Drug Details

General Information of the Drug (ID: DR7812)
Name
Dactolisib
Synonyms
BEZ-235; S14-0511; NVP-BEZ-235; NVP-BEZ235, BEZ235; 2-(4-(2,3-dihydro-3-methyl-2-oxo-8-(quinolin-3-yl)imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile
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Molecular Type
Small molecule
Disease Solid tumour/cancer [ICD-11: 2A00-2F9Z] Phase 2 [1]
Structure
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2D MOL

3D MOL

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Formula
C30H23N5O
PubChem CID
11977753
Canonical SMILES
CC(C)(C#N)C1=CC=C(C=C1)N2C3=C4C=C(C=CC4=NC=C3N(C2=O)C)C5=CC6=CC=CC=C6N=C5
InChI
1S/C30H23N5O/c1-30(2,18-31)22-9-11-23(12-10-22)35-28-24-15-19(21-14-20-6-4-5-7-25(20)32-16-21)8-13-26(24)33-17-27(28)34(3)29(35)36/h4-17H,1-3H3
InChIKey
JOGKUKXHTYWRGZ-UHFFFAOYSA-N
CAS Number
CAS 915019-65-7
GDSC
Dactolisib
TTD Drug ID
D0VG0D
DrugBank ID
DB11651
Combinatorial Therapeutic Effect(s) Validated Clinically or Experimentally
    α. A List of Natural Product(s) Able to Enhance the Efficacy of This Drug
          Curcumin      Hellenia speciosa     Click to Show/Hide the Molecular Data of This NP
                 Achieving Therapeutic Synergy     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [2]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Down-regulation Expression BCL-2  Molecule Info 
Pathway MAP
Down-regulation Expression MCL1  Molecule Info 
Pathway MAP
                    In-vitro Model Caki-1 CVCL_0234 Clear cell renal cell carcinoma Homo sapiens
ACHN CVCL_1067 Papillary renal cell carcinoma Homo sapiens
A-498 CVCL_1056 Renal cell carcinoma Homo sapiens
MDA-MB-231 CVCL_0062 Breast adenocarcinoma Homo sapiens
U-87MG ATCC CVCL_0022 Glioblastoma Homo sapiens
                    Experimental
                    Result(s)		 The combined treatment with NVP-BEZ235 and curcumin induces apoptosis through p53-dependent Bcl-2 mRNA down-regulation at the transcriptional level and Mcl-1 protein down-regulation at the post-transcriptional level.
          Diosmin      Capsella bursa-pastoris     Click to Show/Hide the Molecular Data of This NP
                 Achieving Therapeutic Synergy     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [3]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Down-regulation Phosphorylation AKT1  Molecule Info 
Pathway MAP
Down-regulation Expression p105  Molecule Info 
Pathway MAP
                    In-vitro Model HCT 116 CVCL_0291 Colon carcinoma Homo sapiens
CCD-18Co CVCL_2379 Healthy Homo sapiens
                    Experimental
                    Result(s)		 The synergistic anti-proliferative effect of the combination of diosmin and BEZ-235 (dactolisib) on the HCT-116 colorectal cancer cell line occurs through inhibition of the PI3K/Akt/mTOR/NF-kappaB axis.
Target and Pathway
Target(s) PI3-kinase gamma (PIK3CG)  Molecule Info  [4]
Serine/threonine-protein kinase mTOR (mTOR)  Molecule Info  [4]
KEGG Pathway ErbB signaling pathway Click to Show/Hide
2 HIF-1 signaling pathway
3 mTOR signaling pathway
4 PI3K-Akt signaling pathway
5 AMPK signaling pathway
6 Insulin signaling pathway
7 Thyroid hormone signaling pathway
8 Adipocytokine signaling pathway
9 Type II diabetes mellitus
10 Pathways in cancer
11 Proteoglycans in cancer
12 MicroRNAs in cancer
13 Glioma
14 Prostate cancer
15 Acute myeloid leukemia
16 Central carbon metabolism in cancer
17 Choline metabolism in cancer
18 Inositol phosphate metabolism
19 Ras signaling pathway
20 Rap1 signaling pathway
21 cGMP-PKG signaling pathway
22 cAMP signaling pathway
23 Chemokine signaling pathway
24 FoxO signaling pathway
25 Phosphatidylinositol signaling system
26 Sphingolipid signaling pathway
27 Apoptosis
28 Adrenergic signaling in cardiomyocytes
29 VEGF signaling pathway
30 Osteoclast differentiation
31 Focal adhesion
32 Signaling pathways regulating pluripotency of stem cells
33 Platelet activation
34 Toll-like receptor signaling pathway
35 Jak-STAT signaling pathway
36 Natural killer cell mediated cytotoxicity
37 T cell receptor signaling pathway
38 B cell receptor signaling pathway
39 Fc epsilon RI signaling pathway
40 Fc gamma R-mediated phagocytosis
41 TNF signaling pathway
42 Leukocyte transendothelial migration
43 Neurotrophin signaling pathway
44 Cholinergic synapse
45 Inflammatory mediator regulation of TRP channels
46 Regulation of actin cytoskeleton
47 Progesterone-mediated oocyte maturation
48 Estrogen signaling pathway
49 Prolactin signaling pathway
50 Oxytocin signaling pathway
51 Regulation of lipolysis in adipocytes
52 Non-alcoholic fatty liver disease (NAFLD)
53 Aldosterone-regulated sodium reabsorption
54 Carbohydrate digestion and absorption
55 Bacterial invasion of epithelial cells
56 Chagas disease (American trypanosomiasis)
57 Toxoplasmosis
58 Amoebiasis
59 Hepatitis C
60 Hepatitis B
61 Measles
62 Influenza A
63 HTLV-I infection
64 Epstein-Barr virus infection
65 Viral carcinogenesis
66 Colorectal cancer
67 Renal cell carcinoma
68 Pancreatic cancer
69 Endometrial cancer
70 Melanoma
71 Chronic myeloid leukemia
72 Small cell lung cancer
73 Non-small cell lung cancer
Panther Pathway Hypoxia response via HIF activation Click to Show/Hide
2 Interleukin signaling pathway
Pathwhiz Pathway Leucine Stimulation on Insulin Signaling Click to Show/Hide
2 Inositol Metabolism
3 Phosphatidylinositol Phosphate Metabolism
4 Intracellular Signalling Through Adenosine Receptor A2a and Adenosine
5 Intracellular Signalling Through Adenosine Receptor A2b and Adenosine
6 Fc Epsilon Receptor I Signaling in Mast Cells
Pathway Interaction Database IL4-mediated signaling events Click to Show/Hide
2 Signaling events mediated by Hepatocyte Growth Factor Receptor (c-Met)
3 IL12-mediated signaling events
4 CDC42 signaling events
5 LKB1 signaling events
6 Regulation of Telomerase
7 mTOR signaling pathway
8 CXCR4-mediated signaling events
9 EGFR-dependent Endothelin signaling events
10 IL2 signaling events mediated by PI3K
11 IFN-gamma pathway
12 ErbB1 downstream signaling
13 ErbB2/ErbB3 signaling events
14 CXCR3-mediated signaling events
15 Class I PI3K signaling events mediated by Akt
Reactome PIP3 activates AKT signaling Click to Show/Hide
2 Macroautophagy
3 mTORC1-mediated signalling
4 HSF1-dependent transactivation
5 CD28 dependent PI3K/Akt signaling
6 VEGFR2 mediated vascular permeability
7 TP53 Regulates Metabolic Genes
8 Constitutive Signaling by AKT1 E17K in Cancer
9 PI3K Cascade
10 GPVI-mediated activation cascade
11 Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants
12 PI3K events in ERBB4 signaling
13 GAB1 signalosome
14 PI3K events in ERBB2 signaling
15 PI3K/AKT activation
16 Role of phospholipids in phagocytosis
17 Tie2 Signaling
18 Constitutive Signaling by Aberrant PI3K in Cancer
19 DAP12 signaling
20 Role of LAT2/NTAL/LAB on calcium mobilization
21 Nephrin interactions
22 Costimulation by the CD28 family
23 G beta:gamma signalling through PI3Kgamma
24 G alpha (q) signalling events
25 G alpha (12/13) signalling events
26 VEGFA-VEGFR2 Pathway
27 Interleukin-3, 5 and GM-CSF signaling
28 Constitutive Signaling by EGFRvIII
29 PI-3K cascade:FGFR1
30 PI-3K cascade:FGFR2
31 PI-3K cascade:FGFR3
32 PI-3K cascade:FGFR4
33 Interleukin receptor SHC signaling
34 Regulation of signaling by CBL
WikiPathways ErbB Signaling Pathway Click to Show/Hide
2 Senescence and Autophagy in Cancer
3 Interferon type I signaling pathways
4 Insulin Signaling
5 EGF/EGFR Signaling Pathway
6 Wnt Signaling Pathway Netpath
7 Extracellular vesicle-mediated signaling in recipient cells
8 Cardiac Hypertrophic Response
9 Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)
10 PIP3 activates AKT signaling
11 Polycystic Kidney Disease Pathway
12 Alpha 6 Beta 4 signaling pathway
13 BDNF signaling pathway
14 Oncostatin M Signaling Pathway
15 Prostate Cancer
16 TSLP Signaling Pathway
17 FSH signaling pathway
18 Leptin signaling pathway
19 TSH signaling pathway
20 RANKL/RANK Signaling Pathway
21 SREBF and miR33 in cholesterol and lipid homeostasis
22 Integrated Breast Cancer Pathway
23 SREBP signalling
24 Signaling by Insulin receptor
25 Costimulation by the CD28 family
26 Type II diabetes mellitus
27 MicroRNAs in cardiomyocyte hypertrophy
28 TOR Signaling
29 AMPK Signaling
30 Toll-like receptor signaling pathway
31 Serotonin HTR1 Group and FOS Pathway
32 DNA Damage Response (only ATM dependent)
33 G13 Signaling Pathway
34 Regulation of Actin Cytoskeleton
35 IL-4 Signaling Pathway
36 Copper homeostasis
37 Signaling of Hepatocyte Growth Factor Receptor
38 Transcriptional activation by NRF2
39 IL1 and megakaryotyces in obesity
40 Signaling by ERBB4
41 Signaling by ERBB2
42 Fc epsilon receptor (FCERI) signaling
43 PI Metabolism
44 Interleukin-2 signaling
45 Fcgamma receptor (FCGR) dependent phagocytosis
46 Signaling by SCF-KIT
47 DAP12 interactions
48 Gastrin-CREB signalling pathway via PKC and MAPK
49 Integrated Pancreatic Cancer Pathway
50 Signaling Pathways in Glioblastoma
51 Regulation of Microtubule Cytoskeleton
52 TCR signaling
53 Signaling by PDGF
54 Signaling by FGFR
55 Signaling by EGFR
56 NGF signalling via TRKA from the plasma membrane
57 Nephrin interactions
58 Interleukin-3, 5 and GM-CSF signaling
59 GPVI-mediated activation cascade
60 GPCR downstream signaling
61 Cell surface interactions at the vascular wall
62 Angiogenesis
63 Regulation of toll-like receptor signaling pathway
References
Reference 1 URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7950).
Reference 2 Curcumin significantly enhances dual PI3K/Akt and mTOR inhibitor NVP-BEZ235-induced apoptosis in human renal carcinoma Caki cells through down-regulation of p53-dependent Bcl-2 expression and inhibition of Mcl-1 protein stability. PLoS One. 2014 Apr 17;9(4):e95588.
Reference 3 The synergistic anti-proliferative effect of the combination of diosmin and BEZ-235 (dactolisib) on the HCT-116 colorectal cancer cell line occurs through inhibition of the PI3K/Akt/mTOR/NF-kappaB axis. Mol Biol Rep. 2020 Mar;47(3):2217-2230.
Reference 4 The dual PI3K/mTOR inhibitor NVP-BEZ235 is a potent inhibitor of ATM- and DNA-PKCs-mediated DNA damage responses. Neoplasia. 2012 Jan;14(1):34-43.
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