Drug Information

Drug (ID: DG00648) and It's Reported Resistant Information

• Name: Idelalisib
• Synonyms: Idelalisib; 870281-82-6; CAL-101; Zydelig; GS-1101; CAL 101; CAL101; (S)-2-(1-((9H-Purin-6-yl)amino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one; 1146702-54-6; Idelalisib (CAL-101); UNII-YG57I8T5M0; CAL-101 (Idelalisib, GS-1101); GS 1101; (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one; YG57I8T5M0; CHEMBL2216870; CHEBI:82701; 5-Fluoro-3-phenyl-2-((S)-1-(9H-purin-6-ylamino)-propyl)-3H-quinazolin-4-one; Idelalisib; CAL-101; 5-fluoro-3-phenyl-2-((1s)-1-(9h-purin-6-ylamino)propyl)-4(3h)-quinazolinone; 5-fluoro-3-phenyl-2-[(1S)-1-(7H-purin-6-ylamino)propyl]quinazolin-4-one; 5-fluoro-3-phenyl-2-[(1S)-1-(3H-purin-6-ylamino)propyl]quinazolin-4(3H)-one; 5-Fluoro-3-Phenyl-2-[(1s)-1-(7h-Purin-6-Ylamino)propyl]quinazolin-4(3h)-One; Idelalisib [USAN:INN]; Idealisib; 5-FLUORO-3-PHENYL-2-[(1S)-1-(9H-PURIN-6-YLAMINO)PROPYL]-4(3H)-QUINAZOLINONE; Zydelig (TN); MLS006010985; Idelalisib (JAN/USAN/INN); SCHEMBL356400; C22H18FN7O; GTPL6741; QCR-36; SCHEMBL16782604; HSDB 8408; AMY9239; CAL-101/CAL101; EX-A330; GS-11CAL-101; BCPP000307; DTXSID701007266; AOB87313; BCP02532; EX-A1242; BDBM50403068; MFCD19443647; NSC759224; NSC762828; NSC800771; s2226; ZINC13986658; AKOS022186334; Idelalisib (CAL-101,GS-1101); BCP9000471; CCG-264949; CS-0256; DB09054; LS41100; NSC-759224; NSC-762828; NSC-800771; CAL-101 (GS-1101); NCGC00262603-01; NCGC00262603-02; NCGC00262603-04; AC-28394; HY-13026; IC489666; SMR004702787; SW219823-1; X7435; A-1138; D10560; J-517532; Q5908266; BRD-K60866521-001-01-4; (S)-5-fluoro-3-phenyl-2-[1-(9H-purin-6-ylamino)-propyl]-3H-quinazolin-4-one; 4(3H)-Quinazolinone,5-fluoro-3-phenyl-2-[(1S)-1-(1H-purin-6-ylamino)propyl]-; 5-Fluoro-3-phenyl-2-{1-[(9H-purin-6-yl)amino]propyl}quinazolin-4(3H)-one; 1453810-72-4; 40L
• Indication:
  In total 2 Indication(s)
  Chronic lymphocytic leukaemia [ICD-11: 2A82]; Approved; [1]
  Chronic lymphocytic leukaemia [ICD-11: 2A82]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (5 diseases)
  B cell lymphoma [ICD-11: 2A86]; [2]
  Bacterial infection [ICD-11: 1A00-1C4Z]; [3]
  Mature B-cell neoplasms/lymphoma [ICD-11: 2A85]; [1]
  Pneumonia [ICD-11: CA40]; [4]
  Shigellosis [ICD-11: 1A02]; [5]
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
  Unspecified carcinoma of unspecified site [ICD-11: 2D41]; [6]
• Target: PI3-kinase delta (PIK3CD); PK3CD_HUMAN; [1]
• Formula: C22H18FN7O
• IsoSMILES: CC[C@@H](C1=NC2=C(C(=CC=C2)F)C(=O)N1C3=CC=CC=C3)NC4=NC=NC5=C4NC=N5
• InChI: 1S/C22H18FN7O/c1-2-15(28-20-18-19(25-11-24-18)26-12-27-20)21-29-16-10-6-9-14(23)17(16)22(31)30(21)13-7-4-3-5-8-13/h3-12,15H,2H2,1H3,(H2,24,25,26,27,28)/t15-/m0/s1
• InChIKey: IFSDAJWBUCMOAH-HNNXBMFYSA-N
• PubChem CID: 11625818
• ChEBI ID: CHEBI:82701
• TTD Drug ID: D0J5VR
• VARIDT ID: DR00219
• INTEDE ID: DR0854
• DrugBank ID: DB09054

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 lymphoblastic leukaemia [ICD-11: 2A70]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Glucocorticoid receptor (NR3C1) [7]

• Sensitive Disease: b-lymphoblastic leukemia [ICD-11: 2A70]
• Molecule Alteration: Phosphorylation; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Nalm-6 cells; Peripheral blood; Homo sapiens (Human); CVCL_0092
• In Vitro Model: Sup-B15 cells; Bone marrow; Homo sapiens (Human); CVCL_0103
• In Vitro Model: RCH-ACV cells; Bone marrow; Homo sapiens (Human); CVCL_1851
• Experiment for Molecule Alteration: Gene expression assay; MS analysis; Electrophoretic mobility shift assay; Phospho-GR Western blot assay
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: Through this comprehensive analysis, we discovered growth factor receptor-bound protein 2 (Grb2) as a central interactor bridging the pathways related to PI3Kalpha and beta1 integrin.

Key Molecule: Glucocorticoid receptor (NR3C1) [7]

• Sensitive Disease: b-lymphoblastic leukemia [ICD-11: 2A70]
• Molecule Alteration: Phosphorylation; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Nalm-6 cells; Peripheral blood; Homo sapiens (Human); CVCL_0092
• In Vitro Model: Sup-B15 cells; Bone marrow; Homo sapiens (Human); CVCL_0103
• In Vitro Model: RCH-ACV cells; Bone marrow; Homo sapiens (Human); CVCL_1851
• Experiment for Molecule Alteration: Gene expression assay; MS analysis; Electrophoretic mobility shift assay; Phospho-GR Western blot assay
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: Through this comprehensive analysis, we discovered growth factor receptor-bound protein 2 (Grb2) as a central interactor bridging the pathways related to PI3Kalpha and beta1 integrin.

Key Molecule: Glucocorticoid receptor (NR3C1) [7]

• Sensitive Disease: b-lymphoblastic leukemia [ICD-11: 2A70]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Nalm-6 cells; Peripheral blood; Homo sapiens (Human); CVCL_0092
• In Vitro Model: Sup-B15 cells; Bone marrow; Homo sapiens (Human); CVCL_0103
• In Vitro Model: RCH-ACV cells; Bone marrow; Homo sapiens (Human); CVCL_1851
• Experiment for Molecule Alteration: Gene expression assay; MS analysis; Electrophoretic mobility shift assay; Phospho-GR Western blot assay
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: Through this comprehensive analysis, we discovered growth factor receptor-bound protein 2 (Grb2) as a central interactor bridging the pathways related to PI3Kalpha and beta1 integrin.

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: CXC chemokine receptor type 4 (CXCR4) [1]

• Resistant Disease: Waldenstrom macroglobulinemia [ICD-11: 2A85.4]
• Molecule Alteration: Mutation; .
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: CXCR4 mutation led to idelalisib in the waldenstrom macroglobulinemia.

Merkel cell carcinoma [ICD-11: 2C34]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: PI3-kinase alpha (PIK3CA) [8]

• Sensitive Disease: Merkel cell carcinoma [ICD-11: 2C34.0]
• Molecule Alteration: Missense mutation; p.P471L (c.1412C>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Skin; N.A.
• Experiment for Molecule Alteration: Real-time PCR

Unspecified carcinoma of unspecified site [ICD-11: 2D41]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Phosphatidylinositol 3-kinase delta short isoform (PI3Kdelta-S) [6]

• Resistant Disease: endocrine/solid tumors [ICD-11: 2D41]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT/mTOR signaling pathway; Activation; hsa04150
• In Vitro Model: 22Rv-1 cells; Prostate; Homo sapiens (Human); CVCL_1045
• In Vitro Model: PC-3 cells; Bone; Homo sapiens (Human); CVCL_0035
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: MDA PCa 2b cells; Prostate; Homo sapiens (Human); CVCL_4748
• In Vitro Model: DU145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: MDA-MB-231cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: MCF7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: NCI-H1299 cells; Lymph node; Homo sapiens (Human); CVCL_0060
• Experiment for Molecule Alteration: Immunohistochemistry; Immunofluorescence staining assay; RT-PCR; Western blot assay
• Experiment for Drug Resistance: MTT assay; ELISA assay
• Mechanism Description: Overexpression of PIK3CD-S splice variant in PCa confers AA PCa resistance to PI3Kdelta inhibitor, such as Idelalisib. We also uncovered that the synthesis of aberrant PIK3CD-S splice variant is likely mediated by the splicing factor SRSF2, and inhibition of SRSF2 by SRPK1/2 inhibitor SRPIN340 significantly sensitizes AA PCa to Idelalisib.

References

• Ref 1: Genomics, Signaling, and Treatment of Waldenstr m Macroglobulinemia .J Clin Oncol. 2017 Mar 20;35(9):994-1001. doi: 10.1200/JCO.2016.71.0814. Epub 2017 Feb 13. 10.1200/JCO.2016.71.0814
• Ref 2: Genetic and Non-Genetic Mechanisms of Resistance to BCR Signaling Inhibitors in B Cell Malignancies .Front Oncol. 2020 Oct 26;10:591577. doi: 10.3389/fonc.2020.591577. 10.3389/fonc.2020.591577
• Ref 3: Increased resistance of gram-negative urinary pathogens after kidney transplantation .BMC Nephrol. 2017 May 19;18(1):164. doi: 10.1186/s12882-017-0580-z. 10.1186/s12882-017-0580-z
• Ref 4: Antimicrobial resistance profile and multidrug resistance patterns of Streptococcus pneumoniae isolates from patients suspected of pneumococcal infections in EthiopiaAnn Clin Microbiol Antimicrob. 2021 Apr 20;20(1):26. doi: 10.1186/s12941-021-00432-z.
• Ref 5: Update on Shigella and Nontyphoidal Salmonella Antimicrobial Drug Resistance: Implications on Empirical Treatment of Acute Infectious Diarrhea in CambodiaAntimicrob Agents Chemother. 2021 Oct 18;65(11):e0067121. doi: 10.1128/AAC.00671-21. Epub 2021 Aug 16.
• Ref 6: Aberrant PI3Kdelta splice isoform as a potential biomarker and novel therapeutic target for endocrine cancers. Front Endocrinol (Lausanne). 2023 Aug 21;14:1190479.
• Ref 7: PI3Kdelta Inhibition Potentiates Glucocorticoids in B-lymphoblastic Leukemia by Decreasing Receptor Phosphorylation and Enhancing Gene Regulation. Cancers (Basel). 2023 Dec 27;16(1):143.
• Ref 8: Response to Idelalisib in a Patient with Stage IV Merkel-Cell CarcinomaN Engl J Med. 2015 Oct 15;373(16):1580-2. doi: 10.1056/NEJMc1507446.