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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
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].
Ligand Activity Visualisation ChartsThese 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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Classification  |
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| Compound class | Synthetic organic |
| Approved drug? | Yes (FDA (2018), EMA (2019)) |
| International Nonproprietary Names |
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| INN number | INN |
| 10278 | lorlatinib |
| 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 |
| Database Links |
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| 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 |
