Drug Information

Drug (ID: DG01596) and It's Reported Resistant Information

• Name: APR-246
• Synonyms: APR-246; 5291-32-7; PRIMA-1MET; Eprenetapopt; APR 246; 2-(Hydroxymethyl)-2-(methoxymethyl)-1-azabicyclo[2.2.2]octan-3-one; 2-(Hydroxymethyl)-2-(methoxymethyl)quinuclidin-3-one; Prima 1MET; Eprenetapopt [USAN]; MLS006010767; APR246; SCHEMBL2228161; 3-Quinuclidinone, 2-(hydroxymethyl)-2-(methoxymethyl)-; CHEMBL3186011; SCHEMBL21636035; PRIMA-1MET(APR-246); APR-246 (PRIMA-1MET); BCP20294; EX-A2772; MFCD20620963; NSC791496; s7724; WHO 11387; 1-Azabicyclo(2.2.2)octan-3-one, 2-(hydroxymethyl)-2-(methoxymethyl)-; AKOS024457764; CCG-266578; CS-7614; DB11684; NSC-791496; SB19737; NCGC00346881-01; AC-32964; AS-72033; BA176962; HY-19980; SMR004701457; A901731; Q27294965; 2-hydroxymethyl-2-methoxymethyl-1-azabicyclo[2.2.2]octan-3-one
• Indication:
  In total 1 Indication(s)
  Discovery agent [ICD-11: N.A.]; Phase 2; [1]
• Target: Bromodomain-containing protein 2 (BRD2); BRD2_HUMAN; [2]
• Target: Bromodomain-containing protein 3 (BRD3); BRD3_HUMAN; [2]
• Target: Bromodomain-containing protein 4 (BRD4); BRD4_HUMAN; [2]
• Formula: 3
• IsoSMILES: COCC1(C(=O)C2CCN1CC2)CO
• InChI: InChI=1S/C10H17NO3/c1-14-7-10(6-12)9(13)8-2-4-11(10)5-3-8/h8,12H,2-7H2,1H3
• InChIKey: BGBNULCRKBVAKL-UHFFFAOYSA-N
• PubChem CID: 52918385
• TTD Drug ID: D0WU1S
• DrugBank ID: DB11684

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  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 Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Cellular tumor antigen p53 (TP53) [2]

• Sensitive Disease: Acute myeloid leukemia [ICD-11: 2A60.0]
• Molecule Alteration: Missense mutation; p.V173M (c.517G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Blood; N.A.
• Experiment for Molecule Alteration: TP53 gene mutation status analysis
• Experiment for Drug Resistance: Pharmacokinetic Analysis
• Mechanism Description: The missense mutation p.V173M (c.517G>A) in gene TP53 cause the sensitivity of APR-246 by unusual activation of pro-survival pathway

Lung cancer [ICD-11: 2C25]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Cellular tumor antigen p53 (TP53) [1]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Missense mutation; p.S241F (c.722C>T)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: DMS456 cells; Lung; Homo sapiens (Human); CVCL_0B92
• In Vivo Model: Nude male NMRI mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The missense mutation p.S241F (c.722C>T) in gene TP53 cause the sensitivity of APR-246 by aberration of the drug's therapeutic target

Key Molecule: Cellular tumor antigen p53 (TP53) [1]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Missense mutation; p.R273L (c.818G>T)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: DMS456 cells; Lung; Homo sapiens (Human); CVCL_0B92
• In Vivo Model: Nude male NMRI mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The missense mutation p.R273L (c.818G>T) in gene TP53 cause the sensitivity of APR-246 by aberration of the drug's therapeutic target

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: NFE2-related factor 2 (NRF2) [3]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: NRF2/SLC7A11/GSH signalling pathway; Regulation; N.A.
• In Vitro Model: H460/CIS cells; Lung; Homo sapiens (Human); CVCL_A9CH
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: MTT assay; Colony formation assay; Apoptosis assay
• Mechanism Description: In this study, we identify NADPH metabolism and reactive oxygen species (ROS) levels as the main causes accounting for cisplatin resistance. Based on a small panel consisting of common chemotherapy drugs or compounds, APR-246 is proved to be an effective compound targeting cisplatin-resistant NSCLC cells. APR-246 specially inhibits proliferation and colony formation of cisplatin-resistant cells. In details, APR-246 can significantly cause G0/G1 accumulation and S phase arrest of cisplatin resistant cells and gives rise to severe mitochondria dysfunction as well as elevated apoptosis. Further study proves that it is the aberrant ROS levels as well as NRF2/SLC7A11/GSH axis dysfunction accounting for the specific antitumor effects of APR-246. Scavenging ROS with N-acetylcysteine (NAC) disrupts the inhibitory effect of APR-246 on cisplatin-resistant cells.

References

• Ref 1: PRIMA-1Met/APR-246 induces apoptosis and tumor growth delay in small cell lung cancer expressing mutant p53Clin Cancer Res. 2011 May 1;17(9):2830-41. doi: 10.1158/1078-0432.CCR-10-3168. Epub 2011 Mar 17.
• Ref 2: Targeting p53 in vivo: a first-in-human study with p53-targeting compound APR-246 in refractory hematologic malignancies and prostate cancerJ Clin Oncol. 2012 Oct 10;30(29):3633-9. doi: 10.1200/JCO.2011.40.7783. Epub 2012 Sep 10.
• Ref 3: Aberrant ROS Served as an Acquired Vulnerability of Cisplatin-Resistant Lung Cancer. Oxid Med Cell Longev. 2022 Jun 20;2022:1112987.