Drug Information

Drug (ID: DG02031) and It's Reported Resistant Information

• Name: Pimozide
• Synonyms: Antalon; Neoperidole; Opiran; Orap; Pimozida; Pimozidum; Primozida; ASTA Medica Brand of Pimozide; Janssen Brand of Pimozide;Orap forte; Pharmascience Brand of Pimozide; P 1793; R 6238; McN-JR 6238; Orap (TN); Pimozida [INN-Spanish]; Pimozidum [INN-Latin]; Primozida [INN-Spanish]; R-6238; McN-JR-6238; Pimozide (JAN/USP/INN); Pimozide [USAN:INN:BAN:JAN]; 1-(1-(4,4-Bis(p-fluorophenyl)butyl)-4-piperidyl)-2-benzimidazolinone; 1-(4,4-Bis(p-fluorophenyl)butyl)-4-(2-oxo-1-benzimidazolinyl)piperidine; 1-[1-[4,4-Bis(4-fluorophenyl)butyl]-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one; 1-[1-[4,4-Bis(p-fluorophenyl)butyl]-4-piperidyl]-2-benzimidazolinone; 1-[1-[4,4-bis(4-Fluorophenyl)butyl]-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one; 1-[4,4-Bis(p-fluorophenyl)butyl]-4-(2-oxo-1-benzimidazolinyl)piperidine; 1-{1-[4,4-bis(4-fluorophenyl)butyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one; 1-{1-[4,4-bis(4-fluorophenyl)butyl]piperidin-4-yl}-2,3-dihydro-1H-1,3-benzodiazol-2-one; 3-[1-[4,4-bis(4-fluorophenyl)butyl]piperidin-4-yl]-1H-benzimidazol-2-one
• Indication:
  In total 1 Indication(s)
  Schizophrenia [ICD-11: 6A20]; Approved
• Drug Resistance Disease(s):
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
  Brain cancer [ICD-11: 2A00]; [1]
• Target: Dopamine D2 receptor (D2R); DRD2_HUMAN
• Formula: C28H29F2N3O
• IsoSMILES: C1CN(CCC1N2C3=CC=CC=C3NC2=O)CCCC(C4=CC=C(C=C4)F)C5=CC=C(C=C5)F
• InChI: InChI=1S/C28H29F2N3O/c29-22-11-7-20(8-12-22)25(21-9-13-23(30)14-10-21)4-3-17-32-18-15-24(16-19-32)33-27-6-2-1-5-26(27)31-28(33)34/h1-2,5-14,24-25H,3-4,15-19H2,(H,31,34)
• InChIKey: YVUQSNJEYSNKRX-UHFFFAOYSA-N
• PubChem CID: 16362
• ChEBI ID: CHEBI:8212
• TTD Drug ID: D00KHM
• VARIDT ID: DR00484
• INTEDE ID: DR1291

Type(s) of Resistant Mechanism of This Drug

  MRAP: Metabolic Reprogramming via Altered Pathways

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

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Sterol regulatory element-binding protein 1 (SREBP-1) [1]

• Metabolic Type: Glutamine metabolism
• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: LN cells; Brain; Homo sapiens (Human); N.A.
• In Vitro Model: T98 cells; Brain; Homo sapiens (Human); CVCL_B368
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U373 cells; Brain; Homo sapiens (Human); CVCL_2219
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: LC-MS
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: These elevations are driven by SREBP-1, which we find upregulates the expression of ASCT2, a key glutamine transporter. Glutamine, in turn, intensifies SREBP-1 activation through the release of ammonia, creating a feedforward loop that amplifies both glutamine metabolism and lipid synthesis, leading to drug resistance. Disrupting this loop via pharmacological targeting of ASCT2 or glutaminase, in combination with pimozide, induces remarkable mitochondrial damage and oxidative stress, leading to GBM cell death in vitro and in vivo.

Key Molecule: Alanine-serine-cysteine transporter 2 (ASCT2) [1]

• Metabolic Type: Glutamine metabolism
• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: LN cells; Brain; Homo sapiens (Human); N.A.
• In Vitro Model: T98 cells; Brain; Homo sapiens (Human); CVCL_B368
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U373 cells; Brain; Homo sapiens (Human); CVCL_2219
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: LC-MS
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: These elevations are driven by SREBP-1, which we find upregulates the expression of ASCT2, a key glutamine transporter. Glutamine, in turn, intensifies SREBP-1 activation through the release of ammonia, creating a feedforward loop that amplifies both glutamine metabolism and lipid synthesis, leading to drug resistance. Disrupting this loop via pharmacological targeting of ASCT2 or glutaminase, in combination with pimozide, induces remarkable mitochondrial damage and oxidative stress, leading to GBM cell death in vitro and in vivo.

References

• Ref 1: Combinatorial targeting of glutamine metabolism and lysosomal-based lipid metabolism effectively suppresses glioblastoma. Cell Rep Med. 2024 Sep 17;5(9):101706.