Ensartinib

Summary

Ensartinib (CHEMBL4113131) is an approved small molecule targeting MET and ALK; indicated across 3 conditions including non-small cell lung carcinoma and melanoma; with CIViC clinical evidence for 3 variant-indication associations (e.g. ALK G1269A AND v::ALK Fusion in lung non-small cell carcinoma).

At a glance

• Status: Approved (max clinical phase 4)
• Modality: Small molecule
• Targets: 2 (MET, ALK)
• Indications: 3 conditions
• Clinical trials: 30
• Precision-oncology evidence (CIViC): 3 variant–indication associations
• Chemistry: 561.4 Da · C26H27Cl2FN6O3

Identifiers

Drug identity and classification

Field	Value
ChEMBL ID	CHEMBL4113131
Name	Ensartinib
Type	Small molecule
Max phase	4
FDA approved	no
PubChem CID	56960363
Molecular formula	C26H27Cl2FN6O3
Molecular weight	561.4
InChIKey	GLYMPHUVMRFTFV-QLFBSQMISA-N

SMILES: C[C@@H]1CN(C[C@@H](N1)C)C(=O)C2=CC=C(C=C2)NC(=O)C3=NN=C(C(=C3)O[C@H](C)C4=C(C=CC(=C4Cl)F)Cl)N

IUPAC name: 6-amino-5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-N-[4-[(3R,5S)-3,5-dimethylpiperazine-1-carbonyl]phenyl]pyridazine-3-carboxamide

Also known as: Ensacove, Ensartinib, X-396, ENSARTINIB, US9126947, 18

Parent form; salt/anhydrous children: CHEMBL4297219

Patent coverage: 290 distinct patent families (679 SureChEMBL compound mentions), from 4 matched compound structure(s). One matched structure accounts for 660 (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
MET	MET proto-oncogene, receptor tyrosine kinase	Inhibition	9.13	2.4%	P08581
ALK	ALK receptor tyrosine kinase	Inhibition	9.4	0.8%	Q9UM73

Broader ChEMBL bioactivity targets: 1 (assay-derived). Sample: Hepatocyte growth factor receptor.

Bioactivity

ChEMBL activities: 1 potent at pChembl ≥ 5 of 1 total. Top 100 by potency (10 = 0.1 nM, 6 = 1 µM):

Target	pChembl	Type	Value	Unit	Activity ID
MET	9.13	IC50	0.74	nM	CHEMBL_ACT_19145487

Target pathways

Aggregated over 2 target gene(s): MET, ALK.

Top Reactome pathways

57 total, by targets touching each:

Pathway	Targets	Genes
Signal Transduction	2	ALK, MET
Disease	2	ALK, MET
Diseases of signal transduction by growth factor receptors and second messengers	2	ALK, MET
Signaling by Receptor Tyrosine Kinases	2	ALK, MET
PIP3 activates AKT signaling	1	MET
Developmental Biology	1	MET
Negative regulation of the PI3K/AKT network	1	MET
Signaling by ALK	1	ALK
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
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
MET receptor recycling	1	MET
MET activates STAT3	1	MET
MET promotes cell motility	1	MET
Listeria monocytogenes entry into host cells	1	MET
Transcriptional Regulation by MECP2	1	MET
Intracellular signaling by second messengers	1	MET
MECP2 regulates neuronal receptors and channels	1	MET
Nervous system development	1	MET
Signaling by ALK in cancer	1	ALK
ALK mutants bind TKIs	1	ALK
Drug resistance of ALK mutants	1	ALK
ASP-3026-resistant ALK mutants	1	ALK
NVP-TAE684-resistant ALK mutants	1	ALK
alectinib-resistant ALK mutants	1	ALK
brigatinib-resistant ALK mutants	1	ALK
ceritinib-resistant ALK mutants	1	ALK
crizotinib-resistant ALK mutants	1	ALK
lorlatinib-resistant ALK mutants	1	ALK

Dominant GO biological processes

GO term	Targets
cell surface receptor protein tyrosine kinase signaling pathway	2
protein phosphorylation	2
signal transduction	2
endothelial cell morphogenesis	1
liver development	1
cell surface receptor 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

Indications & clinical

Indications

3 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
non-small cell lung carcinoma	3	MONDO:0005233	EFO:0003060
melanoma	2	MONDO:0005105	EFO:0000756
lung neoplasm	2	MONDO:0021117	MONDO:0008903

Clinical trials

Total trials: 30.

Phase distribution

Phase	Trials
PHASE2	17
PHASE1	4
PHASE3	3
PHASE1/PHASE2	3
Not specified	2
PHASE4	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06785584	PHASE4	NOT_YET_RECRUITING	Efficacy and Safety of Ensartinib in Neoadjuvant Therapy for Stage IIA - IIIB (Operable or Potentially Operable) ALK-Positive Lung Adenocarcinoma ：A Multicenter, Real-World Clinical Study
NCT02767804	PHASE3	ACTIVE_NOT_RECRUITING	eXalt3: Study Comparing X-396 (Ensartinib) to Crizotinib in ALK Positive Non-Small Cell Lung Cancer (NSCLC) Patients
NCT05341583	PHASE3	RECRUITING	Ensartinib as Adjuvant Treatment in Anaplastic Lymphoma Kinase (ALK) Positive Non-small Cell Lung Cancer
NCT06955325	PHASE3	NOT_YET_RECRUITING	Umbrella Trial of Adjuvant Therapy in Completely Resected High-risk Stage IA-IB NSCLC: Focus on Driver Mutations
NCT03155620	PHASE2	ACTIVE_NOT_RECRUITING	Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders (The Pediatric MATCH Screening Trial)
NCT03213652	PHASE2	ACTIVE_NOT_RECRUITING	Ensartinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With ALK or ROS1 Genomic Alterations (A Pediatric MATCH Treatment Trial)
NCT03420508	PHASE2	ACTIVE_NOT_RECRUITING	Treating Patients With Melanoma and ALK Alterations With Ensartinib
NCT05241028	PHASE2	RECRUITING	Adjuvant Therapy of Ensartinib in Stage IB-IIIA ALK-positive Non-small Cell Lung Cancer
NCT05491811	PHASE2	ACTIVE_NOT_RECRUITING	Ensartinib in Combination With Bevacizumab in ALK-positive NSCLC Patients With TP53 Mutation
NCT06563999	PHASE2	RECRUITING	Neoadjuvant Umbrella Trial for Patients With Unresectable Stage III NSCLC Harboring Rare Mutations.
NCT06762327	PHASE2	NOT_YET_RECRUITING	Ensartinib in the Treatment of ALK Positive or MET Exon 14 Skipping Anvanced Solid Tumors Excluded Lung Cancer
NCT06772610	PHASE2	NOT_YET_RECRUITING	The Efficacy and Safety of Ensartinib As Adjuvant Therapy in Stage I ALK-positive NSCLC Patients with High Risk Factors
NCT06779539	PHASE2	NOT_YET_RECRUITING	Neoadjuvant Ensartinib in ALK Positive Resectable Stage II to III Non-Small Cell Lung Cancer
NCT06780839	PHASE2	NOT_YET_RECRUITING	Adjuvant Treatment of ALK-positive Non-small Cell Lung Cancer with Ensartinib Guided by MRD
NCT07235306	PHASE2	NOT_YET_RECRUITING	Ensartinib After Chemoradiotherapy in Stage III ALK-Mutated NSCLC
NCT07354061	PHASE1/PHASE2	RECRUITING	Neoadjuvant Therapy With Ensartinib Combined With Chemotherapy for ALK-positive Non - Small Cell Lung Cancer (NSCLC)
NCT07448116	PHASE1/PHASE2	RECRUITING	Study of MCLA-129 in Combination With Ensartinib in Patients With Advanced Solid Tumors.
NCT02898116	PHASE1/PHASE2	COMPLETED	Phase 1/2 Study of Ensartinib and Durvalumab, in ALK-rearranged Non-small Cell Lung Cancer
NCT03215693	PHASE2	UNKNOWN	X-396 Capsule in Patients With ALK-positive Non-small Cell Lung Cancer Previously Treated With Crizotinib
NCT03574402	PHASE2	UNKNOWN	Phase II Umbrella Study Directed by Next Generation Sequencing
NCT03608007	PHASE2	UNKNOWN	X-396 Capsule in Advanced NSCLC Patients With ROS1 Gene Rearrangement
NCT03737994	PHASE2	TERMINATED	Targeted Treatment for ALK Positive Patients Who Have Previously Been Treated for Non-squamous Non-small Cell Lung Cancer
NCT05178511	PHASE2	UNKNOWN	Ensatinib Treat Second-generation ALK-TKI Resistance After Second-generation ALK-TKI Resistance
NCT05380024	PHASE2	UNKNOWN	A Study of Ensartinib as Neoadjuvant Therapy for Patients With ALK Positive Resectable Non-Small Cell Lung Cancer
NCT04837716	PHASE1	ACTIVE_NOT_RECRUITING	Ensartinib, Carboplatin, Pemetrexed and Bevacizumab for the Treatment of Stage IIIC or IV or Recurrent ALK-Positive Non-small Cell Lung Cancer
NCT06492525	PHASE1	NOT_YET_RECRUITING	A Study To Evaluate The Effect Of Rifampicin Or Ltraconazole On Pharmacokinetics Of Ensartinib In Healthy Volunteers
NCT02959619	PHASE1	COMPLETED	Ensartinib in Non-small Cell Lung Cancer Patients With Positive ALK
NCT03804541	PHASE1	UNKNOWN	The Absorption, Metabolism and Excretion of [14C]Ensartinib in Human
NCT04146571	Not specified	AVAILABLE	Expanded Access to Ensartinib for Participants With ALK+ NSCLC
NCT05498064	Not specified	RECRUITING	A Real World Study of Ensartinib in Advanced ALK-positive NSCLC

Clinical evidence (CIViC)

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

Variant	Indication	Effect	Therapy	Level	CIViC
ALK G1269A AND v::ALK Fusion	Lung Non-small Cell Carcinoma	Sensitivity/Response	Ensartinib	CIViC B	EID8861
EML4::ALK Fusion AND ALK C1156Y	Lung Non-small Cell Carcinoma	Sensitivity/Response	Ensartinib	CIViC B	EID8860
EML4::ALK Fusion AND ALK L1196M	Lung Non-small Cell Carcinoma	Sensitivity/Response	Ensartinib	CIViC B	EID7865

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.

102 molecules share ≥1 primary target. Top 100 by shared-target count:

Molecule	Source	Status	Shared targets
AFATINIB	ChEMBL + PubChem	Phase 4 (approved)	ALK, MET
CRIZOTINIB	ChEMBL + PubChem	Phase 4 (approved)	ALK, MET
GEFITINIB	ChEMBL + PubChem	Phase 4 (approved)	ALK, MET
PAZOPANIB	ChEMBL + PubChem	Phase 4 (approved)	ALK, MET
BOSUTINIB	ChEMBL	Phase 4 (approved)	ALK, MET
BRIGATINIB	ChEMBL	Phase 4 (approved)	ALK, MET
CERITINIB	ChEMBL	Phase 4 (approved)	ALK, MET
ENTRECTINIB	ChEMBL	Phase 4 (approved)	ALK, MET
ERLOTINIB	ChEMBL	Phase 4 (approved)	ALK, MET
FEDRATINIB	ChEMBL	Phase 4 (approved)	ALK, MET
INFIGRATINIB	ChEMBL	Phase 4 (approved)	ALK, MET
MIDOSTAURIN	ChEMBL	Phase 4 (approved)	ALK, MET
NINTEDANIB	ChEMBL	Phase 4 (approved)	ALK, MET
PALBOCICLIB	ChEMBL	Phase 4 (approved)	ALK, MET
SUNITINIB	ChEMBL	Phase 4 (approved)	ALK, MET
VANDETANIB	ChEMBL	Phase 4 (approved)	ALK, MET
CANERTINIB	ChEMBL	Phase 3	ALK, MET
CEDIRANIB	ChEMBL	Phase 3	ALK, MET
DACTOLISIB	ChEMBL	Phase 3	ALK, MET
LESTAURTINIB	ChEMBL	Phase 3	ALK, MET
LINIFANIB	ChEMBL	Phase 3	ALK, MET
QUERCETIN	ChEMBL	Phase 3	ALK, MET
BEMCENTINIB	ChEMBL	Phase 2	ALK, MET
BI-2536	ChEMBL	Phase 2	ALK, MET
BMS-754807	ChEMBL	Phase 2	ALK, MET
CENISERTIB	ChEMBL	Phase 2	ALK, MET
ENVONALKIB	ChEMBL	Phase 2	ALK, MET
FORETINIB	ChEMBL	Phase 2	ALK, MET
ILORASERTIB	ChEMBL	Phase 2	ALK, MET
OSI-632	ChEMBL	Phase 2	ALK, MET
PELITINIB	ChEMBL	Phase 2	ALK, MET
R-406	ChEMBL	Phase 2	ALK, MET
SU-014813	ChEMBL	Phase 2	ALK, MET
TOZASERTIB	ChEMBL	Phase 2	ALK, MET
Idelalisib	PubChem	Approved	ALK, MET
Selumetinib	PubChem	Approved	ALK, MET
AFATINIB DIMALEATE	ChEMBL	Phase 4 (approved)	MET
ALECTINIB	ChEMBL	Phase 4 (approved)	ALK
AXITINIB	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
DABRAFENIB	ChEMBL	Phase 4 (approved)	MET
GILTERITINIB	ChEMBL	Phase 4 (approved)	ALK
LORLATINIB	ChEMBL	Phase 4 (approved)	ALK
NERATINIB	ChEMBL	Phase 4 (approved)	MET
OSIMERTINIB	ChEMBL	Phase 4 (approved)	ALK
REPOTRECTINIB	ChEMBL	Phase 4 (approved)	ALK
RUXOLITINIB	ChEMBL	Phase 4 (approved)	ALK
SORAFENIB	ChEMBL	Phase 4 (approved)	MET
TEPOTINIB	ChEMBL	Phase 4 (approved)	MET
TIVOZANIB	ChEMBL	Phase 4 (approved)	MET
UPADACITINIB	ChEMBL	Phase 4 (approved)	ALK
ALVOCIDIB	ChEMBL	Phase 3	ALK
DOVITINIB	ChEMBL	Phase 3	ALK
ENZASTAURIN	ChEMBL	Phase 3	MET
EPIGALOCATECHIN GALLATE	ChEMBL	Phase 3	MET
LINSITINIB	ChEMBL	Phase 3	MET
POZIOTINIB	ChEMBL	Phase 3	MET
RIGOSERTIB	ChEMBL	Phase 3	MET
ROCILETINIB	ChEMBL	Phase 3	ALK
SAVOLITINIB	ChEMBL	Phase 3	MET
SEMAXANIB	ChEMBL	Phase 3	ALK
SITRAVATINIB	ChEMBL	Phase 3	MET
TIVANTINIB	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
BMS-777607	ChEMBL	Phase 2	MET
CEP-11981	ChEMBL	Phase 2	ALK
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
GLESATINIB	ChEMBL	Phase 2	MET
GOLVATINIB	ChEMBL	Phase 2	MET
GUMARONTINIB	ChEMBL	Phase 2	MET
IRUPLINALKIB	ChEMBL	Phase 2	ALK
MERESTINIB	ChEMBL	Phase 2	MET
MK-2461	ChEMBL	Phase 2	MET
NINGETINIB	ChEMBL	Phase 2	MET
RAF-265	ChEMBL	Phase 2	MET
RAVOXERTINIB	ChEMBL	Phase 2	MET
REBASTINIB	ChEMBL	Phase 2	MET
SAR-125844	ChEMBL	Phase 2	MET
SELICICLIB	ChEMBL	Phase 2	ALK
SELITRECTINIB	ChEMBL	Phase 2	ALK
TAK-715	ChEMBL	Phase 2	ALK
UCN-01	ChEMBL	Phase 2	MET
VABAMETKIB	ChEMBL	Phase 2	MET
VEBRELTINIB	ChEMBL	Phase 2	MET
VX-702	ChEMBL	Phase 2	ALK
ZOTIZALKIB	ChEMBL	Phase 2	ALK
belumosudil	PubChem	Approved	ALK
Binimetinib	PubChem	Approved	MET
dacomitinib	PubChem	Approved	MET
Fostamatinib	PubChem	Approved	MET