lorlatinib   Click here for help

GtoPdb Ligand ID: 7476

Synonyms: (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-4,8-methenopyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile | Lorbrena® | Lorviqua® | PF-06463922 | PF06463922
Approved drug PDB Ligand
lorlatinib is an approved drug (FDA (2018), EMA (2019))
Compound class: Synthetic organic
Comment: Lorlatinib (PF-06463922) is a kinase inhibitor with action on ALK and ROS1 proto-oncogenes [3,7]. It is a reversible, ATP-competitive small molecule inhibitor. Lorlatinib is a third generation ALK inhibitor designed to have improved blood-brain barrier penetrance compared to older second generation ALK inhibitors such as the approved drugs ceritinib, alectinib, and brigatinib, with the aim of better targeting metastatic NSCLC lesions in the brain. Advanced generation ALK inhibitors are those which target acquired ALK mutations resistant to the original first generation inhibitor crizotinib, which occur in virtually all AKL-rearranged NSCLC tumours within a year of starting crizotinib therapy. In fact, the cyano group of lortatinib is highly selective for the ALK mutation L1196M [4]. Facchinetti et al. (2016) [1] review the progress in ALK inhibitor development and discuss the importance of targeting therapies based on individual patient tumour profiles. Shaw et al.(2016) [5] publish a case report of a patient with metastatic ALK-rearranged NSCLC whose tumours acquired sequential resistance to crizotinib, ceritinib and finally lorlatinib. However, the patient subsequently showed a resensitization to crizotinib. This patient was identified in a substudy of Phase 1/2 clinical trial NCT01970865, which is designed to compare lorlatinib against crizotinib in advanced NSCLC harbouring specific molecular alterations, such as the lorlatinib resistance-conferring mutation L1198F. The molecular biology behind this pheomenon is outlined in the Nature Reviews Cancer Research Highlight commentary by Shipman (2016) [6].
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Ligand Activity Visualisation Charts

These are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts.

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View interactive charts of activity data across species

lorlatinib is commercially available from our sponsors

2D Structure
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2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

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Physico-chemical Properties
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Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the CDK toolkit. All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

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Hydrogen bond acceptors 6
Hydrogen bond donors 1
Rotatable bonds 0
Topological polar surface area 110.06
Molecular weight 406.16
XLogP 2.58
No. Lipinski's rules broken 0
SMILES / InChI / InChIKey
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SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

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Canonical SMILES N#Cc1n(C)nc2c1c1cnc(c(c1)OC(C)c1c(C(=O)N(C2)C)ccc(c1)F)N
Isomeric SMILES N#Cc1n(C)nc2c1c1cnc(c(c1)O[C@H](C)c1c(C(=O)N(C2)C)ccc(c1)F)N
InChI InChI=1S/C21H19FN6O2/c1-11-15-7-13(22)4-5-14(15)21(29)27(2)10-16-19(17(8-23)28(3)26-16)12-6-18(30-11)20(24)25-9-12/h4-7,9,11H,10H2,1-3H3,(H2,24,25)/t11-/m1/s1
InChI Key IIXWYSCJSQVBQM-LLVKDONJSA-N
Classification Click here for help
Compound class Synthetic organic
Approved drug? Yes (FDA (2018), EMA (2019))
International Nonproprietary Names Click here for help
INN number INN
10278 lorlatinib
Synonyms Click here for help
(10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-4,8-methenopyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile | Lorbrena® | Lorviqua® | PF-06463922 | PF06463922
Database Links Click here for help
CAS Registry No. 1454846-35-5 (source: WHO INN record)
ChEMBL Ligand CHEMBL3286830
DrugCentral Ligand 5302
GtoPdb PubChem SID 187051779
PubChem CID 71731823
RCSB PDB Ligand 53P, 5P8, QB4
Search Google for chemical match using the InChIKey IIXWYSCJSQVBQM-LLVKDONJSA-N
Search Google for chemicals with the same backbone IIXWYSCJSQVBQM
Search PubMed clinical trials lorlatinib
Search PubMed titles lorlatinib
Search PubMed titles/abstracts lorlatinib
SynPHARM 79786 (in complex with anaplastic lymphoma receptor tyrosine kinase)
UniChem Compound Search for chemical match using the InChIKey IIXWYSCJSQVBQM-LLVKDONJSA-N
UniChem Connectivity Search for chemical match using the InChIKey IIXWYSCJSQVBQM-LLVKDONJSA-N

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Tocris
PF 06463922 (links to external site)
Cat. No. 5640