Drug Information

Drug (ID: DG00429) and It's Reported Resistant Information

• Name: Lestaurtinib
• Synonyms: A 1544750; CEP 701; KT 5555; KT5555; SP 924; CEP-701; KT-5555; SPM-924; Lestaurtinib (USAN/INN)
• Indication:
  In total 3 Indication(s)
  Acute myeloid leukaemia [ICD-11: 2A60]; Approved (orphan drug); [1]
  Malignant haematopoietic neoplasm [ICD-11: 2B33]; Phase 3; [1]
  Psoriasis [ICD-11: EA90]; Phase 2/3; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
  Acute myeloid leukemia [ICD-11: 2A60]; [1]
• Target: Fms-like tyrosine kinase 3 (FLT-3); FLT3_HUMAN; [1]
• Formula: C26H21N3O4
• IsoSMILES: C[C@@]12[C@](C[C@@H](O1)N3C4=CC=CC=C4C5=C6C(=C7C8=CC=CC=C8N2C7=C53)CNC6=O)(CO)O
• InChI: 1S/C26H21N3O4/c1-25-26(32,12-30)10-18(33-25)28-16-8-4-2-6-13(16)20-21-15(11-27-24(21)31)19-14-7-3-5-9-17(14)29(25)23(19)22(20)28/h2-9,18,30,32H,10-12H2,1H3,(H,27,31)/t18-,25+,26+/m1/s1
• InChIKey: UIARLYUEJFELEN-LROUJFHJSA-N
• PubChem CID: 126565
• ChEBI ID: CHEBI:91471
• TTD Drug ID: D0V9WF
• DrugBank ID: DB06469

Type(s) of Resistant Mechanism of This Drug

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

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

Acute myeloid leukemia [ICD-11: 2A60]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [1]

• Molecule Alteration: Missense mutation; p.D835E
• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Whole-exome sequencing assay
• Mechanism Description: Among the mutational patterns underlying relapse, the authors detected the acquisition of proliferative advantage by signaling activation (PTPN11 and FLT3-TkD mutations) and the increased resistance to apoptosis (hyperactivation of TYk2). Moreover, FLT3/TkD and ITD being subclonal mutations is one of the plausible explanations of unsatisfying results of FLT3 inhibitors, along with many others concerning inadequate in vivo inhibition of the target, development of secondary pharmacokinetic or pharmacodynamic resistance, and influence of FLT3-mutant allelic burden.

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [1]

• Molecule Alteration: Chromosome variation; FLT3/ITD (Internal tandem duplication )
• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bone marrow; Blood; Homo sapiens (Human); N.A.
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Whole-exome sequencing assay
• Mechanism Description: Among the mutational patterns underlying relapse, the authors detected the acquisition of proliferative advantage by signaling activation (PTPN11 and FLT3-TkD mutations) and the increased resistance to apoptosis (hyperactivation of TYk2). Moreover, FLT3/TkD and ITD being subclonal mutations is one of the plausible explanations of unsatisfying results of FLT3 inhibitors, along with many others concerning inadequate in vivo inhibition of the target, development of secondary pharmacokinetic or pharmacodynamic resistance, and influence of FLT3-mutant allelic burden.

References

• Ref 1: FLT3 Inhibitors in Acute Myeloid Leukemia: Current Status and Future Directions. Mol Cancer Ther. 2017 Jun;16(6):991-1001. doi: 10.1158/1535-7163.MCT-16-0876.