Naporafenib

Summary

Naporafenib (CHEMBL4583691) is a phase-3 clinical-stage small molecule targeting PDGFRB, DDR1, and DDR2; indicated across 3 conditions including melanoma and non-small cell lung carcinoma.

At a glance

• Status: Max clinical phase 3 (not approved)
• Modality: Small molecule
• Targets: 5 (PDGFRB, DDR1, DDR2…)
• Indications: 3 conditions
• Clinical trials: 7
• Chemistry: 502.5 Da · C25H25F3N4O4

Identifiers

Drug identity and classification

Field	Value
ChEMBL ID	CHEMBL4583691
Name	Naporafenib
Type	Small molecule
Max phase	3
FDA approved	no
PubChem CID	90456533
Molecular formula	C25H25F3N4O4
Molecular weight	502.5
InChIKey	UEPXBTCUIIGYCY-UHFFFAOYSA-N

SMILES: CC1=C(C=C(C=C1)NC(=O)C2=CC(=NC=C2)C(F)(F)F)C3=CC(=NC(=C3)OCCO)N4CCOCC4

IUPAC name: N-[3-[2-(2-hydroxyethoxy)-6-morpholin-4-yl-4-pyridinyl]-4-methylphenyl]-2-(trifluoromethyl)pyridine-4-carboxamide

Also known as: ERAS-254, Lxh 254, LXH-254, Lxh254, LXH254, Naporafenib, PAN-RAF INHIBITOR LXH254, NAPORAFENIB

Patent coverage: 436 distinct patent families (1,168 SureChEMBL compound mentions), from 4 matched compound structure(s). One matched structure accounts for 978 (84%) 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
PDGFRB	platelet derived growth factor receptor beta	Inhibition	7.85	2.3%	P09619
DDR1	discoidin domain receptor tyrosine kinase 1	Inhibition	8.74	0.1%	Q08345
DDR2	discoidin domain receptor tyrosine kinase 2	Inhibition	8	0%	Q16832
BRAF	B-Raf proto-oncogene, serine/threonine kinase	Inhibition	8.89	8.6%	P15056
RAF1	Raf-1 proto-oncogene, serine/threonine kinase	Inhibition	8.44		P04049

Broader ChEMBL bioactivity targets: 6 (assay-derived). Sample: Serine/threonine-protein kinase A-Raf, RAF proto-oncogene serine/threonine-protein kinase, Platelet-derived growth factor receptor beta, Discoidin domain-containing receptor 2, Serine/threonine-protein kinase B-raf, Epithelial discoidin domain-containing receptor 1.

Bioactivity

ChEMBL activities: 21 potent at pChembl ≥ 5 of 21 total. Top 30 by potency (10 = 0.1 nM, 6 = 1 µM):

Target	pChembl	Type	Value	Unit	Activity ID
RAF1	9.7	IC50	0.2	nM	CHEMBL_ACT_18997672
RAF1	9.7	IC50	0.2	nM	CHEMBL_ACT_27491654
RAF1	9.7	IC50	0.2	nM	CHEMBL_ACT_28031687
BRAF	9.4	IC50	0.4	nM	CHEMBL_ACT_18997695
BRAF	9.14	IC50	0.73	nM	CHEMBL_ACT_26686376
BRAF	9.14	IC50	0.73	nM	CHEMBL_ACT_27491651
BRAF	9	IC50	1	nM	CHEMBL_ACT_26027097
BRAF	8.89	Kd	1.3	nM	CHEMBL_ACT_18997707
DDR1	8.74	Kd	1.8	nM	CHEMBL_ACT_18997709
RAF1	8.44	Kd	3.6	nM	CHEMBL_ACT_18997708
RAF1	8.43	IC50	3.7	nM	CHEMBL_ACT_26027098
BRAF	8.43	IC50	3.7	nM	CHEMBL_ACT_26027103
RAF1	8.4	IC50	4	nM	CHEMBL_ACT_26027099
RAF1	8.07	IC50	8.6	nM	CHEMBL_ACT_24390427
RAF1	8.07	IC50	8.6	nM	CHEMBL_ACT_24845839
DDR2	8	Kd	10	nM	CHEMBL_ACT_18997710
RAF1	7.85	EC50	14	nM	CHEMBL_ACT_18997662
PDGFRB	7.85	Kd	14	nM	CHEMBL_ACT_18997711
BRAF	7.31	IC50	49.2	nM	CHEMBL_ACT_26027111
BRAF	7.11	IC50	78	nM	CHEMBL_ACT_22760325
ARAF	6.38	IC50	414	nM	CHEMBL_ACT_26027122

Target pathways

Aggregated over 5 target gene(s): PDGFRB, DDR1, DDR2, BRAF, RAF1.

Top Reactome pathways

50 total, by targets touching each:

Pathway	Targets	Genes
Non-integrin membrane-ECM interactions	2	DDR1, DDR2
RAF activation	2	BRAF, RAF1
RAF/MAP kinase cascade	2	BRAF, PDGFRB
MAP2K and MAPK activation	2	BRAF, RAF1
Negative feedback regulation of MAPK pathway	2	BRAF, RAF1
Negative regulation of MAPK pathway	2	BRAF, RAF1
Signaling by moderate kinase activity BRAF mutants	2	BRAF, RAF1
Signaling by high-kinase activity BRAF mutants	2	BRAF, RAF1
Signaling by BRAF and RAF1 fusions	2	BRAF, RAF1
Paradoxical activation of RAF signaling by kinase inactive BRAF	2	BRAF, RAF1
Signaling downstream of RAS mutants	2	BRAF, RAF1
Signaling by RAF1 mutants	2	BRAF, RAF1
SHOC2 M1731 mutant abolishes MRAS complex function	2	BRAF, RAF1
Gain-of-function MRAS complexes activate RAF signaling	2	BRAF, RAF1
PIP3 activates AKT signaling	1	PDGFRB
Spry regulation of FGF signaling	1	BRAF
Signal Transduction	1	BRAF
Disease	1	BRAF
Signaling by NTRKs	1	BRAF
Prolonged ERK activation events	1	BRAF
Frs2-mediated activation	1	BRAF
ARMS-mediated activation	1	BRAF
Downstream signal transduction	1	PDGFRB
Signaling by PDGF	1	PDGFRB
Signaling by NTRK1 (TRKA)	1	BRAF
Signalling to ERKs	1	BRAF
Signalling to p38 via RIT and RIN	1	BRAF
Signaling by FGFR	1	BRAF
Constitutive Signaling by Aberrant PI3K in Cancer	1	PDGFRB
Stimuli-sensing channels	1	RAF1

Dominant GO biological processes

GO term	Targets
protein phosphorylation	5
signal transduction	4
cell surface receptor protein tyrosine kinase signaling pathway	3
protein autophosphorylation	3
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	3
positive regulation of ERK1 and ERK2 cascade	3
negative regulation of apoptotic process	3
positive regulation of cell population proliferation	2
peptidyl-tyrosine phosphorylation	2
cell adhesion	2
negative regulation of cell population proliferation	2
regulation of extracellular matrix disassembly	2
positive regulation of neuron projection development	2
collagen-activated tyrosine kinase receptor signaling pathway	2
response to muscle stretch	2

Indications & clinical

Indications

3 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
melanoma	3	MONDO:0005105	EFO:0000756
non-small cell lung carcinoma	1	MONDO:0005233	EFO:0003060
neoplasm	1	MONDO:0005070	EFO:0000616

Clinical trials

Total trials: 7.

Phase distribution

Phase	Trials
PHASE1	5
PHASE3	1
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06346067	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Assess Naporafenib (ERAS-254) Administered With Trametinib in Patients With NRAS-mutant Melanoma (SEACRAFT-2)
NCT04417621	PHASE2	ACTIVE_NOT_RECRUITING	Study of Efficacy and Safety of LXH254 Combinations in Patients With Previously Treated Unresectable or Metastatic Melanoma
NCT03333343	PHASE1	ACTIVE_NOT_RECRUITING	Study of EGF816 in Combination With Selected Targeted Agents in EGFR-mutant NSCLC
NCT05907304	PHASE1	ACTIVE_NOT_RECRUITING	A Study to Assess Naporafenib (ERAS-254) Administered With Trametinib in Patients With RAS Q61X Mutations
NCT02607813	PHASE1	TERMINATED	Phase I Study of LXH254 in Patients With Advanced Solid Tumors Haboring MAPK Pathway Alterations
NCT02974725	PHASE1	TERMINATED	A Phase Ib Study of LXH254-centric Combinations in NSCLC or Melanoma
NCT04294160	PHASE1	TERMINATED	A Study of Select Drug Combinations in Adult Patients With Advanced/Metastatic BRAF V600 Colorectal Cancer

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.

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

Molecule	Source	Status	Shared targets
Crizotinib	ChEMBL + PubChem	Phase 4 (approved)	BRAF, DDR1, DDR2, PDGFRB, RAF1
DASATINIB	ChEMBL + PubChem	Phase 4 (approved)	BRAF, DDR1, DDR2, PDGFRB, RAF1
ERLOTINIB	ChEMBL + PubChem	Phase 4 (approved)	BRAF, DDR1, DDR2, PDGFRB, RAF1
PAZOPANIB	ChEMBL + PubChem	Phase 4 (approved)	BRAF, DDR1, DDR2, PDGFRB, RAF1
REGORAFENIB	ChEMBL + PubChem	Phase 4 (approved)	BRAF, DDR1, DDR2, PDGFRB, RAF1
SORAFENIB	ChEMBL + PubChem	Phase 4 (approved)	BRAF, DDR1, DDR2, PDGFRB, RAF1
TOVORAFENIB	ChEMBL + PubChem	Phase 4 (approved)	BRAF, DDR1, DDR2, PDGFRB, RAF1
IMATINIB	ChEMBL	Phase 4 (approved)	BRAF, DDR1, DDR2, PDGFRB, RAF1
NILOTINIB	ChEMBL	Phase 4 (approved)	BRAF, DDR1, DDR2, PDGFRB, RAF1
CEP-32496	ChEMBL	Phase 2	BRAF, DDR1, DDR2, PDGFRB, RAF1
DORAMAPIMOD	ChEMBL	Phase 2	BRAF, DDR1, DDR2, PDGFRB, RAF1
FORETINIB	ChEMBL	Phase 2	BRAF, DDR1, DDR2, PDGFRB, RAF1
R-406	ChEMBL	Phase 2	BRAF, DDR1, DDR2, PDGFRB, RAF1
RAF-265	ChEMBL	Phase 2	BRAF, DDR1, DDR2, PDGFRB, RAF1
Afatinib	PubChem	Approved	BRAF, DDR1, DDR2, PDGFRB, RAF1
Idelalisib	PubChem	Approved	BRAF, DDR1, DDR2, PDGFRB, RAF1
Selumetinib	PubChem	Approved	BRAF, DDR1, DDR2, PDGFRB, RAF1
FEDRATINIB	ChEMBL + PubChem	Phase 4 (approved)	BRAF, DDR1, DDR2, PDGFRB
Gefitinib	ChEMBL + PubChem	Phase 4 (approved)	BRAF, DDR1, DDR2, RAF1
PONATINIB	ChEMBL + PubChem	Phase 4 (approved)	BRAF, DDR1, DDR2, PDGFRB
MASITINIB	ChEMBL	Phase 3	BRAF, DDR1, DDR2, PDGFRB
MOTESANIB	ChEMBL	Phase 3	BRAF, DDR1, PDGFRB, RAF1
BAFETINIB	ChEMBL	Phase 2	BRAF, DDR1, DDR2, PDGFRB
BELVARAFENIB	ChEMBL	Phase 2	BRAF, DDR1, DDR2, RAF1
REBASTINIB	ChEMBL	Phase 2	BRAF, DDR1, DDR2, RAF1
Binimetinib	PubChem	Approved	BRAF, DDR1, DDR2, PDGFRB
dacomitinib	PubChem	Approved	BRAF, DDR1, DDR2, PDGFRB
Fostamatinib	PubChem	Approved	BRAF, DDR1, DDR2, PDGFRB
Trametinib	PubChem	Approved	BRAF, DDR1, DDR2, PDGFRB
Cobimetinib	ChEMBL + PubChem	Phase 4 (approved)	BRAF, DDR1, DDR2
Dabrafenib	ChEMBL + PubChem	Phase 4 (approved)	BRAF, DDR1, RAF1
LAPATINIB	ChEMBL + PubChem	Phase 4 (approved)	DDR1, DDR2, PDGFRB
PEXIDARTINIB	ChEMBL + PubChem	Phase 4 (approved)	DDR1, DDR2, PDGFRB
QUIZARTINIB	ChEMBL + PubChem	Phase 4 (approved)	DDR1, DDR2, PDGFRB
Ruxolitinib	ChEMBL + PubChem	Phase 4 (approved)	BRAF, DDR1, DDR2
VANDETANIB	ChEMBL + PubChem	Phase 4 (approved)	DDR1, DDR2, PDGFRB
Vemurafenib	ChEMBL + PubChem	Phase 4 (approved)	BRAF, DDR1, RAF1
AXITINIB	ChEMBL	Phase 4 (approved)	DDR1, DDR2, PDGFRB
BOSUTINIB	ChEMBL	Phase 4 (approved)	DDR1, DDR2, PDGFRB
LENVATINIB	ChEMBL	Phase 4 (approved)	DDR1, DDR2, PDGFRB
NINTEDANIB	ChEMBL	Phase 4 (approved)	DDR1, DDR2, PDGFRB
SUNITINIB	ChEMBL	Phase 4 (approved)	DDR1, DDR2, PDGFRB
TIVOZANIB	ChEMBL	Phase 4 (approved)	DDR1, DDR2, PDGFRB
CEDIRANIB	ChEMBL	Phase 3	DDR1, DDR2, PDGFRB
DOVITINIB	ChEMBL	Phase 3	DDR1, DDR2, PDGFRB
LESTAURTINIB	ChEMBL	Phase 3	DDR1, DDR2, PDGFRB
LINIFANIB	ChEMBL	Phase 3	DDR1, DDR2, PDGFRB
SARACATINIB	ChEMBL	Phase 3	DDR1, DDR2, PDGFRB
AEE-788	ChEMBL	Phase 2	DDR1, DDR2, PDGFRB
DEFOSBARASERTIB	ChEMBL	Phase 2	DDR1, DDR2, PDGFRB
EXARAFENIB	ChEMBL	Phase 2	BRAF, DDR1, RAF1
GLESATINIB	ChEMBL	Phase 2	DDR1, DDR2, PDGFRB
GOLVATINIB	ChEMBL	Phase 2	DDR1, DDR2, PDGFRB
LUCITANIB	ChEMBL	Phase 2	DDR1, DDR2, PDGFRB
MILCICLIB	ChEMBL	Phase 2	DDR1, DDR2, PDGFRB
OSI-632	ChEMBL	Phase 2	DDR1, DDR2, PDGFRB
PEXMETINIB	ChEMBL	Phase 2	BRAF, DDR1, DDR2
TANDUTINIB	ChEMBL	Phase 2	DDR1, DDR2, PDGFRB
TOZASERTIB	ChEMBL	Phase 2	DDR1, DDR2, PDGFRB
CABOZANTINIB	ChEMBL + PubChem	Phase 4 (approved)	DDR1, DDR2