Tesevatinib

Summary

Tesevatinib (CHEMBL3544983) is a phase-3 clinical-stage small-molecule antineoplastic agent targeting EGFR, KDR, and FLT4; indicated across 7 conditions including non-small cell lung carcinoma and glioblastoma.

At a glance

• Status: Max clinical phase 3 (not approved)
• Modality: Small molecule
• Targets: 5 (EGFR, KDR, FLT4…)
• Indications: 7 conditions
• Clinical trials: 14
• Chemistry: 491.4 Da · C24H25Cl2FN4O2

Identifiers

Drug identity and classification

Field	Value
ChEMBL ID	CHEMBL3544983
Name	Tesevatinib
Type	Small molecule
Max phase	3
FDA approved	no
PubChem CID	10458325
ChEBI	CHEBI:167674
Molecular formula	C24H25Cl2FN4O2
Molecular weight	491.4
InChIKey	HVXKQKFEHMGHSL-GOOCMWNKSA-N

SMILES: CN1C[C@H]2CC(C[C@H]2C1)COC3=C(C=C4C(=C3)N=CN=C4NC5=C(C(=C(C=C5)Cl)Cl)F)OC

IUPAC name: 7-[[(3aS,6aR)-2-methyl-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]methoxy]-N-(3,4-dichloro-2-fluorophenyl)-6-methoxyquinazolin-4-amine

ChEBI definition: A member of the class of quinazolines that is quinazoline substituted by (3,4-dichloro-2-fluorophenyl)amino, methoxy, and [(3aR,5r,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methoxy groups at positions 4, 6 and 7, respectively. It is a multi-target tyrosine kinase inhibitor of EGFR, ErbB2, KDR, Flt4 and EphB4 and exhibits anti-cancer properties.

Pharmacological roles (ChEBI): antineoplastic agent, EC 2.7.10.1 (receptor protein-tyrosine kinase) inhibitor, epidermal growth factor receptor antagonist.

Also known as: EXEL-7647, KD-019, KD-020, KD019, Tesevatinib, Xl-647, XL647, TESEVATINIB

Parent form; salt/anhydrous children: CHEMBL3544982

Patent coverage: 1,097 distinct patent families (2,819 SureChEMBL compound mentions), from 1 matched compound structure(s). 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	9.52	17.5%	P00533
KDR	kinase insert domain receptor	Inhibition	8.82	1.1%	P35968
FLT4	fms related receptor tyrosine kinase 4	Inhibition	8.06	0.2%	P35916
EPHB4	EPH receptor B4	Inhibition	8.85	0%	P54760
ERBB2	erb-b2 receptor tyrosine kinase 2	Inhibition	7.8	17.7%	P04626

Broader ChEMBL bioactivity targets: 37 (assay-derived). Sample: Receptor-interacting serine/threonine-protein kinase 3, Tyrosine-protein kinase ABL1, Vascular endothelial growth factor receptor 1, Epidermal growth factor receptor, Proto-oncogene tyrosine-protein kinase receptor Ret, Ephrin type-A receptor 2, Tyrosine-protein kinase Yes, MAP kinase-activated protein kinase 2, Tyrosine-protein kinase Lck, Proto-oncogene tyrosine-protein kinase Src.

Bioactivity

ChEMBL activities: 37 potent at pChembl ≥ 5 of 38 total. Top 30 by potency (10 = 0.1 nM, 6 = 1 µM):

Target	pChembl	Type	Value	Unit	Activity ID
EGFR	9.52	IC50	0.3	nM	CHEMBL_ACT_19218786
MAPKAPK3	8.7	Kd	2	nM	CHEMBL_ACT_17916920
EPHA1	8.1	Kd	8	nM	CHEMBL_ACT_17899255
EPHA7	7.66	Kd	22	nM	CHEMBL_ACT_17900194
RIPK2	7.48	Kd	33	nM	CHEMBL_ACT_17935447
EPHB4	7.43	Kd	37	nM	CHEMBL_ACT_17900924
EGFR	7.42	Kd	38	nM	CHEMBL_ACT_17898307
FLT1	7.3	IC50	50	nM	CHEMBL_ACT_16906755
RET	7.19	Kd	64	nM	CHEMBL_ACT_17935251
DDR1	7.14	Kd	73	nM	CHEMBL_ACT_17896004
BCR	6.95	Kd	113	nM	CHEMBL_ACT_17884588
PTK6	6.76	Kd	172	nM	CHEMBL_ACT_17933117
LCK	6.68	Kd	207	nM	CHEMBL_ACT_17909307
EPHB6	6.59	Kd	259	nM	CHEMBL_ACT_17901103
RIPK3	6.44	Kd	366	nM	CHEMBL_ACT_17935688
EPHA4	6.36	Kd	440	nM	CHEMBL_ACT_17899719
EPHB2	6.35	Kd	448	nM	CHEMBL_ACT_17900450
EPHA2	6.3	Kd	501	nM	CHEMBL_ACT_17899435
GAK	6.21	Kd	615	nM	CHEMBL_ACT_17904370
ABL2	6.2	Kd	628	nM	CHEMBL_ACT_17878872
ABL1	6.04	Kd	921	nM	CHEMBL_ACT_17878614
MAP4K5	6.04	Kd	908	nM	CHEMBL_ACT_17914277
CSNK1E	5.99	Kd	1017	nM	CHEMBL_ACT_17893870
LYN	5.95	Kd	1130	nM	CHEMBL_ACT_17910115
SRC	5.95	Kd	1127	nM	CHEMBL_ACT_17940197
HCK	5.93	Kd	1161	nM	CHEMBL_ACT_17905828
IRAK4	5.93	Kd	1174	nM	CHEMBL_ACT_17908586
DDR2	5.82	Kd	1523	nM	CHEMBL_ACT_17896204
MAPKAPK2	5.82	Kd	1519	nM	CHEMBL_ACT_17916851
BTK	5.79	Kd	1623	nM	CHEMBL_ACT_17886023

Target pathways

Aggregated over 5 target gene(s): EGFR, KDR, FLT4, EPHB4, ERBB2.

Top Reactome pathways

65 total, by targets touching each:

Pathway	Targets	Genes
Signaling by ERBB2	2	EGFR, ERBB2
SHC1 events in ERBB2 signaling	2	EGFR, ERBB2
PLCG1 events in ERBB2 signaling	2	EGFR, ERBB2
PIP3 activates AKT signaling	2	EGFR, ERBB2
VEGF binds to VEGFR leading to receptor dimerization	2	FLT4, KDR
GRB2 events in ERBB2 signaling	2	EGFR, ERBB2
PI3K events in ERBB2 signaling	2	EGFR, ERBB2
Constitutive Signaling by Aberrant PI3K in Cancer	2	EGFR, ERBB2
RAF/MAP kinase cascade	2	EGFR, ERBB2
ERBB2 Regulates Cell Motility	2	EGFR, ERBB2
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	2	EGFR, ERBB2
ERBB2 Activates PTK6 Signaling	2	EGFR, ERBB2
Downregulation of ERBB2 signaling	2	EGFR, ERBB2
TFAP2 (AP-2) family regulates transcription of growth factors and their receptors	2	EGFR, ERBB2
Signaling by ERBB2 KD Mutants	2	EGFR, ERBB2
Signaling by ERBB2 ECD mutants	2	EGFR, ERBB2
Signaling by ERBB2 TMD/JMD mutants	2	EGFR, ERBB2
High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells	2	FLT4, KDR
Developmental Lineage of Mammary Gland Myoepithelial Cells	2	EGFR, ERBB2
Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants	1	EGFR
Signaling by ERBB4	1	EGFR
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
Neuropilin interactions with VEGF and VEGFR	1	KDR
EGFR interacts with phospholipase C-gamma	1	EGFR

Dominant GO biological processes

GO term	Targets
protein phosphorylation	5
cell surface receptor protein tyrosine kinase signaling pathway	5
negative regulation of apoptotic process	4
positive regulation of MAPK cascade	4
positive regulation of protein phosphorylation	3
positive regulation of cell population proliferation	3
positive regulation of cell migration	3
positive regulation of epithelial cell proliferation	3
positive regulation of ERK1 and ERK2 cascade	3
angiogenesis	3
peptidyl-tyrosine phosphorylation	3
signal transduction	2
cell surface receptor signaling pathway	2
epidermal growth factor receptor signaling pathway	2
neuron differentiation	2

Indications & clinical

Indications

7 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
glioblastoma	2	MONDO:0018177	EFO:0000519
autosomal dominant polycystic kidney disease	2	MONDO:0004691	EFO:1001496
brain neoplasm	2	MONDO:0021211	EFO:0003833
breast neoplasm	1	MONDO:0021100	MONDO:0007254
neoplasm	1	MONDO:0005070	MONDO:0004992

1 further indication record 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	5
PHASE1/PHASE2	2
PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01487174	PHASE3	TERMINATED	KD019 Versus Erlotinib in Subjects With Stage IIIB/IV Non Small Cell Lung Cancer With Progression After First- or Second-Line Chemotherapy
NCT00364780	PHASE2	COMPLETED	Study of XL647 in Subjects With Non-Small-Cell Lung Cancer
NCT00522145	PHASE2	COMPLETED	Study of XL647 in Subjects With NSCLC Who Have Progressed After Responding to Treatment With Gefitinib or Erlotinib
NCT01559363	PHASE1/PHASE2	COMPLETED	A Safety, Pharmacokinetic & Dose-Escalation Study of KD019 in Subjects With Autosomal Dominant Polycystic Kidney Disease
NCT02154529	PHASE1/PHASE2	TERMINATED	Study of the Combination of KD019 and Trastuzumab in Subjects With HER2-Positive Metastatic Breast Cancer
NCT02616055	PHASE2	TERMINATED	Long-Term Treatment and Follow up of Subjects Completing 24 Months of Treatment With Tesevatinib on Study KD019-101
NCT02616393	PHASE2	COMPLETED	Phase 2 Study of Study of Tesevatinib in Subjects With NSCLC and Brain or Leptomeningeal Metastases
NCT02844439	PHASE2	COMPLETED	Study of Tesevatinib Monotherapy in Patients With Recurrent Glioblastoma
NCT03203642	PHASE2	COMPLETED	Study of the Efficacy and Safety of Tesevatinib in Subjects With ADPKD
NCT00086528	PHASE1	COMPLETED	Safety and Pharmacokinetics of XL647 Administered Orally to Subjects With Solid Tumors
NCT00336765	PHASE1	COMPLETED	Study of XL647 Administered Orally Daily to Patients With Solid Tumors
NCT00704392	PHASE1	WITHDRAWN	Safety Study of XL647 and XL147 Administered in Combination Daily in Adults With Solid Tumors
NCT02205463	PHASE1	WITHDRAWN	KD019 and Trastuzumab in Patients With Esophagus, Gastroesophageal Junction and Stomach Cancer
NCT03096080	PHASE1	COMPLETED	A Safety, Pharmacokinetic, Single Ascending Dose Study of Tesevatinib in Pediatric Subjects With Autosomal Recessive Polycystic Kidney Disease (ARPKD)

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.

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

Molecule	Source	Status	Shared targets
AFATINIB	ChEMBL + PubChem	Phase 4 (approved)	EGFR, EPHB4, ERBB2, FLT4, KDR
CRIZOTINIB	ChEMBL + PubChem	Phase 4 (approved)	EGFR, EPHB4, ERBB2, FLT4, KDR
ERLOTINIB	ChEMBL + PubChem	Phase 4 (approved)	EGFR, EPHB4, ERBB2, FLT4, KDR
GEFITINIB	ChEMBL + PubChem	Phase 4 (approved)	EGFR, EPHB4, ERBB2, FLT4, KDR
Pazopanib	ChEMBL + PubChem	Phase 4 (approved)	EGFR, EPHB4, ERBB2, FLT4, KDR
SELUMETINIB	ChEMBL + PubChem	Phase 4 (approved)	EGFR, EPHB4, ERBB2, FLT4, KDR
SORAFENIB	ChEMBL + PubChem	Phase 4 (approved)	EGFR, EPHB4, ERBB2, FLT4, KDR
VANDETANIB	ChEMBL	Phase 4 (approved)	EGFR, EPHB4, ERBB2, FLT4, KDR
CEDIRANIB	ChEMBL	Phase 3	EGFR, EPHB4, ERBB2, FLT4, KDR
ELLAGIC ACID	ChEMBL	Phase 2	EGFR, EPHB4, ERBB2, FLT4, KDR
FORETINIB	ChEMBL	Phase 2	EGFR, EPHB4, ERBB2, FLT4, KDR
R-406	ChEMBL	Phase 2	EGFR, EPHB4, ERBB2, FLT4, KDR
FEDRATINIB	ChEMBL + PubChem	Phase 4 (approved)	EGFR, EPHB4, FLT4, KDR
IBRUTINIB	ChEMBL + PubChem	Phase 4 (approved)	EGFR, EPHB4, ERBB2, KDR
PONATINIB	ChEMBL + PubChem	Phase 4 (approved)	EGFR, EPHB4, ERBB2, KDR
BRIGATINIB	ChEMBL	Phase 4 (approved)	EGFR, ERBB2, FLT4, KDR
CABOZANTINIB	ChEMBL	Phase 4 (approved)	EGFR, ERBB2, FLT4, KDR
DASATINIB	ChEMBL	Phase 4 (approved)	EGFR, EPHB4, ERBB2, KDR
SUNITINIB	ChEMBL	Phase 4 (approved)	EGFR, EPHB4, FLT4, KDR
ALISERTIB	ChEMBL	Phase 3	EGFR, EPHB4, ERBB2, KDR
CANERTINIB	ChEMBL	Phase 3	EGFR, EPHB4, ERBB2, KDR
LESTAURTINIB	ChEMBL	Phase 3	EGFR, EPHB4, FLT4, KDR
LINIFANIB	ChEMBL	Phase 3	EGFR, EPHB4, FLT4, KDR
AEE-788	ChEMBL	Phase 2	EGFR, EPHB4, ERBB2, KDR
CENISERTIB	ChEMBL	Phase 2	EGFR, ERBB2, FLT4, KDR
DEFOSBARASERTIB	ChEMBL	Phase 2	EGFR, ERBB2, FLT4, KDR
DORAMAPIMOD	ChEMBL	Phase 2	EGFR, EPHB4, FLT4, KDR
ILORASERTIB	ChEMBL	Phase 2	EGFR, ERBB2, FLT4, KDR
PELITINIB	ChEMBL	Phase 2	EGFR, EPHB4, ERBB2, KDR
SOTRASTAURIN	ChEMBL	Phase 2	EGFR, ERBB2, FLT4, KDR
TOZASERTIB	ChEMBL	Phase 2	EGFR, EPHB4, FLT4, KDR
Binimetinib	PubChem	Approved	EGFR, EPHB4, ERBB2, KDR
DACOMITINIB	ChEMBL + PubChem	Phase 4 (approved)	EGFR, EPHB4, ERBB2
LAPATINIB	ChEMBL + PubChem	Phase 4 (approved)	EGFR, EPHB4, ERBB2
QUIZARTINIB	ChEMBL + PubChem	Phase 4 (approved)	EPHB4, FLT4, KDR
REGORAFENIB	ChEMBL + PubChem	Phase 4 (approved)	EPHB4, FLT4, KDR
ACALABRUTINIB	ChEMBL	Phase 4 (approved)	EGFR, ERBB2, KDR
AXITINIB	ChEMBL	Phase 4 (approved)	EGFR, FLT4, KDR
BOSUTINIB	ChEMBL	Phase 4 (approved)	EGFR, EPHB4, ERBB2
HEXACHLOROPHENE	ChEMBL	Phase 4 (approved)	EGFR, ERBB2, KDR
IMATINIB	ChEMBL	Phase 4 (approved)	EGFR, ERBB2, KDR
MIDOSTAURIN	ChEMBL	Phase 4 (approved)	EGFR, FLT4, KDR
NERATINIB	ChEMBL	Phase 4 (approved)	EGFR, ERBB2, KDR
NINTEDANIB	ChEMBL	Phase 4 (approved)	EPHB4, FLT4, KDR
OSIMERTINIB	ChEMBL	Phase 4 (approved)	EGFR, ERBB2, KDR
TIVOZANIB	ChEMBL	Phase 4 (approved)	EPHB4, FLT4, KDR
BRIVANIB	ChEMBL	Phase 3	EGFR, FLT4, KDR
DOVITINIB	ChEMBL	Phase 3	EGFR, FLT4, KDR
MOTESANIB	ChEMBL	Phase 3	EGFR, FLT4, KDR
POZIOTINIB	ChEMBL	Phase 3	EGFR, EPHB4, ERBB2
SARACATINIB	ChEMBL	Phase 3	EGFR, EPHB4, KDR
VATALANIB	ChEMBL	Phase 3	EGFR, FLT4, KDR
CEP-32496	ChEMBL	Phase 2	EGFR, EPHB4, KDR
DANUSERTIB	ChEMBL	Phase 2	EPHB4, FLT4, KDR
MILCICLIB	ChEMBL	Phase 2	EGFR, EPHB4, FLT4
OSI-632	ChEMBL	Phase 2	EGFR, FLT4, KDR
REBASTINIB	ChEMBL	Phase 2	EPHB4, FLT4, KDR
SAPITINIB	ChEMBL	Phase 2	EGFR, EPHB4, ERBB2
SU-014813	ChEMBL	Phase 2	EGFR, FLT4, KDR
TAK-715	ChEMBL	Phase 2	EGFR, FLT4, KDR