Details of the Drug-Related molecule(s) Interaction Atlas

General Information of Drug (ID: DMFP8WE)

• Drug Name: ZM-447439 Drug Info
• Synonyms: 331771-20-1; ZM-447439; ZM447439; ZM 447439; N-[4-[[6-METHOXY-7-[3-(4-MORPHOLINYL)PROPOXY]-4-QUINAZOLINYL]AMINO]PHENYL]BENZAMIDE; TCMDC-125873; UNII-RSN3P9776R; CHEMBL202721; RSN3P9776R; N-(4-((6-methoxy-7-(3-morpholinopropoxy)quinazolin-4-yl)amino)phenyl)benzamide; C29H31N5O4; N-[4-({6-methoxy-7-[3-(morpholin-4-yl)propoxy]quinazolin-4-yl}amino)phenyl]benzamide; N-(4-{[6-Methoxy-7-(3-Morpholin-4-Ylpropoxy)quinazolin-4-Yl]amino}phenyl)benzamide

Indication

Disease Entry	ICD 11	Status	REF
Discovery agent	N.A.	Investigative	[1]

• Cross-matching ID:
  PubChem CID: 9914412
  ChEBI ID: CHEBI:91376
  CAS Number: CAS 331771-20-1
  TTD Drug ID: DMFP8WE

Molecule-Related Drug Atlas

Drug(s) Targeting Aurora kinase A (AURKA)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AT9283	DMQ94CT	Solid tumour/cancer	2A00-2F9Z	Phase 3	[5]
MLN8237	DMO8PT9	Solid tumour/cancer	2A00-2F9Z	Phase 3	[6]
PHA-739358	DMGYBZI	Prostate cancer	2C82.0	Phase 2	[7]
VX-680	DM93YKJ	Solid tumour/cancer	2A00-2F9Z	Phase 2	[8]
ABT-348	DMMZOYN	Haematological malignancy	2B33.Y	Phase 2	[9]
ENMD-2076	DMJZVPB	Acute myeloid leukaemia	2A60	Phase 2	[7]
LY3295668	DM8RJTB	Solid tumour/cancer	2A00-2F9Z	Phase 1/2	[10]
HPP-607	DM5VSZR	Solid tumour/cancer	2A00-2F9Z	Phase 1	[11]
MLN8054	DMUANF3	Solid tumour/cancer	2A00-2F9Z	Phase 1	[8]
CYC116	DMUMHXT	Solid tumour/cancer	2A00-2F9Z	Phase 1	[12]

Drug(s) Affected By Neurogenic locus notch homolog protein 1 (NOTCH1)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Hydrogen peroxide	DM1NG5W	Infectious disease	1A00-CA43.1	Approved	[13]
Tretinoin	DM49DUI	Acne vulgaris	ED80	Approved	[14]
Arsenic trioxide	DM61TA4	Acute lymphoblastic leukaemia	2A85	Approved	[15]
Propranolol	DM79NTF	Angina pectoris	BA40	Approved	[16]
Testosterone	DM7HUNW	Hot flushes	GA30	Approved	[17]
Valproate	DMCFE9I	Epilepsy	8A60-8A68	Approved	[18]
Enzalutamide	DMGL19D	Prostate cancer	2C82.0	Approved	[19]
Niclosamide	DMJAGXQ	Cestodes infection	1F70-1F76	Approved	[20]
Temozolomide	DMKECZD	Adenocarcinoma	2D40	Approved	[21]
Mebendazole	DMO14SG	Ascariasis	1F62	Approved	[22]

Drug(s) Affected By Aurora kinase B (AURKB)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Cannabidiol	DM0659E	Dravet syndrome	8A61.11	Approved	[23]
Fulvestrant	DM0YZC6	Breast cancer	2C60-2C65	Approved	[24]
Hydrogen peroxide	DM1NG5W	Infectious disease	1A00-CA43.1	Approved	[25]
Colchicine	DM2POTE	Acute gout flare	FA25.0	Approved	[26]
Troglitazone	DM3VFPD	Diabetic complication	5A2Y	Approved	[27]
Tretinoin	DM49DUI	Acne vulgaris	ED80	Approved	[28]
Testosterone	DM7HUNW	Hot flushes	GA30	Approved	[29]
Calcitriol	DM8ZVJ7	Congenital alopecia	LC30	Approved	[29]
Leflunomide	DMR8ONJ	Arthritis	FA20	Approved	[30]
Clodronate	DM9Y6X7	Hypercalcaemia	5B91.0	Approved	[31]

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Aurora kinase A (AURKA)	TTPS3C0	AURKA_HUMAN	Inhibitor	[2]

Drug Off-Target (DOT)

DOT Name	DOT ID	UniProt ID	Interaction	REF
Aurora kinase B (AURKB)	OTIY4VHU	AURKB_HUMAN	Protein Interaction/Cellular Processes	[3]
Neurogenic locus notch homolog protein 1 (NOTCH1)	OTI1WADQ	NOTC1_HUMAN	Gene/Protein Processing	[4]

References

• [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: 8353).
• [2] Accurate prediction of the relative potencies of members of a series of kinase inhibitors using molecular docking and MM-GBSA scoring. J Med Chem. 2006 Aug 10;49(16):4805-8.
• [3] DNA double-strand breaks and Aurora B mislocalization induced by exposure of early mitotic cells to H(2)O(2) appear to increase chromatin bridges and resultant cytokinesis failure. Free Radic Biol Med. 2017 Jul;108:129-145. doi: 10.1016/j.freeradbiomed.2017.03.025. Epub 2017 Mar 24.
• [4] PLK1 targets NOTCH1 during DNA damage and mitotic progression. J Biol Chem. 2019 Nov 22;294(47):17941-17950. doi: 10.1074/jbc.RA119.009881. Epub 2019 Oct 9.
• [5] A phase I trial of AT9283 (a selective inhibitor of aurora kinases) in children and adolescents with solid tumors: a Cancer Research UK study. Clin Cancer Res. 2015 Jan 15;21(2):267-73.
• [6] Effect of Aurora A kinase inhibitor MLN8237 combined with rituximab on antitumor activity in preclinical B-cell non-Hodgkin's lymphoma models. Journal of Clinical Oncology, 2009:8553.
• [7] Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66.
• [8] A comparison of physicochemical property profiles of marketed oral drugs and orally bioavailable anti-cancer protein kinase inhibitors in clinical development. Curr Top Med Chem. 2007;7(14):1408-22.
• [9] Preclinical characterization of ABT-348, a kinase inhibitor targeting the aurora, vascular endothelial growth factor receptor/platelet-derived growth factor receptor, and Src kinase families. J Pharmacol Exp Ther. 2012 Dec;343(3):617-27.
• [10] Aurora A-Selective Inhibitor LY3295668 Leads to Dominant Mitotic Arrest, Apoptosis in Cancer Cells, and Shows Potent Preclinical Antitumor Efficacy. Mol Cancer Ther. 2019 Dec;18(12):2207-2219.
• [11] 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. (Target id: 1936).
• [12] Clinical pipeline report, company report or official report of Cyclacel.
• [13] Quercetin attenuates cell apoptosis of oxidant-stressed SK-N-MC cells while suppressing up-regulation of the defensive element, HIF-1alpha. Neuroscience. 2014 Sep 26;277:780-93.
• [14] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [15] Arsenic trioxide inhibits cell growth and induces apoptosis through inactivation of notch signaling pathway in breast cancer. Int J Mol Sci. 2012;13(8):9627-9641. doi: 10.3390/ijms13089627. Epub 2012 Aug 2.
• [16] Propranolol inhibits proliferation and invasion of hemangioma-derived endothelial cells by suppressing the DLL4/Notch1/Akt pathway. Chem Biol Interact. 2018 Oct 1;294:28-33. doi: 10.1016/j.cbi.2018.08.018. Epub 2018 Aug 18.
• [17] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [18] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [19] NOTCH signaling is activated in and contributes to resistance in enzalutamide-resistant prostate cancer cells. J Biol Chem. 2019 May 24;294(21):8543-8554. doi: 10.1074/jbc.RA118.006983. Epub 2019 Apr 2.
• [20] The autonomous notch signal pathway is activated by baicalin and baicalein but is suppressed by niclosamide in K562 cells. J Cell Biochem. 2009 Mar 1;106(4):682-92. doi: 10.1002/jcb.22065.
• [21] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [22] Mebendazole is a potent inhibitor to chemoresistant T cell acute lymphoblastic leukemia cells. Toxicol Appl Pharmacol. 2020 Jun 1;396:115001. doi: 10.1016/j.taap.2020.115001. Epub 2020 Apr 8.
• [23] Cannabidiol Activates Neuronal Precursor Genes in Human Gingival Mesenchymal Stromal Cells. J Cell Biochem. 2017 Jun;118(6):1531-1546. doi: 10.1002/jcb.25815. Epub 2016 Dec 29.
• [24] mTOR inhibition reverses acquired endocrine therapy resistance of breast cancer cells at the cell proliferation and gene-expression levels. Cancer Sci. 2008 Oct;99(10):1992-2003. doi: 10.1111/j.1349-7006.2008.00955.x.
• [25] Gene expression after treatment with hydrogen peroxide, menadione, or t-butyl hydroperoxide in breast cancer cells. Cancer Res. 2002 Nov 1;62(21):6246-54.
• [26] Synthesis and antitumor evaluation of nitrovinyl biphenyls: anticancer agents based on allocolchicines. ChemMedChem. 2011 May 2;6(5):859-68. doi: 10.1002/cmdc.201100019. Epub 2011 Apr 6.
• [27] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [28] Effect of retinoic acid on gene expression in human conjunctival epithelium: secretory phospholipase A2 mediates retinoic acid induction of MUC16. Invest Ophthalmol Vis Sci. 2005 Nov;46(11):4050-61.
• [29] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [30] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [31] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.