Drug Details

General Information of the Drug (ID: DR6631)
Name
ABT-737
Synonyms
ABT 737; ABT737; UNII-Z5NFR173NV; Z5NFR173NV; 4-[4-[(4'-Chloro[1,1'-biphenyl]-2-yl)methyl]-1-piperazinyl]-N-[[4-[[(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl]amino]-3-nitrophenyl]sulfonyl]benzamide; CHEMBL376408; C42H45ClN6O5S2; 4-{4-[(4'-Chlorobiphenyl-2-Yl)methyl]piperazin-1-Yl}-N-{[4-({(1r)-3-(Dimethylamino)-1-[(Phenylthio)methyl]propyl}amino)-3-Nitrophenyl]sulfonyl}benzamide
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Molecular Type
Small molecule
Disease Ovarian cancer [ICD-11: 2C73] Phase 1 [1]
Structure
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2D MOL

3D MOL

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Formula
C42H45ClN6O5S2
PubChem CID
11228183
Canonical SMILES
CN(C)CCC(CSC1=CC=CC=C1)NC2=C(C=C(C=C2)S(=O)(=O)NC(=O)C3=CC=C(C=C3)N4CCN(CC4)CC5=CC=CC=C5C6=CC=C(C=C6)Cl)[N+](=O)[O-]
InChI
1S/C42H45ClN6O5S2/c1-46(2)23-22-35(30-55-37-9-4-3-5-10-37)44-40-21-20-38(28-41(40)49(51)52)56(53,54)45-42(50)32-14-18-36(19-15-32)48-26-24-47(25-27-48)29-33-8-6-7-11-39(33)31-12-16-34(43)17-13-31/h3-21,28,35,44H,22-27,29-30H2,1-2H3,(H,45,50)/t35-/m1/s1
InChIKey
HPLNQCPCUACXLM-PGUFJCEWSA-N
CAS Number
CAS 852808-04-9
TTD Drug ID
D0L8WH
Combinatorial Therapeutic Effect(s) Validated Clinically or Experimentally
    α. A List of Natural Product(s) Able to Enhance the Efficacy of This Drug
          Arsenic trioxide      Realgar and orpiment     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 BCL-xL  Molecule Info 
Pathway MAP
Up-regulation Cleavage CASP3  Molecule Info 
Pathway MAP
Up-regulation Cleavage CASP9  Molecule Info 
Pathway MAP
Down-regulation Expression MCL1  Molecule Info 
Pathway MAP
                    In-vitro Model SGC-7901 CVCL_0520 Human gastric cancer Homo sapiens
MGC-803 CVCL_5334 Gastric mucinous adenocarcinoma Homo sapiens
                    Experimental
                    Result(s)		 ABT-737 synergizes with arsenic trioxide to induce apoptosis of gastric carcinoma cells in vitro and in vivo.
          Celastrol      Celastrus strigillosus     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		 Up-regulation Expression BAX  Molecule Info 
Pathway MAP
Down-regulation Expression BCL-2  Molecule Info 
Pathway MAP
Up-regulation Cleavage CASP3  Molecule Info 
Pathway MAP
Up-regulation Cleavage PARP1  Molecule Info 
Pathway MAP
Up-regulation Expression PMAIP1  Molecule Info 
Pathway MAP
                    In-vitro Model Hep-G2 CVCL_0027 Hepatocellular carcinoma Homo sapiens
BEL-7402 CVCL_5492 Human hepatocellular carcinoma Homo sapiens
                    Experimental
                    Result(s)		 Celastrol exerts synergistic anti-cancer activity in combination with ABT-737 in human hepatocellular carcinoma cells by upregulating Noxa.
          Curcumin      Hellenia speciosa     Click to Show/Hide the Molecular Data of This NP
                 Augmenting Drug Sensitivity     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [4]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Biological
                    Regulation		 Up-regulation ROS generation
                    In-vitro Model Hep-G2 CVCL_0027 Hepatocellular carcinoma Homo sapiens
                    Experimental
                    Result(s)		 Curcumin markedly enhanced the antitumor effects of ABT-737 on HepG2 cells, which was partially dependent on the induction of apoptosis. The sustained activation of the ROS-ASK1-c-Jun N-terminal kinase pathway may be an important mediator of the synergistic effect of curcumin and ABT-737.
          Naringenin      Potentilla discolor     Click to Show/Hide the Molecular Data of This NP
                 Augmenting Drug Sensitivity     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [5]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Down-regulation Phosphorylation AKT1  Molecule Info 
Pathway MAP
Up-regulation Cleavage CASP3  Molecule Info 
Pathway MAP
Up-regulation Cleavage PARP1  Molecule Info 
Pathway MAP
                    In-vitro Model SGC-7901 CVCL_0520 Human gastric cancer Homo sapiens
                    Experimental
                    Result(s)		 ABT-737 in combination with naringenin showed enhanced anticancer effects on gastric cancer cells.
          Paclitaxel      Taxus brevifolia     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 [6]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Up-regulation Expression BAK  Molecule Info 
Pathway MAP
Up-regulation Expression BCL2L11  Molecule Info 
Pathway MAP
Down-regulation Expression MCL1  Molecule Info 
Pathway MAP
                    In-vitro Model K-562 CVCL_0004 Chronic myelogenous leukemia Homo sapiens
                    Experimental
                    Result(s)		 BH3 mimetics synergize with paclitaxel in the killing of CML cells.
          Resveratrol      Gnetum parvifolium     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 [7]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Up-regulation Expression BAX  Molecule Info 
Pathway MAP
Down-regulation Expression BCL-2  Molecule Info 
Pathway MAP
Up-regulation Expression TP53  Molecule Info 
Pathway MAP
                    In-vitro Model MOLT-4 CVCL_0013 Adult T acute lymphoblastic leukemia Homo sapiens
                    Experimental
                    Result(s)		 Combination of ABT-737 and resveratrol enhances DNA damage and apoptosis in human T-cell acute lymphoblastic leukemia MOLT-4 cells.
Target and Pathway
Target(s) Apoptosis regulator Bcl-2 (BCL-2)  Molecule Info  [8]
KEGG Pathway NF-kappa B signaling pathway Click to Show/Hide
2 HIF-1 signaling pathway
3 Sphingolipid signaling pathway
4 Protein processing in endoplasmic reticulum
5 PI3K-Akt signaling pathway
6 Apoptosis
7 Adrenergic signaling in cardiomyocytes
8 Focal adhesion
9 Neurotrophin signaling pathway
10 Cholinergic synapse
11 Amyotrophic lateral sclerosis (ALS)
12 Toxoplasmosis
13 Tuberculosis
14 Hepatitis B
15 Epstein-Barr virus infection
16 Pathways in cancer
17 MicroRNAs in cancer
18 Colorectal cancer
19 Prostate cancer
20 Small cell lung cancer
NetPath Pathway IL5 Signaling Pathway Click to Show/Hide
2 TCR Signaling Pathway
3 IL2 Signaling Pathway
4 IL3 Signaling Pathway
5 Leptin Signaling Pathway
6 RANKL Signaling Pathway
7 TSLP Signaling Pathway
Panther Pathway Apoptosis signaling pathway Click to Show/Hide
2 Oxidative stress response
3 CCKR signaling map ST
Pathway Interaction Database Role of Calcineurin-dependent NFAT signaling in lymphocytes Click to Show/Hide
2 IL2-mediated signaling events
3 IL2 signaling events mediated by PI3K
4 Ceramide signaling pathway
5 Direct p53 effectors
6 RXR and RAR heterodimerization with other nuclear receptor
7 ATF-2 transcription factor network
8 C-MYB transcription factor network
9 HIV-1 Nef: Negative effector of Fas and TNF-alpha
10 Caspase Cascade in Apoptosis
11 Signaling events mediated by Stem cell factor receptor (c-Kit)
12 EPO signaling pathway
13 IL2 signaling events mediated by STAT5
14 Validated targets of C-MYC transcriptional repression
Reactome Activation of BAD and translocation to mitochondria Click to Show/Hide
2 BH3-only proteins associate with and inactivate anti-apoptotic BCL-2 members
3 The NLRP1 inflammasome
WikiPathways DNA Damage Response (only ATM dependent) Click to Show/Hide
2 Senescence and Autophagy in Cancer
3 IL-2 Signaling Pathway
4 FAS pathway and Stress induction of HSP regulation
5 Focal Adhesion
6 Kit receptor signaling pathway
7 IL-3 Signaling Pathway
8 Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways
9 Apoptosis
10 Nanoparticle triggered autophagic cell death
11 Amyotrophic lateral sclerosis (ALS)
12 Integrated Pancreatic Cancer Pathway
13 Corticotropin-releasing hormone
14 Interleukin-11 Signaling Pathway
15 Prostate Cancer
16 miR-targeted genes in muscle cell - TarBase
17 miR-targeted genes in lymphocytes - TarBase
18 miR-targeted genes in leukocytes - TarBase
19 Integrated Breast Cancer Pathway
20 Integrated Cancer pathway
21 Intrinsic Pathway for Apoptosis
22 Apoptosis Modulation and Signaling
23 TP53 Network
24 Influenza A virus infection
25 IL-5 Signaling Pathway
References
Reference 1 ClinicalTrials.gov (NCT01440504) Ex Vivo Evaluation of the Interest of the Association of Platinum With a Molecule BH3-mimetic ABT-737 in Samples of Ovarian Tumors
Reference 2 ABT-737 synergizes with arsenic trioxide to induce apoptosis of gastric carcinoma cells in vitro and in vivo. J Int Med Res. 2012;40(4):1251-64.
Reference 3 Upregulating Noxa by ER stress, celastrol exerts synergistic anti-cancer activity in combination with ABT-737 in human hepatocellular carcinoma cells. PLoS One. 2012;7(12):e52333.
Reference 4 Curcumin enhances the antitumor effect of ABT-737 via activation of the ROS-ASK1-JNK pathway in hepatocellular carcinoma cells. Mol Med Rep. 2016 Feb;13(2):1570-6.
Reference 5 Enhanced anticancer effect of ABT-737 in combination with naringenin on gastric cancer cells. Exp Ther Med. 2016 Feb;11(2):669-673.
Reference 6 Mechanism of synergy of BH3 mimetics and paclitaxel in chronic myeloid leukemia cells: Mcl-1 inhibition. Eur J Pharm Sci. 2015 Apr 5;70:64-71.
Reference 7 Combination of ABT-737 and resveratrol enhances DNA damage and apoptosis in human T-cell acute lymphoblastic leukemia MOLT-4 cells. Toxicol In Vitro. 2017 Aug;42:38-46.
Reference 8 Studies leading to potent, dual inhibitors of Bcl-2 and Bcl-xL. J Med Chem. 2007 Feb 22;50(4):641-62.
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