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Compound Detail

CHEMBL4583691

NAPORAFENIB
🧪 Phase III
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🧪 Phase III
Cc1ccc(NC(=O)c2ccnc(C(F)(F)F)c2)cc1-c1cc(OCCO)nc(N2CCOCC2)c1
ChEMBL ↗ Properties Compare Identifier

Basic Information

ChEMBL ID CHEMBL4583691
Name NAPORAFENIB
Phase Phase III
Structure Type MOL
InChI Key UEPXBTCUIIGYCY-UHFFFAOYSA-N

Known Names

ERAS-254 Lxh 254 LXH-254 Lxh254 Naporafenib PAN-RAF INHIBITOR LXH254
9
Targets
26
Activities
3
Assay Types
26
PK Parameters
20
Publications
6
Known Names
3
Indications
1
Mechanisms

Molecular Properties

502.5
MW (Da)
3.93
ALogP
7
HBA
2
HBD
96.8
PSA (Ų)
0.51
QED
1
Ro5 Violations
7
Rot. Bonds

Drug Information

Molecule Type Small molecule
Chirality Achiral
USAN Stem -rafenib
USAN Year 2023

Extended Properties

Molecular Formula C25H25F3N4O4
MW 502.49
Aromatic Rings 3
Heavy Atoms 36
NP-Likeness -1.57

Mechanism of Action

Mechanism Action Type Target Direct Efficacy
B-raf/RAF proto-oncogene serine/threonine-protein kinase inhibitor INHIBITOR B-raf/RAF proto-oncogene serine/threonine-protein kinase ✓ ✓

Indications

Melanoma Carcinoma, Non-Small-Cell Lung Neoplasms

Activity Summary

IC50 18 meas. best 9.7
Kd 5 meas. best 8.89
EC50 3 meas. best 7.85

Target Activity Profile

Target Type Best pChEMBL Mean pChEMBL Best (nM) # Data
RAF proto-oncogene serine/threonine-protein kinase
CHEMBL1906
 IC50 9.7 8.8671 0.2 7
Unchecked
CHEMBL612545
 IC50 9.7 9.42 0.2 2
Serine/threonine-protein kinase B-raf
CHEMBL5145
 IC50 9.4 8.5043 0.4 7
Serine/threonine-protein kinase B-raf
CHEMBL5145
 Kd 8.89 8.89 1.3 1
Epithelial discoidin domain-containing receptor 1
CHEMBL5319
 Kd 8.74 8.74 1.8 1
RAF proto-oncogene serine/threonine-protein kinase
CHEMBL1906
 Kd 8.44 8.44 3.6 1
Discoidin domain-containing receptor 2
CHEMBL5122
 Kd 8.0 8.0 10.0 1
RAF proto-oncogene serine/threonine-protein kinase
CHEMBL1906
 EC50 7.85 7.85 14.0 1
Platelet-derived growth factor receptor beta
CHEMBL1913
 Kd 7.85 7.85 14.0 1
Unchecked
CHEMBL612545
 EC50 6.8 6.8 160.0 1
A-375
CHEMBL613859
 IC50 6.62 6.62 240.0 1
Calu-6
CHEMBL614535
 EC50 6.55 6.55 280.0 1
Serine/threonine-protein kinase A-Raf
CHEMBL1169596
 IC50 6.38 6.38 414.0 1

Pharmacokinetic Data

Parameter Value Units Species
AUC 2160.71 ng.hr.mL-1 Mus musculus
AUC 904.48 ng.hr.mL-1 Rattus norvegicus
AUC 1557.72 ng.hr.mL-1 Canis lupus familiaris
AUC 3976.2 ng.hr.mL-1 Rattus norvegicus
AUC 12667.77 ng.hr.mL-1 Rattus norvegicus
AUC 52515.23 ng.hr.mL-1 Rattus norvegicus
AUC 108879.53 ng.hr.mL-1 Rattus norvegicus
CL 13.5 mL.min-1.g-1 Homo sapiens
CL 19.0 mL.min-1.kg-1 Mus musculus
CL 31.0 mL.min-1.kg-1 Rattus norvegicus
CL 3.5 mL.min-1.kg-1 Canis lupus familiaris
Cmax 1600.0 nM Mus musculus
Cmax 500.0 nM Rattus norvegicus
Cmax 400.0 nM Canis lupus familiaris
Cmax 878.0 nM Rattus norvegicus
Cmax 2347.0 nM Rattus norvegicus
Cmax 8680.0 nM Rattus norvegicus
Cmax 12671.0 nM Rattus norvegicus
F 65.0 % Mus musculus
F 38.0 % Rattus norvegicus
F 79.0 % Canis lupus familiaris
T1/2 6.5 hr Homo sapiens
Tmax 3.0 hr Rattus norvegicus
Tmax 3.0 hr Rattus norvegicus
Tmax 2.0 hr Rattus norvegicus
Tmax 5.5 hr Rattus norvegicus

Activity Data Samples

Top measurements by pChEMBL value

Target Type Rel. Value Units pChEMBL Assay PubMed
RAF proto-oncogene serine/threonine-protein kinase IC50 = 0.2 nM 9.7 Inhibition of CRAF Y340E/Y341E mutant (unknown origin) using human MEK1 K97R mut... 31059256
Unchecked IC50 = 0.2 nM 9.7 Raf Activity Assay: Raf and biotinylated Mek, kinase dead, were combined at 2x f... -
RAF proto-oncogene serine/threonine-protein kinase IC50 = 0.2 nM 9.7 In Vitro Raf Activity: Raf and biotinylated Mek, kinase dead, were combined at 2... -
RAF proto-oncogene serine/threonine-protein kinase IC50 = 0.2 nM 9.7 In Vitro Activity Assay: C-Raf TR refers to a truncated C-Raf protein, a Δ1-324 ... -
Serine/threonine-protein kinase B-raf IC50 = 0.4 nM 9.4 Inhibition of full-length BRAF (unknown origin) 31059256
Unchecked IC50 = 0.73 nM 9.14 In Vitro Activity Assay: C-Raf TR refers to a truncated C-Raf protein, a Δ1-324 ... -
Serine/threonine-protein kinase B-raf IC50 = 0.73 nM 9.14 Raf Activity Assay: Raf and biotinylated Mek, kinase dead, were combined at 2x f... -
Serine/threonine-protein kinase B-raf IC50 = 0.73 nM 9.14 In Vitro Raf Activity: Raf and biotinylated Mek, kinase dead, were combined at 2... -
Serine/threonine-protein kinase B-raf IC50 = 1.0 nM 9.0 Inhibition of N-terminal 6His-tagged wild type B-RAF (unknown origin) extracted ... 38954961
Serine/threonine-protein kinase B-raf Kd = 1.3 nM 8.89 Binding affinity to wild-type human partial length BRAF (S429 to E741 residues) ... 31059256
Epithelial discoidin domain-containing receptor 1 Kd = 1.8 nM 8.74 Binding affinity to wild-type human partial length DDR1 (R565 to V876 residues) ... 31059256
RAF proto-oncogene serine/threonine-protein kinase Kd = 3.6 nM 8.44 Binding affinity to wild-type human partial length CRAF (I330 to T640 residues) ... 31059256
RAF proto-oncogene serine/threonine-protein kinase IC50 = 3.7 nM 8.43 Inhibition of C-terminal 6His-tagged C-RAF (308 to 648 residues) (unknown origin... 38954961
Serine/threonine-protein kinase B-raf IC50 = 3.7 nM 8.43 Inhibition of wild-type B-RAF (unknown origin) 38954961
RAF proto-oncogene serine/threonine-protein kinase IC50 = 4.0 nM 8.4 Inhibition of wild type C-RAF (unknown origin) 38954961
RAF proto-oncogene serine/threonine-protein kinase IC50 = 8.6 nM 8.07 Inhibition of human recombinant cRAF measured after 60 mins by TR-FRET assay 34906761
RAF proto-oncogene serine/threonine-protein kinase IC50 = 8.6 nM 8.07 Inhibition of human recombinant cRAF measured after 1 hr by TR-FRET assay 35276360
Discoidin domain-containing receptor 2 Kd = 10.0 nM 8.0 Binding affinity to wild-type human partial length DDR2 (V555 to E855 residues) ... 31059256
RAF proto-oncogene serine/threonine-protein kinase EC50 = 14.0 nM 7.85 Inhibition of CRAF in human Calu6 cells assessed as reduction MEK phosphorylatio... 31059256
Platelet-derived growth factor receptor beta Kd = 14.0 nM 7.85 Binding affinity to wild-type human partial length PDGFRB (V582 to Y1009 residue... 31059256

Literature References

PubMed DOI Target Context # Activities
31059256 10.1021/acs.jmedchem.9b00161 ADMET 39
31059256 10.1021/acs.jmedchem.9b00161 Calu-6 6
31059256 10.1021/acs.jmedchem.9b00161 No relevant target 5
31059256 10.1021/acs.jmedchem.9b00161 RAF proto-oncogene serine/threonine-protein kinase 5
31059256 10.1021/acs.jmedchem.9b00161 Serine/threonine-protein kinase B-raf 4
38954961 10.1016/j.ejmech.2024.116631 Serine/threonine-protein kinase B-raf 3
31059256 10.1021/acs.jmedchem.9b00161 Epithelial discoidin domain-containing receptor 1 2
31059256 10.1021/acs.jmedchem.9b00161 Discoidin domain-containing receptor 2 2
31059256 10.1021/acs.jmedchem.9b00161 Platelet-derived growth factor receptor beta 2
31059256 10.1021/acs.jmedchem.9b00161 Rattus norvegicus 2
38954961 10.1016/j.ejmech.2024.116631 RAF proto-oncogene serine/threonine-protein kinase 2
31059256 10.1021/acs.jmedchem.9b00161 Unchecked 1
31059256 10.1021/acs.jmedchem.9b00161 Voltage-gated inwardly rectifying potassium channel KCNH2 1
32910655 10.1021/acs.jmedchem.0c01170 A-375 1
32910655 10.1021/acs.jmedchem.0c01170 Serine/threonine-protein kinase B-raf 1
34906761 10.1016/j.ejmech.2021.114040 RAF proto-oncogene serine/threonine-protein kinase 1
34906761 10.1016/j.ejmech.2021.114040 NCI-H358 1
37852032 10.1016/j.ejmech.2023.115857 SW837 1
34906761 10.1016/j.ejmech.2021.114040 Calu-6 1
35276360 10.1016/j.bmcl.2022.128666 RAF proto-oncogene serine/threonine-protein kinase 1

Data from ChEMBL 36 via Core Engine