variant	Indication	Effect	Therapy	Level	CIViC
ERBB2 Amplification	Breast Cancer	Sensitivity/Response	Trastuzumab + Tucatinib + Capecitabine	CIViC A	EID11250
ERBB2 Overexpression	Colorectal Cancer	Sensitivity/Response	Trastuzumab + Tucatinib	CIViC A	EID11444

Pharmacology

Pharmacogenomics

No CPIC/DPWG dosing guideline or drug-level clinical/variant annotations in PharmGKB for this molecule.

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.

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

Molecule	Source	Status	Shared targets
AFATINIB	ChEMBL + PubChem	Phase 4 (approved)	EGFR, ERBB2, ERBB4
CRIZOTINIB	ChEMBL + PubChem	Phase 4 (approved)	EGFR, ERBB2, ERBB4
DACOMITINIB	ChEMBL + PubChem	Phase 4 (approved)	EGFR, ERBB2, ERBB4
GEFITINIB	ChEMBL + PubChem	Phase 4 (approved)	EGFR, ERBB2, ERBB4
MOBOCERTINIB	ChEMBL + PubChem	Phase 4 (approved)	EGFR, ERBB2, ERBB4
SELUMETINIB	ChEMBL + PubChem	Phase 4 (approved)	EGFR, ERBB2, ERBB4
ZANUBRUTINIB	ChEMBL + PubChem	Phase 4 (approved)	EGFR, ERBB2, ERBB4
ACALABRUTINIB	ChEMBL	Phase 4 (approved)	EGFR, ERBB2, ERBB4
AFATINIB DIMALEATE	ChEMBL	Phase 4 (approved)	EGFR, ERBB2, ERBB4
BOSUTINIB	ChEMBL	Phase 4 (approved)	EGFR, ERBB2, ERBB4
BRIGATINIB	ChEMBL	Phase 4 (approved)	EGFR, ERBB2, ERBB4
DASATINIB	ChEMBL	Phase 4 (approved)	EGFR, ERBB2, ERBB4
ERLOTINIB	ChEMBL	Phase 4 (approved)	EGFR, ERBB2, ERBB4
IBRUTINIB	ChEMBL	Phase 4 (approved)	EGFR, ERBB2, ERBB4
LAPATINIB	ChEMBL	Phase 4 (approved)	EGFR, ERBB2, ERBB4
NERATINIB	ChEMBL	Phase 4 (approved)	EGFR, ERBB2, ERBB4
VANDETANIB	ChEMBL	Phase 4 (approved)	EGFR, ERBB2, ERBB4
ALISERTIB	ChEMBL	Phase 3	EGFR, ERBB2, ERBB4
ALVOCIDIB	ChEMBL	Phase 3	EGFR, ERBB2, ERBB4
CANERTINIB	ChEMBL	Phase 3	EGFR, ERBB2, ERBB4
CEDIRANIB	ChEMBL	Phase 3	EGFR, ERBB2, ERBB4
REMIBRUTINIB	ChEMBL	Phase 3	EGFR, ERBB2, ERBB4
AEE-788	ChEMBL	Phase 2	EGFR, ERBB2, ERBB4
ALLITINIB	ChEMBL	Phase 2	EGFR, ERBB2, ERBB4
ATUZABRUTINIB	ChEMBL	Phase 2	EGFR, ERBB2, ERBB4
CENISERTIB	ChEMBL	Phase 2	EGFR, ERBB2, ERBB4
DEFOSBARASERTIB	ChEMBL	Phase 2	EGFR, ERBB2, ERBB4
FORETINIB	ChEMBL	Phase 2	EGFR, ERBB2, ERBB4
ILORASERTIB	ChEMBL	Phase 2	EGFR, ERBB2, ERBB4
PELITINIB	ChEMBL	Phase 2	EGFR, ERBB2, ERBB4
R-406	ChEMBL	Phase 2	EGFR, ERBB2, ERBB4
TG100-115	ChEMBL	Phase 2	EGFR, ERBB2, ERBB4
VARLITINIB	ChEMBL	Phase 2	EGFR, ERBB2, ERBB4
Pazopanib	PubChem	Approved	EGFR, ERBB2, ERBB4
LAPATINIB DITOSYLATE	ChEMBL + PubChem	Phase 4 (approved)	EGFR, ERBB2
LAZERTINIB	ChEMBL + PubChem	Phase 4 (approved)	EGFR, ERBB2
RITLECITINIB	ChEMBL + PubChem	Phase 4 (approved)	ERBB2, ERBB4
ASTEMIZOLE	ChEMBL	Phase 4 (approved)	EGFR, ERBB2
BITHIONOL	ChEMBL	Phase 4 (approved)	EGFR, ERBB2
CABOZANTINIB	ChEMBL	Phase 4 (approved)	EGFR, ERBB2
CHLORPROMAZINE	ChEMBL	Phase 4 (approved)	EGFR, ERBB2
CLOTRIMAZOLE	ChEMBL	Phase 4 (approved)	EGFR, ERBB2
COLISTIN	ChEMBL	Phase 4 (approved)	EGFR, ERBB2
EBASTINE	ChEMBL	Phase 4 (approved)	EGFR, ERBB2
ECONAZOLE	ChEMBL	Phase 4 (approved)	EGFR, ERBB2
FEDRATINIB	ChEMBL	Phase 4 (approved)	EGFR, ERBB4
FLUPHENAZINE	ChEMBL	Phase 4 (approved)	EGFR, ERBB2
HEXACHLOROPHENE	ChEMBL	Phase 4 (approved)	EGFR, ERBB2
IMATINIB	ChEMBL	Phase 4 (approved)	EGFR, ERBB2
MICONAZOLE	ChEMBL	Phase 4 (approved)	EGFR, ERBB2
MIDOSTAURIN	ChEMBL	Phase 4 (approved)	EGFR, ERBB4
MITOXANTRONE	ChEMBL	Phase 4 (approved)	EGFR, ERBB2
OSIMERTINIB	ChEMBL	Phase 4 (approved)	EGFR, ERBB2
PONATINIB	ChEMBL	Phase 4 (approved)	EGFR, ERBB2
SORAFENIB	ChEMBL	Phase 4 (approved)	EGFR, ERBB2
TAMOXIFEN	ChEMBL	Phase 4 (approved)	EGFR, ERBB2
TIRABRUTINIB	ChEMBL	Phase 4 (approved)	ERBB2, ERBB4
TRIBROMSALAN	ChEMBL	Phase 4 (approved)	EGFR, ERBB2
CANDESARTAN	ChEMBL	Phase 3	EGFR, ERBB2
ENCLOMIPHENE	ChEMBL	Phase 3	EGFR, ERBB2