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].
Click here for help
2D Structure
Click here for help
Click here for structure editor
Physico-chemical Properties
Click here for help
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
Click here for help
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
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

Product suppliers

View disclaimer

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