LAROTRECTINIB

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Synonyms
Status
Molecule Category Free-form
ATC L01EX12
UNII PF9462I9HX

Structure

InChI Key NYNZQNWKBKUAII-KBXCAEBGSA-N
Smiles O=C(Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12)N1CC[C@H](O)C1
InChI
InChI=1S/C21H22F2N6O2/c22-13-3-4-16(23)15(10-13)18-2-1-7-28(18)19-6-9-29-20(26-19)17(11-24-29)25-21(31)27-8-5-14(30)12-27/h3-4,6,9-11,14,18,30H,1-2,5,7-8,12H2,(H,25,31)/t14-,18+/m0/s1

Physicochemical Descriptors

Property Name Value
Molecular Formula C21H22F2N6O2
Molecular Weight 428.44
AlogP 2.95
Hydrogen Bond Acceptor 6.0
Hydrogen Bond Donor 2.0
Number of Rotational Bond 3.0
Polar Surface Area 86.0
Molecular species NEUTRAL
Aromatic Rings 3.0
Heavy Atoms 31.0

Bioactivity

Mechanism of Action Action Reference
Neurotrophic tyrosine kinase receptor inhibitor INHIBITOR PubMed Other
Targets EC50(nM) IC50(nM) Kd(nM) Ki(nM) Inhibition(%)
Enzyme Kinase Protein Kinase TK protein kinase group Tyrosine protein kinase Trk family
- 1-69 - - -
Assay Description Organism Bioactivity Reference
Inhibition of TrkA (unknown origin) by cell based assay Homo sapiens 9.7 nM
Inhibition of TrkB (unknown origin) by cell based assay Homo sapiens 24.0 nM
Inhibition of TrkC (unknown origin) by cell based assay Homo sapiens 24.0 nM
ELISA Assay: An enzyme-linked immunosorbant assay (ELISA) was used to assess TrkA kinase activity in the presence of inhibitors. Immulon 4HBX 384-well microtiter plates (Thermo part #8755) were coated with a 0.025 mg/mL solution of poly (Glu, Ala, Tyr; 6:3:1; Sigma P3899). Various concentrations of test compound, 2.5 nM TrkA (Invitrogen Corp., histidine-tagged recombinant human TrkA, cytoplasmic domain), and 500 uM ATP were incubated for 25 minutes at ambient temperature in the coated plates while shaking. The assay buffer consisted of 25 mM MOPS pH 7.5, 0.005% (v/v) Triton X-100 and 5 mM MgCl2. The reaction mixture was removed from the plate by washing with PBS containing 0.1% (v/v) Tween 20. The phosphorylated reaction product was detected using 0.2 ug/mL of a phosphotyrosine specific monoclonal antibody (clone PY20) conjugated to horseradish peroxidase in conjunction with the TMB Peroxidase Substrate System (KPL). None 9.7 nM
Inhibition of TRKA (unknown origin) by FISH assay Homo sapiens 2.0 nM
Inhibition of TRKA G595R mutant (unknown origin) using poly-EAY peptide as substrate in presence of gamma-33ATP by LanthaScreen assay Homo sapiens 69.0 nM
Inhibition of TRKA G667C mutant (unknown origin) using poly-EAY peptide as substrate in presence of gamma-33ATP by LanthaScreen assay Homo sapiens 45.0 nM
Inhibition of TRKC G623R mutant (unknown origin) using poly-EAY peptide as substrate in presence of gamma-33ATP by LanthaScreen assay Homo sapiens 48.0 nM
Inhibition of recombinant human His-tagged TrkA catalytic domain (441 to 796 residues) expressed in baculovirus expression system using tyr 01 as substrate incubated for 1 hr by Z'-Lyte assay Homo sapiens 3.34 nM
Inhibition of recombinant human His-tagged TrkB catalytic domain (526 to 838 residues) expressed in baculovirus expression system using tyr 01 as substrate incubated for 1 hr by Z'-Lyte assay Homo sapiens 5.21 nM
Inhibition of recombinant human His-tagged TrkC cytoplasmic domain (510 to 825 residues) expressed in baculovirus using tyr 01 as substrate incubated for 1 hr by Z'-Lyte assay Homo sapiens 3.49 nM
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate Severe acute respiratory syndrome coronavirus 2 13.68 %
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging Chlorocebus sabaeus -0.13 % Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging Chlorocebus sabaeus -0.13 %
Inhibition of Trk-C (unknown origin) Homo sapiens 2.1 nM
Inhibition of Trk-B (unknown origin) Homo sapiens 2.1 nM
Inhibition of Trk-A (unknown origin) Homo sapiens 1.2 nM
Inhibition of TrkA (unknown origin) using Tyr1 peptide as substrate in presence of ATP measured after 2 hrs by FRET-based Z-Lyte kinase assay Homo sapiens 2.9 nM
Inhibition of TrkB (unknown origin) using Tyr1 peptide as substrate in presence of ATP measured after 2 hrs by FRET-based Z-Lyte kinase assay Homo sapiens 2.3 nM
Inhibition of TrkC (unknown origin) using Tyr1 peptide as substrate in presence of ATP measured after 2 hrs by FRET-based Z-Lyte kinase assay Homo sapiens 1.7 nM
Antiproliferative activity against mouse BaF3 cells transfected with wild type CD74-NTRK1 (unknown origin) assessed as cell viability measured after 72 hrs by Micro plate reader method Mus musculus 16.0 nM
Antiproliferative activity against mouse BaF3 cells transfected with wild type ETV6-NTRK2 (unknown origin) assessed as cell viability measured after 72 hrs by Micro plate reader method Mus musculus 40.0 nM
Antiproliferative activity against mouse BaF3 cells transfected with wild type ETV6-NTRK3 (unknown origin) assessed as cell viability measured after 72 hrs by Micro plate reader method Mus musculus 13.0 nM
Antiproliferative activity against mouse BaF3 cells transfected with wild type CD74-NTRK1 (unknown origin) harbouring G595R mutation assessed as cell viability measured after 72 hrs by Micro plate reader method Mus musculus 539.0 nM
Antiproliferative activity against mouse BaF3 cells transfected with wild type CD74-NTRK1 (unknown origin) harbouring G667C mutation assessed as cell viability measured after 72 hrs by Micro plate reader method Mus musculus 184.0 nM
Antiproliferative activity against mouse BaF3 cells transfected with wild type ETV6-NTRK3 (unknown origin) harbouring G696A mutation assessed as cell viability measured after 72 hrs by Micro plate reader method Mus musculus 54.0 nM
Inhibition of wild type TRKC (unknown origin) Homo sapiens 5.0 nM
Inhibition of wild type TRKA (unknown origin) Homo sapiens 5.0 nM
Inhibition of wild type TRKB (unknown origin) Homo sapiens 5.0 nM
Inhibition of TRKA (unknown origin) at 500 nM Homo sapiens 100.5 %
Inhibition of TRKA G595R mutant (unknown origin) Homo sapiens 237.4 nM
Antiproliferative activity against mouse BaF3 cells harboring LMNA fused NTRKA1 Mus musculus 18.0 nM
Inhibition of wildtype TRKA (unknown origin) preincubated for 30 mins followed by biotinylated TK-peptide substrate addition and measured after 40 mins by FRET-based Z-lyte kinase assay Homo sapiens 1.2 nM
Inhibition of TRKA GS95R mutant (unknown origin) preincubated for 30 mins followed by biotinylated TK-peptide substrate addition and measured after 40 mins by FRET-based Z-lyte kinase assay Homo sapiens 109.4 nM
Inhibition of TRKA G667C mutant (unknown origin) preincubated for 30 mins followed by biotinylated TK-peptide substrate addition and measured after 40 mins by FRET-based Z-lyte kinase assay Homo sapiens 32.2 nM
Inhibition of TRKA F589L mutant (unknown origin) preincubated for 30 mins followed by biotinylated TK-peptide substrate addition and measured after 40 mins by FRET-based Z-lyte kinase assay Homo sapiens 43.1 nM
Inhibition of TRKC G623R mutant (unknown origin) preincubated for 30 mins followed by biotinylated TK-peptide substrate addition and measured after 40 mins by FRET-based Z-lyte kinase assay Homo sapiens 74.5 nM
Inhibition of TRKC G696A mutant (unknown origin) preincubated for 30 mins followed by biotinylated TK-peptide substrate addition and measured after 40 mins by FRET-based Z-lyte kinase assay Homo sapiens 5.9 nM
Cytotoxicity against mouse BaF3 cells expressing TEL fused TrkA assessed as inhibition of cell growth incubated for 3 days by CCK-8 assay Mus musculus 11.0 nM
Cytotoxicity against mouse BaF3 cells expressing CD74 fused TrkA assessed as inhibition of cell growth incubated for 3 days by CCK-8 assay Mus musculus 1.0 nM
Cytotoxicity against mouse BaF3 cells expressing TEL fused TrkC assessed as inhibition of cell growth incubated for 3 days by CCK-8 assay Mus musculus 59.0 nM
Cytotoxicity against mouse BaF3 cells expressing LMNA fused TrkA G667S mutant assessed as inhibition of cell growth incubated for 3 days by CCK-8 assay Mus musculus 321.0 nM
Cytotoxicity against mouse BaF3 cells expressing LMNA fused TrkA F589L mutant assessed as inhibition of cell growth incubated for 3 days by CCK-8 assay Mus musculus 547.0 nM
Cytotoxicity against mouse BaF3 cells expressing TEL fused TrkC G696C assessed as inhibition of cell growth incubated for 3 days by CCK-8 assay Mus musculus 586.0 nM
Cytotoxicity against human KM12-Luc cells expressing TPM3 fused TrkA assessed as inhibition of cell growth incubated for 3 days by CCK-8 assay Homo sapiens 11.0 nM

Cross References

Resources Reference
ChEMBL CHEMBL3889654
DrugBank DB14723
DrugCentral 5305
FDA SRS PF9462I9HX
Guide to Pharmacology 8909
PubChem 46188928
SureChEMBL SCHEMBL2241012
ZINC ZINC000118399834
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