Drug Information

Drug (ID: DG00545) and It's Reported Resistant Information

• Name: PKI-587
• Synonyms: Gedatolisib; 1197160-78-3; PKI-587; PF-05212384; PKI 587; PKI587; 1-(4-(4-(Dimethylamino)piperidine-1-carbonyl)phenyl)-3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)urea; PF 05212384; UNII-96265TNH2R; PF-05212384 (PKI-587); CHEMBL592445; 96265TNH2R; 1-[4-[4-(dimethylamino)piperidine-1-carbonyl]phenyl]-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea; N-[4-[[4-(Dimethylamino)-1-piperidinyl]carbonyl]phenyl]-N'-[4-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]phenyl]urea; Gedatolisib (PF-05212384, PKI-587); PKI-587; PF-05212384; 1-(4-((4-(dimethylamino)piperidin-1-yl)carbonyl)phenyl)-3-(4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl)urea; Urea, N-(4-((4-(dimethylamino)-1-piperidinyl)carbonyl)phenyl)-N'-(4-(4,6-di-4-morpholinyl-1,3,5-triazin-2-yl)phenyl)-; Gedatolisib [USAN:INN]; 1-(4-{[4-(Dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea; Urea, N-[4-[[4-(dimethylamino)-1-piperidinyl]carbonyl]phenyl]-N'-[4-(4,6-di-4-morpholinyl-1,3,5-triazin-2-yl)phenyl]-; PK 587; PK 1587; Gedatolisib(PKI-587); Gedatolisib (USAN/INN); Gedatolisib (PKI-587); SCHEMBL32393; GTPL7940; AOB5085; DTXSID40152557; EX-A028; QCR-208; C32H41N9O4; HMS3748M11; BCP01986; BDBM50308135; MFCD16875679; NSC758256; NSC801014; s2628; ZINC49757175; AKOS005766013; CCG-264662; CS-0449; DB11896; FE-0013; NSC-758256; NSC-801014; SB16571; NCGC00370777-01; NCGC00370777-04; AC-31519; HY-10681; FT-0700110; PKI-587,PF-05212384; X7445; A25474; D10635; J-004182; J-523339; Q27077788; PKI-587; 1197160-78-3; PKI587; PKI 587; N-[4-[[4-(Dimethylamino)-1-piperidinyl]carbonyl]phenyl]-N'-[4-(4,6-di-4-morpholinyl-1,3,5-triazin-2-yl)phenyl]urea; N-{4-[4,6-bis(morpholin-4-yl)-1,3,5-triazin-2-yl]phenyl}-N'-{4-[4-(dimethylamino)piperidine-1-carbonyl]phenyl}urea; VL1
• Indication:
  In total 1 Indication(s)
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; Investigative; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (2 diseases)
  Chordoma [ICD-11: 2B5J]; [1]
  Lung cancer [ICD-11: 2C25]; [2]
• Target: PI3-kinase gamma (PIK3CG); PK3CG_HUMAN; [1]
• Target: Serine/threonine-protein kinase mTOR (mTOR); MTOR_HUMAN; [1]
• Formula: C32H41N9O4
• IsoSMILES: CN(C)C1CCN(CC1)C(=O)C2=CC=C(C=C2)NC(=O)NC3=CC=C(C=C3)C4=NC(=NC(=N4)N5CCOCC5)N6CCOCC6
• InChI: 1S/C32H41N9O4/c1-38(2)27-11-13-39(14-12-27)29(42)24-5-9-26(10-6-24)34-32(43)33-25-7-3-23(4-8-25)28-35-30(40-15-19-44-20-16-40)37-31(36-28)41-17-21-45-22-18-41/h3-10,27H,11-22H2,1-2H3,(H2,33,34,43)
• InChIKey: DWZAEMINVBZMHQ-UHFFFAOYSA-N
• PubChem CID: 44516953
• TTD Drug ID: D0D8JB
• DrugBank ID: DB11896

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

Chordoma [ICD-11: 2B5J]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Y-box-binding protein 1 (YBX1) [1]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Chordoma [ICD-11: 2B5J.0]
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: EGFR/AKT signaling pathway; Regulation; hsa04012
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• In Vitro Model: Chordoma tissue; N.A.
• In Vivo Model: NOD/SCID/IL2Rgamma null (NOG) mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: YBX1 regulated protein expression of pEGFR, pAKT and its downstream target genes that influenced cell apoptosis, cell cycle transition and cell invasion. YBX1 activated the EGFR/AKT pathway in chordoma and YBX1-induced elevated expression of key molecules in the EGFR/AKT pathway were downregulated by EGFR and AKT pathway inhibitors. These in vitro results were further confirmed by in vivo data. These data showed that YBX1 promoted tumorigenesis and progression in spinal chordoma via the EGFR/AKT pathway. YBX1 might serve as a prognostic and predictive biomarker, as well as a rational therapeutic target, for chordoma.

Colon cancer [ICD-11: 2B90]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [3]

• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Experimental Note: Identified from the Human Clinical Data

Lung cancer [ICD-11: 2C25]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: GTPase Nras (NRAS) [2]

• Molecule Alteration: Missense mutation; p.Q61K (c.181C>A)
• Resistant Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Identified from the Human Clinical Data

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Epidermal growth factor receptor (EGFR) [4]

• Molecule Alteration: IF-deletion; p.E746_A750delELREA (c.2236_2250del15)
• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Cellular tumor antigen p53 (TP53) [5]

• Molecule Alteration: Missense mutation; p.R158G (c.472C>G)
• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Identified from the Human Clinical Data

Breast cancer [ICD-11: 2C60]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: PI3-kinase alpha (PIK3CA) [6]

• Molecule Alteration: Missense mutation; p.E545K (c.1633G>A)
• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: BT474 cells; Breast; Homo sapiens (Human); CVCL_0179
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: MDA-MB-468 cells; Breast; Homo sapiens (Human); CVCL_0419
• In Vitro Model: H157 cells; Lung; Homo sapiens (Human); CVCL_2458
• In Vitro Model: H2170 cells; Lung; Homo sapiens (Human); CVCL_1535
• In Vitro Model: MDA-MB-361 cells; Breast; Homo sapiens (Human); CVCL_0620
• In Vitro Model: H1650 cells; Pleural effusion; Homo sapiens (Human); CVCL_4V01
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MIA PaCa-2 cells; Pancreas; Homo sapiens (Human); CVCL_0428
• In Vitro Model: HTB44 cells; Kidney; Homo sapiens (Human); N.A.
• In Vitro Model: H1666 cells; Pleural effusion; Homo sapiens (Human); CVCL_1485
• In Vitro Model: 786-0 cells; Kidney; Homo sapiens (Human); CVCL_1051
• In Vivo Model: Female nude mouse xenograft model; Mus musculus
• Experiment for Drug Resistance: IC50 assay

Key Molecule: PI3-kinase alpha (PIK3CA) [6]

• Molecule Alteration: Missense mutation; p.H1047R (c.3140A>G)
• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_1511
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: H460 cells; Lung; Homo sapiens (Human); CVCL_0459
• In Vitro Model: T47D cells; Breast; Homo sapiens (Human); CVCL_0553
• In Vitro Model: BT474 cells; Breast; Homo sapiens (Human); CVCL_0179
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: MDA-MB-468 cells; Breast; Homo sapiens (Human); CVCL_0419
• In Vitro Model: H157 cells; Lung; Homo sapiens (Human); CVCL_2458
• In Vitro Model: H2170 cells; Lung; Homo sapiens (Human); CVCL_1535
• In Vitro Model: MDA-MB-361 cells; Breast; Homo sapiens (Human); CVCL_0620
• In Vitro Model: H1650 cells; Pleural effusion; Homo sapiens (Human); CVCL_4V01
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MIA PaCa-2 cells; Pancreas; Homo sapiens (Human); CVCL_0428
• In Vitro Model: HTB44 cells; Kidney; Homo sapiens (Human); N.A.
• In Vitro Model: H1666 cells; Pleural effusion; Homo sapiens (Human); CVCL_1485
• In Vitro Model: 786-0 cells; Kidney; Homo sapiens (Human); CVCL_1051
• In Vivo Model: Female nude mouse xenograft model; Mus musculus
• Experiment for Drug Resistance: IC50 assay

Head and neck cancer [ICD-11: 2D42]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: PI3-kinase alpha (PIK3CA) [7]

• Molecule Alteration: Missense mutation; p.H1047R (c.3140A>G)
• Sensitive Disease: Head and neck squamous cell carcinoma [ICD-11: 2D42.1]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: UMSCC cells; Oral cavity; Homo sapiens (Human); CVCL_7707
• In Vivo Model: SCID/NCr-Balb/c mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; qPCR
• Experiment for Drug Resistance: XTT assay

References

• Ref 1: Y-box binding protein-1 promotes tumorigenesis and progression via the epidermal growth factor receptor/AKT pathway in spinal chordoma .Cancer Sci. 2019 Jan;110(1):166-179. doi: 10.1111/cas.13875. Epub 2018 Dec 19. 10.1111/cas.13875
• Ref 2: Mutations of the BRAF gene in human cancerNature. 2002 Jun 27;417(6892):949-54. doi: 10.1038/nature00766. Epub 2002 Jun 9.
• Ref 3: Epigenetic and genetic features of 24 colon cancer cell linesOncogenesis. 2013 Sep 16;2(9):e71. doi: 10.1038/oncsis.2013.35.
• Ref 4: Chemotherapy-induced epidermal growth factor receptor activation determines response to combined gefitinib/chemotherapy treatment in non-small cell lung cancer cellsMol Cancer Ther. 2006 May;5(5):1154-65. doi: 10.1158/1535-7163.MCT-05-0446.
• Ref 5: Integrative radiogenomic profiling of squamous cell lung cancerCancer Res. 2013 Oct 15;73(20):6289-98. doi: 10.1158/0008-5472.CAN-13-1616. Epub 2013 Aug 26.
• Ref 6: Antitumor efficacy of PKI-587, a highly potent dual PI3K/mTOR kinase inhibitorClin Cancer Res. 2011 May 15;17(10):3193-203. doi: 10.1158/1078-0432.CCR-10-1694. Epub 2011 Feb 15.
• Ref 7: MEK Inhibitor PD-0325901 Overcomes Resistance to PI3K/mTOR Inhibitor PF-5212384 and Potentiates Antitumor Effects in Human Head and Neck Squamous Cell CarcinomaClin Cancer Res. 2015 Sep 1;21(17):3946-56. doi: 10.1158/1078-0432.CCR-14-3377. Epub 2015 May 14.