Poziotinib

Summary

Poziotinib (CHEMBL3545154) is a phase-3 clinical-stage small-molecule antineoplastic agent targeting EGFR, ERBB4, and ERBB2; indicated across 9 conditions including non-small cell lung carcinoma and upper aerodigestive tract neoplasm; with CIViC clinical evidence for 3 variant-indication associations (e.g. ERBB2 Exon 20 Insertion in lung non-small cell carcinoma).

At a glance

• Status: Max clinical phase 3 (not approved)
• Modality: Small molecule
• Targets: 3 (EGFR, ERBB4, ERBB2)
• Indications: 9 conditions
• Clinical trials: 17
• Precision-oncology evidence (CIViC): 3 variant–indication associations
• Chemistry: 491.3 Da · C23H21Cl2FN4O3

Identifiers

Drug identity and classification

Field	Value
ChEMBL ID	CHEMBL3545154
Name	Poziotinib
Type	Small molecule
Max phase	3
FDA approved	no
PubChem CID	25127713
ChEBI	CHEBI:195559
Molecular formula	C23H21Cl2FN4O3
Molecular weight	491.3
InChIKey	LPFWVDIFUFFKJU-UHFFFAOYSA-N

SMILES: COC1=C(C=C2C(=C1)N=CN=C2NC3=C(C(=C(C=C3)Cl)Cl)F)OC4CCN(CC4)C(=O)C=C

IUPAC name: 1-[4-[4-(3,4-dichloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl]oxypiperidin-1-yl]prop-2-en-1-one

ChEBI definition: A member of the class of quinazolines that is quinazoline substituted by (3,4-dichloro-2-fluorophenyl)amino, [1-(prop-2-enoyl)piperidin-4-yl]oxy, and methoxy groups at positions 4, 6, and 7, respectively. It is a potent and irreversible tyrosine kinase inhibitor targeting EGFR and HER2 with exon 20 insertion mutations.

Pharmacological roles (ChEBI): antineoplastic agent, apoptosis inducer, epidermal growth factor receptor antagonist.

Also known as: NOV-1201, NOV-120101, Poziotinib, POZIOTINIB

Parent form; salt/anhydrous children: CHEMBL5095402

Patent coverage: 617 distinct patent families (1,560 SureChEMBL compound mentions), from 3 matched compound structure(s). One matched structure accounts for 1,518 (97%) 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	8.1	17.5%	P00533
ERBB4	erb-b2 receptor tyrosine kinase 4	Inhibition	7.63	0.7%	Q15303
ERBB2	erb-b2 receptor tyrosine kinase 2	Inhibition	8.28	17.7%	P04626

Broader ChEMBL bioactivity targets: 13 (assay-derived). Sample: Receptor-interacting serine/threonine-protein kinase 3, Receptor tyrosine-protein kinase erbB-2, Epidermal growth factor receptor, Proto-oncogene tyrosine-protein kinase receptor Ret, Voltage-gated inwardly rectifying potassium channel KCNH2, Ephrin type-B receptor 2, Hepatocyte growth factor receptor, Ephrin type-A receptor 4, Tyrosine-protein kinase Tec, Receptor-interacting serine/threonine-protein kinase 2.

Bioactivity

ChEMBL activities: 40 potent at pChembl ≥ 5 of 40 total. Top 30 by potency (10 = 0.1 nM, 6 = 1 µM):

Target	pChembl	Type	Value	Unit	Activity ID
EGFR	10.21	IC50	0.06	nM	CHEMBL_ACT_25078706
EGFR	10.11	IC50	0.08	nM	CHEMBL_ACT_19310372
EGFR	9.86	IC50	0.14	nM	CHEMBL_ACT_25078762
EGFR	9.82	IC50	0.15	nM	CHEMBL_ACT_25078766
EGFR	9.66	IC50	0.22	nM	CHEMBL_ACT_19310360
EGFR	9.6	IC50	0.25	nM	CHEMBL_ACT_26199036
EGFR	9.58	IC50	0.26	nM	CHEMBL_ACT_25078782
EGFR	9.57	IC50	0.27	nM	CHEMBL_ACT_24848037
EGFR	9.48	IC50	0.33	nM	CHEMBL_ACT_29092502
EGFR	9.4	IC50	0.4	nM	CHEMBL_ACT_26198959
EGFR	9.4	IC50	0.4	nM	CHEMBL_ACT_26199040
EGFR	9.04	IC50	0.91	nM	CHEMBL_ACT_28722257
EGFR	8.89	IC50	1.3	nM	CHEMBL_ACT_16895189
ERBB2	8.88	IC50	1.31	nM	CHEMBL_ACT_25078778
EGFR	8.77	IC50	1.7	nM	CHEMBL_ACT_28722260
ERBB2	8.77	IC50	1.69	nM	CHEMBL_ACT_29092469
EGFR	8.7	Kd	2	nM	CHEMBL_ACT_17898382
EGFR	8.66	IC50	2.2	nM	CHEMBL_ACT_18784600
EGFR	8.64	IC50	2.3	nM	CHEMBL_ACT_28722263
EGFR	8.6	IC50	2.51	nM	CHEMBL_ACT_26198971
BTK	8.52	Kd	3	nM	CHEMBL_ACT_17885999
EGFR	8.52	IC50	3	nM	CHEMBL_ACT_28722266
EGFR	8.49	IC50	3.2	nM	CHEMBL_ACT_18784591
EGFR	8.38	IC50	4.2	nM	CHEMBL_ACT_18784605
EGFR	8.36	IC50	4.4	nM	CHEMBL_ACT_16895214
ERBB2	8.28	IC50	5.3	nM	CHEMBL_ACT_18784596
EGFR	8.28	IC50	5.2	nM	CHEMBL_ACT_28722254
EGFR	8.13	IC50	7.4	nM	CHEMBL_ACT_28722269
ERBB2	7.92	IC50	12	nM	CHEMBL_ACT_22408422
RIPK2	7.32	Kd	48	nM	CHEMBL_ACT_17935261

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

9 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
non-small cell lung carcinoma	3	MONDO:0005233	EFO:0003060
upper aerodigestive tract neoplasm	2	MONDO:0005398	EFO:0004284
lung adenocarcinoma	2	MONDO:0005061	EFO:0000571
esophageal squamous cell carcinoma	2	MONDO:0005580	EFO:0005922
breast neoplasm	2	MONDO:0021100	MONDO:0007254
lung neoplasm	2	MONDO:0021117	MONDO:0008903
neoplasm	1	MONDO:0005070	EFO:0000616
gastric neoplasm	1	MONDO:0021085	MONDO:0001056

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

Clinical trials

Total trials: 17.

Phase distribution

Phase	Trials
PHASE2	11
PHASE1	5
PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05378763	PHASE3	SUSPENDED	A Study of Poziotinib in Previously Treated Participants With Locally Advanced or Metastatic NSCLC Harboring HER2 Exon 20 Mutations
NCT02216916	PHASE2	UNKNOWN	Phase II Trial of HM781-36B in Patients With Metastatic/Recurrent Head and Neck Squamous Cell Carcinoma (HNSCC) After Failure of or Unfit for Platinum-containing Therapy
NCT02544997	PHASE2	COMPLETED	A Phase II, Single-Arm Trial of Poziotinib as Salvage Treatment in Patients With Metastatic Breast Cancer Who Has HER2 or EGFR Mutation or Activated AR or EGFR Pathway
NCT02659514	PHASE2	COMPLETED	Study of Poziotinib in Participants With HER2-Positive Metastatic Breast Cancer
NCT02979821	PHASE2	COMPLETED	Poziotinib in Stage IV Lung Adenocarcinoma With HER2 Mutation (KASTT001)
NCT03066206	PHASE2	TERMINATED	Poziotinib in EGFR Exon 20 Mutant Advanced NSCLC
NCT03292250	PHASE2	COMPLETED	Korean Cancer Study Group: Translational bIomarker Driven UMbrella Project for Head and Neck (TRIUMPH), Esophageal Squamous Cell Carcinoma- Part 1 (HNSCC)]
NCT03318939	PHASE2	TERMINATED	Phase 2 Study of Poziotinib in Participants With NSCLC Having EGFR or HER2 Exon 20 Insertion Mutation
NCT03744715	PHASE2	TERMINATED	A Study to Allow Continued Dosing and/or Follow-up of Patients Who Have Had Previous Exposure to Poziotinib
NCT03770988	PHASE2	UNKNOWN	A Trial to Evaluate the Efficacy of Poziotinib, Pan HER Inhibitor in Recurrent/Metastatic Esophageal Cancer (R/M ESCC)
NCT04044170	PHASE2	TERMINATED	Poziotinib in Patients With NSCLC Having EGFR or HER2 Exon 20 Insertion Mutation
NCT05045404	PHASE2	WITHDRAWN	Poziotinib and Ramucirumab for the Treatment of EGFR Exon 20 Mutant Stage IV Non-small Cell Lung Cancer
NCT01455571	PHASE1	COMPLETED	Phase I Study to Determine the Maximum Tolerated Dose and to Assess the Safety and Pharmacokinetic Profile of HM781-36B in Patients With Advanced Solid Tumors
NCT01455584	PHASE1	COMPLETED	Clinical Trial to Determine the MTD of HM781-36B in Patients With Advanced Solid Tumors
NCT03429101	PHASE1	TERMINATED	A Study of Poziotinib in Combination With T-DM1 in HER2-Positive Breast Cancer
NCT03804515	PHASE1	TERMINATED	A Mass Balance and Pharmacokinetics Study of 14C-Labeled Poziotinib in Cancer Patients Suitable for Treatment With Poziotinib
NCT04981704	PHASE1	COMPLETED	A Study to Evaluate the Effect of Multiple Doses of Itraconazole, Phenytoin, and Paroxetine on the Single-Dose Pharmacokinetics of Poziotinib in Healthy Adult Participants

Clinical evidence (CIViC)

Variant × indication × effect (3 predictive associations from 4 curated evidence items):

Variant	Indication	Effect	Therapy	Level	CIViC
ERBB2 Exon 20 Insertion	Lung Non-small Cell Carcinoma	Sensitivity/Response	Poziotinib	CIViC B	EID12132 +1
EGFR D770_P772dup	Cancer	Sensitivity/Response	Poziotinib	CIViC D	EID12302
EGFR M766Q	Lung Non-small Cell Carcinoma	Sensitivity/Response	Poziotinib	CIViC D	EID7390

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
TUCATINIB	ChEMBL	Phase 4 (approved)	EGFR, ERBB2
CANDESARTAN	ChEMBL	Phase 3	EGFR, ERBB2