Drug Information

Drug (ID: DG01533) and It's Reported Resistant Information

• Name: AZD1480
• Synonyms: AZD1480; 935666-88-9; AZD-1480; AZD 1480; UNII-KL2Z2TLF01; (S)-5-chloro-N2-(1-(5-fluoropyrimidin-2-yl)ethyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine; C14H14ClFN8; KL2Z2TLF01; CHEMBL1231124; 5-Chloro-N2-[(1s)-1-(5-Fluoropyrimidin-2-Yl)ethyl]-N4-(5-Methyl-1h-Pyrazol-3-Yl)pyrimidine-2,4-Diamine; 5-chloro-2-N-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-4-N-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine; 2,4-Pyrimidinediamine,5-chloro-N2-[(1S)-1-(5-fluoro-2-pyrimidinyl)ethyl]-N4-(5-methyl-1H-pyrazol-3-yl)-; 2xa4; MLS006011153; GTPL5933; QCR-23; SCHEMBL3345019; AMMD00048; DTXSID50239469; EX-A450; BCPP000361; AOB87317; BCP02413; AZD1480,AZD 1480; BDBM50335201; NSC756648; NSC799344; s2162; ZINC58631551; AKOS027322548; AM85979; BCP9000361; CCG-268021; DB12588; NSC-756648; NSC-799344; NCGC00242486-01; NCGC00242486-02; NCGC00242486-05; 2,4-Pyrimidinediamine, 5-chloro-N2-((1S)-1-(5-fluoro-2-pyrimidinyl)ethyl)-N4-(5-methyl-1H-pyrazol-3-yl)-; AC-32807; AS-17011; HY-10193; SMR004702927; SW219486-1; X7497; J3.540.767G; J-502241; Q27074711; 935666-88-9, 1260222-79-4 (TFA); (R)-5-chloro-N2-(1-(5-fluoropyrimidin-2-yl)ethyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine; 5-chloro-2-N-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-4-N-(3-methyl-1H-pyrazol-5-yl)pyrimidine-2,4-diamine; 5-chloro-N~2~-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N~4~-(3-methyl-1H-pyrazol-5-yl)pyrimidine-2,4-diamine; 5-chloro-N2-[(1S)-1-(5-fluoro-2-pyrimidinyl)ethyl]-N4-(5-methyl-1H-pyrazol-3-yl)- 2,4-pyrimidinediamine; 5-Chloro-N2-[(1S)-1-(5-fluoro-2-pyrimidinyl)ethyl]-N4-(5-methyl-1H-pyrazol-3-yl)-2,4-pyrimidine-2,4-diamine; AZ5
• Indication:
  In total 1 Indication(s)
  Breast cancer [ICD-11: 2C60]; Phase 2; [1]
• Target: PI3-kinase alpha (PIK3CA); PK3CA_HUMAN; [1]
• Target: PI3-kinase beta (PIK3CB); PK3CB_HUMAN; [1]
• Target: PI3-kinase delta (PIK3CD); PK3CD_HUMAN; [1]
• Target: PI3-kinase gamma (PIK3CG); PK3CG_HUMAN; [1]
• Formula: 5
• IsoSMILES: CC1=CC(=NN1)NC2=NC(=NC=C2Cl)N[C@@H](C)C3=NC=C(C=N3)F
• InChI: InChI=1S/C14H14ClFN8/c1-7-3-11(24-23-7)21-13-10(15)6-19-14(22-13)20-8(2)12-17-4-9(16)5-18-12/h3-6,8H,1-2H3,(H3,19,20,21,22,23,24)/t8-/m0/s1
• InChIKey: PDOQBOJDRPLBQU-QMMMGPOBSA-N
• PubChem CID: 16659841
• TTD Drug ID: D01QSO
• DrugBank ID: DB12588

Type(s) of Resistant Mechanism of This Drug

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Pancreatic cancer [ICD-11: 2C10]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Signal transducer activator transcription 3 (STAT3) [2]

• Sensitive Disease: Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: NF-kB signaling pathway; Activation; hsa04218
• In Vitro Model: QGP-1R cells; carcinoid; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Cell viability assay; Colony formation assay
• Mechanism Description: The activation of the STAT3 pathway induced by TNF is mediated by NF-kB p65. NF-kB p65 and STAT3 inhibitors decrease QGP-1 viability, spheroids growth, and Pa-NETs cell proliferation. These effects are maintained in everolimus-resistant QGP-1R cells.

Key Molecule: Signal transducer activator transcription 3 (STAT3) [2]

• Sensitive Disease: Pancreatic ductal adenocarcinoma [ICD-11: 2C10.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: NF-kB signaling pathway; Activation; hsa04218
• In Vitro Model: QGP-1R cells; carcinoid; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: Cell viability assay; Colony formation assay
• Mechanism Description: The activation of the STAT3 pathway induced by TNF is mediated by NF-kB p65. NF-kB p65 and STAT3 inhibitors decrease QGP-1 viability, spheroids growth, and Pa-NETs cell proliferation. These effects are maintained in everolimus-resistant QGP-1R cells.

Thyroid cancer [ICD-11: 2D10]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [1]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Molecule Alteration: Missense mutation; p.M918T (c.2753T>C)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 1.64 Å; PDB: 7DUA
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 2.12 Å; PDB: 4CKI

RMSD: 0.93; TM score: 0.95555; Amino acid change: M918T

• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: TPC-1 cells; Thyroid; Homo sapiens (Human); CVCL_6298
• In Vitro Model: C643 cells; Thyroid gland; Homo sapiens (Human); CVCL_5969
• In Vitro Model: K1 cells; Thyroid; Homo sapiens (Human); CVCL_2537
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: TUNEL assay
• Mechanism Description: The missense mutation p.M918T (c.2753T>C) in gene RET cause the sensitivity of AZD1480 by unusual activation of pro-survival pathway

Key Molecule: Proto-oncogene tyrosine-protein kinase receptor Ret (RET) [1]

• Sensitive Disease: Thyroid gland cancer [ICD-11: 2D10.0]
• Molecule Alteration: Missense mutation; p.C634W (c.1902C>G)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: TPC-1 cells; Thyroid; Homo sapiens (Human); CVCL_6298
• In Vitro Model: C643 cells; Thyroid gland; Homo sapiens (Human); CVCL_5969
• In Vitro Model: K1 cells; Thyroid; Homo sapiens (Human); CVCL_2537
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: TUNEL assay
• Mechanism Description: The missense mutation p.C634W (c.1902C>G) in gene RET cause the sensitivity of AZD1480 by unusual activation of pro-survival pathway

References

• Ref 1: AZD1480 blocks growth and tumorigenesis of RET- activated thyroid cancer cell linesPLoS One. 2012;7(10):e46869. doi: 10.1371/journal.pone.0046869. Epub 2012 Oct 2.
• Ref 2: Pancreatic neuroendocrine tumor progression and resistance to everolimus: the crucial role of NF-kB and STAT3 interplay. J Endocrinol Invest. 2024 May;47(5):1101-1117.