Drug Information

Drug (ID: DG01270) and It's Reported Resistant Information

• Name: Copanlisib
• Synonyms: Copanlisib; 1032568-63-0; BAY 80-6946; Aliqopa; BAY-80-6946; BAY80-6946; UNII-WI6V529FZ9; BAY 80-6946 (Copanlisib); 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide; WI6V529FZ9; Copanlisib (BAY 80-6946); 2-Amino-N-[2,3-dihydro-7-methoxy-8-[3-(4-morpholinyl)propoxy]imidazo[1,2-c]quinazolin-5-yl]-5-pyrimidinecarboxamide; 2-amino-N-(7-methoxy-8-(3-morpholinopropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide; 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydro-1H-imidazo[1,2-c]quinazolin-5-ylidene]pyrimidine-5-carboxamide; copanlisibum; Copanlisib tris-HCl; Copanlisib (USAN/INN); Copanlisib [USAN:INN]; GTPL7875; SCHEMBL1655478; BAY 80-6946; Copanlisib; BAY-80-6946 tris-HCl; Copanlisib; BAY-80-6946; CHEMBL3218576; SCHEMBL13084037; DTXSID00145728; CHEBI:173077; C23H28N8O4; BCP04754; EX-A2005; 2253AH; BDBM50204093; MFCD18633201; NSC760443; NSC800076; NSC809693; NSC816437; s2802; ZINC68247389; AKOS025290222; BAY-806946; CS-0741; DB12483; NSC-760443; NSC-800076; NSC-809693; NSC-816437; PB22956; VS-0128; NCGC00346457-01; NCGC00346457-02; NCGC00346457-04; 2-amino-N-(7-methoxy-8-(3-morpholinopropoxy)-2,3-dihydroimidazo(1,2-c)quinazolin-4-yl)pyrimidine-5-carboxamide; AC-28438; BC164810; HY-15346; QC-10511; D10867; Q19903876; 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1.2-c]quinazolin-5-yl]pyrimidine-5-carboxamide; 2-amino-N-{7-methoxy-8-[3-(morpholin-4-yl)propoxy]-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl}pyrimidine-5-carboxamide; BAY-80-6946; ; ; 2-Amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide
• Indication:
  In total 3 Indication(s)
  Follicular lymphoma [ICD-11: 2A80]; Approved; [1]
  Non-hodgkin lymphoma [ICD-11: 2B33]; Approved; [1]
  Non-hodgkin lymphoma [ICD-11: 2B33]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
  Mature B-cell neoplasms/lymphoma [ICD-11: 2A85]; [1]
• Target: PI3-kinase alpha (PIK3CA); PK3CA_HUMAN; [1]
• Target: PI3-kinase delta (PIK3CD); PK3CD_HUMAN; [1]
• Target: PI3-kinase gamma (PIK3CG); PK3CG_HUMAN; [1]
• Formula: C23H28N8O4
• IsoSMILES: COC1=C(C=CC2=C3NCCN3C(=NC(=O)C4=CN=C(N=C4)N)N=C21)OCCCN5CCOCC5
• InChI: 1S/C23H28N8O4/c1-33-19-17(35-10-2-6-30-8-11-34-12-9-30)4-3-16-18(19)28-23(31-7-5-25-20(16)31)29-21(32)15-13-26-22(24)27-14-15/h3-4,13-14,25H,2,5-12H2,1H3,(H2,24,26,27)
• InChIKey: MWYDSXOGIBMAET-UHFFFAOYSA-N
• PubChem CID: 135565596
• TTD Drug ID: D0S5LD
• INTEDE ID: DR0378
• DrugBank ID: DB12483

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

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Cyclin-dependent kinase 4 (CDK4) [2]

• Sensitive Disease: Acute promyelocytic leukemia [ICD-11: 2A60.2]
• Molecule Alteration: Expression; Express CDK4
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: MOLM-13 cells; Peripheral blood; Homo sapiens (Human); CVCL_2119
• In Vitro Model: MOLM14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• In Vitro Model: MV-4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• Experiment for Molecule Alteration: Protein component assay; Immunoblotting assay; Immunofluorescence staining assay
• Experiment for Drug Resistance: Cell viability assay; Synergistic effects assay; Cell growth rates assay
• Mechanism Description: Considering the fact that for many tumour cells, inhibition of CDK4/6 can induce cellular quiescence or senescence, we evaluated whether CDK4 expression was affected by copanlisib alone or in combination with palbociclib. Copanlisib was selected as it was more effective than other PI3K inhibitors on its own. While the cells did not react to palbociclib by reducing the expression of CDK4, copanlisib lead to dose-dependent downregulation in CDK4 expression, especially when combined with palbociclib (Additional file 1: Fig. S8). Moreover, the cells did not express p-Akt following treatment with copanlisib (Additional file 1: Fig. S9).

Mature B-cell neoplasms/lymphoma [ICD-11: 2A85]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Interleukin 6 receptor (IL6R) [1]

• Resistant Disease: Non-Hodgkin lymphoma [ICD-11: 2A85.5]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: RWPE-1 cells; Prostate; Homo sapiens (Human); CVCL_3791
• In Vitro Model: SW1116 cells; Colon; Homo sapiens (Human); CVCL_0544
• In Vitro Model: HCT15 cells; Colon; Homo sapiens (Human); CVCL_0292
• In Vitro Model: LS174T cells; Colon; Homo sapiens (Human); CVCL_1384
• In Vitro Model: NCI-H716 cells; Colon; Homo sapiens (Human); CVCL_1581
• In Vitro Model: SW948 cells; Colon; Homo sapiens (Human); CVCL_0632
• In Vitro Model: C4-2B cells; Prostate; Homo sapiens (Human); CVCL_4784
• In Vitro Model: OCI-Ly1 cells; Bone marrow; Homo sapiens (Human); CVCL_1879
• In Vitro Model: Riva cells; Pleural effusion; Homo sapiens (Human); N.A.
• In Vitro Model: SU-DHL2 cells; Pleural effusion; Homo sapiens (Human); CVCL_9550
• In Vitro Model: U2932 (ABC-DLBCL) cells; Ascites; Homo sapiens (Human); CVCL_1896
• In Vitro Model: BJAB cells; Groin; Homo sapiens (Human); CVCL_5711
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: Cytokine arrays revealed upregulation of interleukin (IL)-6 in both copanlisib- and duvelisib-resistant cell lines. Phosphorylated STAT5, AKT, p70S6K and MAPK were increased in copanlisib-resistant B-cell lymphoma cells, whereas phosphorylated STAT3 and NF-kappaB were increased in duvelisib-resistant T cell lymphoma cells. Conversely, depletion of IL-6 sensitized both resistant cell lines, and led to downregulation of phosphorylated STAT3 and STAT5 in copanlisib- and duvelisib-resistant cells, respectively. Moreover, combined treatment with a JAK inhibitor (BSK805) and a PI3K inhibitor circumvented the acquired resistance to PI3K inhibitors in lymphoma, and concurrent inhibition of the activated pathways produced combined effects.IL-6-induced STAT3 or STAT5 activation is a critical mechanism underlying PI3K inhibitor resistance in lymphoma, supporting the utility of IL-6 as an effective biomarker to predict therapeutic response to PI3K inhibitors.

References

• Ref 1: Interleukin-6 mediates resistance to PI3K-pathway-targeted therapy in lymphoma .BMC Cancer. 2019 Oct 10;19(1):936. doi: 10.1186/s12885-019-6057-7. 10.1186/s12885-019-6057-7
• Ref 2: Combination strategies to overcome drug resistance in FLT(+) acute myeloid leukaemia. Cancer Cell Int. 2023 Aug 11;23(1):161.