Drug Information

Drug (ID: DG00053) and It's Reported Resistant Information

• Name: Lorlatinib
• Synonyms: SCHEMBL15274056
• Indication:
  In total 2 Indication(s)
  Lung cancer [ICD-11: 2C25]; Phase 2; [1]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; Phase 1/2; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
  Brain cancer [ICD-11: 2A00]; [2]
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
  Lung cancer [ICD-11: 2C25]; [1]
• Target: ALK tyrosine kinase receptor (ALK); ALK_HUMAN; [1]
• Formula: C21H19FN6O2
• IsoSMILES: C[C@@H]1C2=C(C=CC(=C2)F)C(=O)N(CC3=NN(C(=C3C4=CC(=C(N=C4)N)O1)C#N)C)C
• 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
• InChIKey: IIXWYSCJSQVBQM-LLVKDONJSA-N
• PubChem CID: 71731823
• ChEBI ID: CHEBI:143117
• TTD Drug ID: D04DYC
• INTEDE ID: DR0980
• DrugBank ID: DB12130

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  EADR: Epigenetic Alteration of DNA, RNA or Protein

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Brain cancer [ICD-11: 2A00]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: ALK tyrosine kinase receptor (ALK) [2]

• Resistant Disease: Neuroblastoma [ICD-11: 2A00.11]
• Molecule Alteration: Missense mutation; p.F1174L
• Wild Type Structure: Method: X-ray diffraction; Resolution: 1.75 Å; PDB: 3AOX
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 1.75 Å; PDB: 4FNW

RMSD: 0.34; TM score: 0.99391; Amino acid change: F1174L

• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: NBLW cells; Brain; Homo sapiens (Human); CVCL_VJ90
• In Vitro Model: NBLW-R cells; Brain; Homo sapiens (Human); CVCL_VJ91
• Experiment for Molecule Alteration: Sangersequencing assay; Targeted deep sequencing assay
• Experiment for Drug Resistance: Array CGH assay
• Mechanism Description: Analysis of the sensitivity of NBLW and NBLW-R cells to a panel of ALk inhibitors (TAE-684, Crizotinib, Alectinib and Lorlatinib) revealed differences between the paired cell lines, and overall NBLW-R cells with the F1174L mutation were more resistant to ALk inhibitor induced apoptosis compared with NBLW cells.

Lung cancer [ICD-11: 2C25]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-100-5p [1]

• Resistant Disease: Eml4-alk positive non-small cell lung cancer [ICD-11: 2C25.8]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: mTOR signaling pathway; Inhibition; hsa04150
• In Vitro Model: DFCI032 cells; Lung; Homo sapiens (Human); CVCL_A763
• In Vitro Model: NCI-H2228 cells; Lung; Homo sapiens (Human); CVCL_1543
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Cell viability assay; Toxilight cytotoxicity assay
• Mechanism Description: miR-100-5p confers resistance to ALk tyrosine kinase inhibitors Crizotinib and Lorlatinib in EML4-ALk positive NSCLC.

References

• Ref 1: miR-100-5p confers resistance to ALK tyrosine kinase inhibitors Crizotinib and Lorlatinib in EML4-ALK positive NSCLC. Biochem Biophys Res Commun. 2019 Apr 2;511(2):260-265. doi: 10.1016/j.bbrc.2019.02.016. Epub 2019 Feb 18.
• Ref 2: Identification of different ALK mutations in a pair of neuroblastoma cell lines established at diagnosis and relapse. Oncotarget. 2016 Dec 27;7(52):87301-87311. doi: 10.18632/oncotarget.13541.