lorlantinib

Ligand id: 7476

Name: lorlantinib

Structure and Physico-chemical Properties

2D Structure
Calculated Physico-chemical Properties
Hydrogen bond acceptors 7
Hydrogen bond donors 1
Rotatable bonds 0
Topological polar surface area 110.06
Molecular weight 406.16
XLogP 1.25
No. Lipinski's rules broken 0

Molecular properties generated using the CDK

Classification
Compound class Synthetic organic
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 | PF-06463922
Database Links
CAS Registry No. 1454846-35-5 (source: WHO INN record)
ChEMBL Ligand CHEMBL3286830
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
Search UniChem for chemical match using the InChIKey IIXWYSCJSQVBQM-LLVKDONJSA-N
Search UniChem for chemicals with the same backbone IIXWYSCJSQVBQM
SynPHARM 79786 (in complex with anaplastic lymphoma receptor tyrosine kinase)
Comments
Lorlatinib (PF-06463922) is an investigational kinase inhibitor with inhibitory action on ALK and ROS1 proto-oncogenes [3,6]. 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 and alectinib, and the clinical candidate 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. 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) [4] 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 comparing 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) [5].