Drug Information

Drug (ID: DG01004) and It's Reported Resistant Information

• Name: Pomalidomide
• Synonyms: Pomalidomide; 19171-19-8; Actimid; 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; CC-4047; Pomalyst; Imnovid; 4-Amino-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione; 4-Aminothalidomide; 3-Amino-N-(2,6-dioxo-3-piperidyl)phthalimide; CC 4047; IMiD 3; Pomalidomide (CC-4047); 1H-Isoindole-1,3(2H)-dione, 4-amino-2-(2,6-dioxo-3-piperidinyl)-; (S)-pomalidomide; 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione; IMID-3; CHEBI:72690; MFCD12756407; 4-amino-2-(2,6-dioxo-3-piperidinyl)-1H-Isoindole-1,3(2H)-dione; 4-amino-2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione; 4-amino-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione; Pomalidomide [USAN:INN]; HSDB 8222; Pomalyst (TN); CC4047; Pomalidomide- Bio-X; IMiD1; 3-amino-N-(2,6-dioxo-3-piperidyl)phthalamide; 3-Aminophthalimidoglutarimide; MLS006011261; CHEMBL43452; SCHEMBL369172; GTPL7348; Pomalidomide (JAN/USAN/INN); 3-aminio-phthalimido-glutarimide; SCHEMBL19250920; BDBM65456; IMID-4047; CDC-394; DTXSID40893458; Pomalidomide, >=98% (HPLC); s-3-amino-phthalimido-glutarimide; HMS3655G05; HMS3744K07; Actimid; ; ; CC 4047; ; ; IMiD3; BCP02890; BCP09107; CFC83849; AM9718; NSC767909; NSC775351; s1567; AKOS013400288; CCG-264684; CS-0165; DB08910; LS40023; NSC-767909; NSC-775351; SB16552; NCGC00346551-01; NCGC00346551-03; AC-26970; AS-17905; BP-24477; BP164278; DA-21486; HY-10984; SMR004703012; SY054807; BCP0726000263; FT-0697903; P2074; SW218099-2; V2447; D08976; AB01565777_02; 171P198; SR-01000941573; J-012392; J-514302; Phthalimide, 3-amino-N-(2,6-dioxo-3-piperidyl)-; Q7227206; SR-01000941573-1; 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline; 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione; 4-Amino-2-(2,6-dioxo-3-piperidinyl)isoindole-1,3-dione; 4-Amino-2-(2,6-dioxo-3-piperidyl) isoindoline -1,3-dione; Lipopolysaccharides from Escherichia coli 055:B5 pound>>Lipopolysaccharides pound>> lipoglycans pound>>endotoxins
• Indication:
  In total 1 Indication(s)
  Systemic sclerosis [ICD-11: 4A42]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (2 diseases)
  Epstein-Barr virus [ICD-11: XN0R2]; [2]
  Multiple myeloma [ICD-11: 2A83]; [1]
  Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
  Myeloproliferative neoplasm [ICD-11: 2A22]; [3]
• Target: Angiogenesis/myeloma cell growth (AMCG); NOUNIPROTAC; [1]
• Formula: C13H11N3O4
• IsoSMILES: C1CC(=O)NC(=O)C1N2C(=O)C3=C(C2=O)C(=CC=C3)N
• InChI: 1S/C13H11N3O4/c14-7-3-1-2-6-10(7)13(20)16(12(6)19)8-4-5-9(17)15-11(8)18/h1-3,8H,4-5,14H2,(H,15,17,18)
• InChIKey: UVSMNLNDYGZFPF-UHFFFAOYSA-N
• PubChem CID: 134780
• ChEBI ID: CHEBI:72690
• TTD Drug ID: D0A3ZU
• VARIDT ID: DR00151
• INTEDE ID: DR1313
• DrugBank ID: DB08910

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

Myeloproliferative neoplasm [ICD-11: 2A22]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Protein cereblon (CRBN) [3]

• Resistant Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Molecule Alteration: Nonsense; p.Q100* (c.298C>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bone marrow; N.A.
• Experiment for Molecule Alteration: DNA sequencing assay
• Mechanism Description: The nonsense p.Q100* (c.298C>T) in gene CRBN cause the resistance of Pomalidomide by unusual activation of pro-survival pathway.

Key Molecule: Protein cereblon (CRBN) [3]

• Resistant Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Molecule Alteration: Missense mutation; p.R283K (c.848G>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bone marrow; N.A.
• Experiment for Molecule Alteration: DNA sequencing assay
• Mechanism Description: The missense mutation p.R283K (c.848G>A) in gene CRBN cause the resistance of Pomalidomide by unusual activation of pro-survival pathway

Multiple myeloma [ICD-11: 2A83]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Protein cereblon (CRBN) [1]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Mutation; .
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: AsPC-1 cells; Pancreas; Homo sapiens (Human); CVCL_0152
• Experiment for Molecule Alteration: Whole-genome sequencing assay
• Mechanism Description: Multiple cereblon genetic changes are associated with acquired resistance to lenalidomide or pomalidomide in multiple myeloma.

ICD-X: Extension Codes

Epstein-Barr virus [ICD-11: XN0R2]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Protein cereblon (CRBN) [2]

• Resistant Disease: Epstein-barr virus (ebv) infection [ICD-11: XN0R2]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Daudi cells; Peripheral blood; Homo sapiens (Human); CVCL_0008
• In Vitro Model: Namalwa cells; Lymphoid; Homo sapiens (Human); CVCL_0067
• In Vitro Model: EBV-negative BL41 cells; Lymphoid; Homo sapiens (Human); N.A.
• In Vitro Model: EBV-positive BL41 cells; Lymphoid; Homo sapiens (Human); N.A.
• In Vitro Model: BCBL-1 cells; Peritoneal fluid; Homo sapiens (Human); CVCL_0165
• In Vitro Model: JSC-1 cells; Lymphoid; Homo sapiens (Human); CVCL_3728
• In Vitro Model: PBMCs cells; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: BC-2 cells; N.A.; Homo sapiens (Human); CVCL_1856
• In Vitro Model: HUVEC-C cells; N.A.; Homo sapiens (Human); CVCL_2959
• In Vitro Model: U937 cells; Blood; Homo sapiens (Human); CVCL_0007
• Experiment for Molecule Alteration: Flow cytometry; Immunoblotting assay; Cytokine/Chemokine analysis; RT-qPCR; Chromatin immunoprecipitation assay
• Experiment for Drug Resistance: Cell activation assay
• Mechanism Description: Pom increased B7-2/CD86 mRNA, protein, and surface expression in EBV-infected cells but this was virtually eliminated in EBV-infected cells made resistant to Pom-induced cytostatic effects. This indicates that Pom initiates the upregulation of these markers by interacting with its target, cereblon. Interestingly, Pom increased the proinflammatory cytokines IP-10 and MIP-1alpha/beta in EBV infected cells, supporting a possible role for the phosphoinositide 3-kinase (PI3K)/AKT pathway in Pom's effects. Idelalisib, an inhibitor of the delta subunit of PI3 Kinase, blocked AKT-Ser phosphorylation and Pom-induced B7-2 surface expression. PU.1 is a downstream target for AKT that is expressed in EBV-infected cells. Pom treatment led to an increase in PU.1 binding to the B7-2 promoter based on ChIP analysis. Thus, our data indicates Pom acts through cereblon leading to degradation of Ikaros and activation of the PI3K/AKT/PU.1 pathway resulting in upregulation of B7-2 mRNA and protein expression. The increased immune recognition in addition to the increases in proinflammatory cytokines upon Pom treatment suggests Pom may be useful in the treatment of EBV-positive lymphomas.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: DNA-binding protein Ikaros (IKZF1) [2]

• Sensitive Disease: Epstein-barr virus (ebv) infection [ICD-11: XN0R2]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: Daudi cells; Peripheral blood; Homo sapiens (Human); CVCL_0008
• In Vitro Model: Namalwa cells; Lymphoid; Homo sapiens (Human); CVCL_0067
• In Vitro Model: EBV-negative BL41 cells; Lymphoid; Homo sapiens (Human); N.A.
• In Vitro Model: EBV-positive BL41 cells; Lymphoid; Homo sapiens (Human); N.A.
• In Vitro Model: BCBL-1 cells; Peritoneal fluid; Homo sapiens (Human); CVCL_0165
• In Vitro Model: JSC-1 cells; Lymphoid; Homo sapiens (Human); CVCL_3728
• In Vitro Model: PBMCs cells; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: BC-2 cells; N.A.; Homo sapiens (Human); CVCL_1856
• In Vitro Model: HUVEC-C cells; N.A.; Homo sapiens (Human); CVCL_2959
• In Vitro Model: U937 cells; Blood; Homo sapiens (Human); CVCL_0007
• Experiment for Molecule Alteration: Flow cytometry; Immunoblotting assay; Cytokine/Chemokine analysis; RT-qPCR; Chromatin immunoprecipitation assay
• Experiment for Drug Resistance: Cell activation assay
• Mechanism Description: Pom increased B7-2/CD86 mRNA, protein, and surface expression in EBV-infected cells but this was virtually eliminated in EBV-infected cells made resistant to Pom-induced cytostatic effects. This indicates that Pom initiates the upregulation of these markers by interacting with its target, cereblon. Interestingly, Pom increased the proinflammatory cytokines IP-10 and MIP-1alpha/beta in EBV infected cells, supporting a possible role for the phosphoinositide 3-kinase (PI3K)/AKT pathway in Pom's effects. Idelalisib, an inhibitor of the delta subunit of PI3 Kinase, blocked AKT-Ser phosphorylation and Pom-induced B7-2 surface expression. PU.1 is a downstream target for AKT that is expressed in EBV-infected cells. Pom treatment led to an increase in PU.1 binding to the B7-2 promoter based on ChIP analysis. Thus, our data indicates Pom acts through cereblon leading to degradation of Ikaros and activation of the PI3K/AKT/PU.1 pathway resulting in upregulation of B7-2 mRNA and protein expression. The increased immune recognition in addition to the increases in proinflammatory cytokines upon Pom treatment suggests Pom may be useful in the treatment of EBV-positive lymphomas.

Key Molecule: AKT serine/threonine kinase (AKT) [2]

• Sensitive Disease: Epstein-barr virus (ebv) infection [ICD-11: XN0R2]
• Molecule Alteration: Phosphorylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: Daudi cells; Peripheral blood; Homo sapiens (Human); CVCL_0008
• In Vitro Model: Namalwa cells; Lymphoid; Homo sapiens (Human); CVCL_0067
• In Vitro Model: EBV-negative BL41 cells; Lymphoid; Homo sapiens (Human); N.A.
• In Vitro Model: EBV-positive BL41 cells; Lymphoid; Homo sapiens (Human); N.A.
• In Vitro Model: BCBL-1 cells; Peritoneal fluid; Homo sapiens (Human); CVCL_0165
• In Vitro Model: JSC-1 cells; Lymphoid; Homo sapiens (Human); CVCL_3728
• In Vitro Model: PBMCs cells; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: BC-2 cells; N.A.; Homo sapiens (Human); CVCL_1856
• In Vitro Model: HUVEC-C cells; N.A.; Homo sapiens (Human); CVCL_2959
• In Vitro Model: U937 cells; Blood; Homo sapiens (Human); CVCL_0007
• Experiment for Molecule Alteration: Flow cytometry; Immunoblotting assay; Cytokine/Chemokine analysis; RT-qPCR; Chromatin immunoprecipitation assay
• Experiment for Drug Resistance: Cell activation assay
• Mechanism Description: Pom increased B7-2/CD86 mRNA, protein, and surface expression in EBV-infected cells but this was virtually eliminated in EBV-infected cells made resistant to Pom-induced cytostatic effects. This indicates that Pom initiates the upregulation of these markers by interacting with its target, cereblon. Interestingly, Pom increased the proinflammatory cytokines IP-10 and MIP-1alpha/beta in EBV infected cells, supporting a possible role for the phosphoinositide 3-kinase (PI3K)/AKT pathway in Pom's effects. Idelalisib, an inhibitor of the delta subunit of PI3 Kinase, blocked AKT-Ser phosphorylation and Pom-induced B7-2 surface expression. PU.1 is a downstream target for AKT that is expressed in EBV-infected cells. Pom treatment led to an increase in PU.1 binding to the B7-2 promoter based on ChIP analysis. Thus, our data indicates Pom acts through cereblon leading to degradation of Ikaros and activation of the PI3K/AKT/PU.1 pathway resulting in upregulation of B7-2 mRNA and protein expression. The increased immune recognition in addition to the increases in proinflammatory cytokines upon Pom treatment suggests Pom may be useful in the treatment of EBV-positive lymphomas.

Key Molecule: Transcription factor PU.1 (SPI1) [2]

• Sensitive Disease: Epstein-barr virus (ebv) infection [ICD-11: XN0R2]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: Daudi cells; Peripheral blood; Homo sapiens (Human); CVCL_0008
• In Vitro Model: Namalwa cells; Lymphoid; Homo sapiens (Human); CVCL_0067
• In Vitro Model: EBV-negative BL41 cells; Lymphoid; Homo sapiens (Human); N.A.
• In Vitro Model: EBV-positive BL41 cells; Lymphoid; Homo sapiens (Human); N.A.
• In Vitro Model: BCBL-1 cells; Peritoneal fluid; Homo sapiens (Human); CVCL_0165
• In Vitro Model: JSC-1 cells; Lymphoid; Homo sapiens (Human); CVCL_3728
• In Vitro Model: PBMCs cells; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: BC-2 cells; N.A.; Homo sapiens (Human); CVCL_1856
• In Vitro Model: HUVEC-C cells; N.A.; Homo sapiens (Human); CVCL_2959
• In Vitro Model: U937 cells; Blood; Homo sapiens (Human); CVCL_0007
• Experiment for Molecule Alteration: Flow cytometry; Immunoblotting assay; Cytokine/Chemokine analysis; RT-qPCR; Chromatin immunoprecipitation assay
• Experiment for Drug Resistance: Cell activation assay
• Mechanism Description: Pom increased B7-2/CD86 mRNA, protein, and surface expression in EBV-infected cells but this was virtually eliminated in EBV-infected cells made resistant to Pom-induced cytostatic effects. This indicates that Pom initiates the upregulation of these markers by interacting with its target, cereblon. Interestingly, Pom increased the proinflammatory cytokines IP-10 and MIP-1alpha/beta in EBV infected cells, supporting a possible role for the phosphoinositide 3-kinase (PI3K)/AKT pathway in Pom's effects. Idelalisib, an inhibitor of the delta subunit of PI3 Kinase, blocked AKT-Ser phosphorylation and Pom-induced B7-2 surface expression. PU.1 is a downstream target for AKT that is expressed in EBV-infected cells. Pom treatment led to an increase in PU.1 binding to the B7-2 promoter based on ChIP analysis. Thus, our data indicates Pom acts through cereblon leading to degradation of Ikaros and activation of the PI3K/AKT/PU.1 pathway resulting in upregulation of B7-2 mRNA and protein expression. The increased immune recognition in addition to the increases in proinflammatory cytokines upon Pom treatment suggests Pom may be useful in the treatment of EBV-positive lymphomas.

References

• Ref 1: Multiple cereblon genetic changes are associated with acquired resistance to lenalidomide or pomalidomide in multiple myeloma .Blood. 2021 Jan 14;137(2):232-237. doi: 10.1182/blood.2020007081. 10.1182/blood.2020007081
• Ref 2: Mechanism and therapeutic implications of pomalidomide-induced immune surface marker upregulation in EBV-positive lymphomas. Sci Rep. 2023 Jul 18;13(1):11596.
• Ref 3: Extramedullary myeloma whole genome sequencing reveals novel mutations in Cereblon, proteasome subunit G2 and the glucocorticoid receptor in multi drug resistant disease. Br J Haematol. 2013 Jun;161(5):748-51. doi: 10.1111/bjh.12291. Epub 2013 Mar 11.