lorlatinib   

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
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. Second 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].
2D Structure
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Physico-chemical Properties
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
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
Compound class Synthetic organic
Approved drug? Yes (FDA (2018), EMA (2019))
International Nonproprietary Names
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
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 5P8, 53P, QB4
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SynPHARM 79786 (in complex with anaplastic lymphoma receptor tyrosine kinase)

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Tocris
PF 06463922
Cat. No. 5640