Drug Information

Drug (ID: DG00553) and It's Reported Resistant Information

• Name: Pexidartinib
• Synonyms: Pexidartinib; 1029044-16-3; PLX3397; PLX-3397; Pexidartinib (PLX3397); Turalio; UNII-6783M2LV5X; CML-261; 5-((5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-N-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyridin-2-amine; CHEMBL3813873; 6783M2LV5X; 5-[(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-N-[[6-(trifluoromethyl)pyridin-3-yl]methyl]pyridin-2-amine; 5-[(5-Chloro-1h-Pyrrolo[2,3-B]pyridin-3-Yl)methyl]-N-{[6-(Trifluoromethyl)pyridin-3-Yl]methyl}pyridin-2-Amine; 5-({5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl}methyl)-N-{[6-(trifluoromethyl)pyridin-3-yl]methyl}pyridin-2-amine; Pexidartinib [INN]; pexidartinibum; Pexidartinib [USAN]; Pexidartinib(PLX3397); Pexidartinib (USAN/INN); Pexidartinib [USAN:INN]; GTPL8710; SCHEMBL1267310; EX-A589; CHEBI:145373; HMS3886D19; BCP15183; PLX 3397; BDBM50177716; MFCD28900745; NSC789300; NSC793434; NSC800843; s7818; AKOS026750359; ZINC115705166; CCG-268862; DB12978; NSC-789300; NSC-793434; NSC-800843; SB19178; NCGC00480774-01; NCGC00480774-06; 3-Pyridinemethanamine, N-(5-((5-chloro-1H-pyrrolo(2,3-b)pyridin-3-yl)methyl)-2-pyridinyl)-6-(trifluoromethyl)-; AC-30300; AS-74915; DA-48267; HY-16749; B5854; FT-0699505; PLX 3397;PLX3397;PL-X3397; D11270; A856116; J-690008; Q25100640; B0084-470807; 2(S)-Amino-3-(4-{2-amino-6-[2,2,2-trifluoro-1-(3'-fluoro-biphenyl-4-yl)-ethoxy]-pyrimidin-4-yl}-phenyl)-propionic acid hydrochloride; 5-[(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-N-[[6-(trifluoromethyl)-3-pyridyl]methyl]pyridin-2-amine; N-[5-[(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-2-pyridinyl]-6-(trifluoromethyl)-3-pyridinemethanamine; N-[5-[(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-2-pyridinyl]-6-(trifluoromethyl)-3-pyridinemethanamine;Pexidartinib
• Indication:
  In total 5 Indication(s)
  Alzheimer disease [ICD-11: 8A20]; Approved; [1]
  Neurofibromatosis type 1 [ICD-11: LD2D]; Approved; [1]
  Pigmented villonodular synovitis [ICD-11: FA2Z]; Approved; [1]
  Tenosynovial giant cell tumour [ICD-11: 2F7B]; Approved; [1]
  Tenosynovial giant cell tumour [ICD-11: 2F7B]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (2 diseases)
  Acute myeloid leukemia [ICD-11: 2A60]; [1]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; [2]
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
  Acute myeloid leukemia [ICD-11: 2A60]; [1]
• Target: Fms-like tyrosine kinase 3 (FLT-3); FLT3_HUMAN; [1]
• Target: Macrophage colony-stimulating factor 1 receptor (CSF1R); CSF1R_HUMAN; [1]
• Target: Tyrosine-protein kinase Kit (KIT); KIT_HUMAN; [1]
• Formula: C20H15ClF3N5
• IsoSMILES: C1=CC(=NC=C1CC2=CNC3=C2C=C(C=N3)Cl)NCC4=CN=C(C=C4)C(F)(F)F
• InChI: 1S/C20H15ClF3N5/c21-15-6-16-14(10-28-19(16)29-11-15)5-12-2-4-18(26-7-12)27-9-13-1-3-17(25-8-13)20(22,23)24/h1-4,6-8,10-11H,5,9H2,(H,26,27)(H,28,29)
• InChIKey: JGWRKYUXBBNENE-UHFFFAOYSA-N
• PubChem CID: 25151352
• ChEBI ID: CHEBI:145373
• TTD Drug ID: D09TAB
• INTEDE ID: DR1269
• DrugBank ID: DB12978

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

Drug Resistance Data Categorized by Their Corresponding Diseases

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

Solid tumour/cancer [ICD-11: 2A00-2F9Z]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [2]

• Molecule Alteration: Missense mutation; p.D835Y (c.2503G>T)
• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: MV4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• In Vivo Model: (Nu/Nu) male MV4; 11 xenograft mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter-Glo assay; ATPlite 1step luminescence assay

Key Molecule: Receptor-type tyrosine-protein kinase FLT3 (FLT3) [2]

• Molecule Alteration: Missense mutation; p.D835V (c.2504A>T)
• Resistant Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: MV4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• In Vivo Model: (Nu/Nu) male MV4; 11 xenograft mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter-Glo assay; ATPlite 1step luminescence assay

Acute myeloid leukemia [ICD-11: 2A60]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

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

• Molecule Alteration: Missense mutation; p.D835Y
• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MOLM-14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The pexidartinib IC50 values of cells with D835Y mutation was 206, the pexidartinib IC50 value of cells without mutation was 1.

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

• Molecule Alteration: Missense mutation; p.D835V
• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MOLM-14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The pexidartinib IC50 values of cells with D835V mutation was 320, the pexidartinib IC50 value of cells without mutation was 1.

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

• Molecule Alteration: Missense mutation; p.D835I
• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MOLM-14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The pexidartinib IC50 values of cells with D835I mutation was 1937, the pexidartinib IC50 value of cells without mutation was 1.

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

• Molecule Alteration: Missense mutation; p.D835F
• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MOLM-14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The pexidartinib IC50 values of cells with D835F mutation was 415, the pexidartinib IC50 value of cells without mutation was 1.

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

• Molecule Alteration: Frameshift mutation; p.D835Del
• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MOLM-14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The pexidartinib IC50 values of cells with D835Del mutation was 121, the pexidartinib IC50 value of cells without mutation was 1.

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

• Molecule Alteration: Missense mutation; p.F691L
• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: MOLM-14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• In Vitro Model: MV4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The multiple mutations that can confer resistance to quizartinib and pexidartinib. The gatekeeper mutation F691L was the most common mutation in all protocols involving quizartinib; it was rather frequent even with pexidartinib alone.

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

• Molecule Alteration: Missense mutation; p.F691L
• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: MOLM-14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• In Vitro Model: MV4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The multiple mutations that can confer resistance to quizartinib and pexidartinib. The gatekeeper mutation F691L was the most common mutation in all protocols involving quizartinib; it was rather frequent even with pexidartinib alone.

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

• Molecule Alteration: Missense mutation; p.F691L
• Resistant Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: U87-MG cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: Ishikawa cells; Endometrium; Homo sapiens (Human); CVCL_2529
• Mechanism Description: The gatekeeper mutation F691L confers resistance to specific FLT3 inhibitors such as quizartinib, but pexidartinib is much less resistance to this mutation. Pexidartinib alone is however sensitive to many other resistance mutations.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

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

• Molecule Alteration: Missense mutation+Internal tandem duplication mutation; p.F691L+ FLT3-ITD
• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: U87-MG cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: Ishikawa cells; Endometrium; Homo sapiens (Human); CVCL_2529
• Mechanism Description: The gatekeeper mutation F691L confers resistance to specific FLT3 inhibitors such as quizartinib, but pexidartinib is much less resistance to this mutation. Pexidartinib alone is however sensitive to many other resistance mutations.

References

• Ref 1: Combating drug resistance in acute myeloid leukaemia by drug rotations: the effects of quizartinib and pexidartinib .Cancer Cell Int. 2021 Apr 8;21(1):198. doi: 10.1186/s12935-021-01856-5. 10.1186/s12935-021-01856-5
• Ref 2: Characterizing and Overriding the Structural Mechanism of the Quizartinib-Resistant FLT3 "Gatekeeper" F691L Mutation with PLX3397Cancer Discov. 2015 Jun;5(6):668-79. doi: 10.1158/2159-8290.CD-15-0060. Epub 2015 Apr 6.